Masterpieces in Process Chemistry Group Meeting

11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Selected Syntheses Discussed: HO H NMe N Me Me Me CO2 O HO HO Me O N H H O O OH O NH2 Me Me Zomig F Me AstraZeneca OH O N Me Me Me OH Discodermolide O NH Novartis Me Me F N H O O CO2Et O CO2H HN Cl O Lipitor AcHN HN Ketorolac Pfizer N NH •H PO HN NH Syntex 2 3 4 Tamiflu O N H H CO H CN Hoffmann-LaRoche 2 F O S N H N N N O Biotin OAc H H Tanabe Seiyaku Co. OH CF3 EGFR Irreversible Inhibitor MeHN N O N Pfizer O Me O O OH O MIV-105 Me Me Chiron SB-273005 H CO2H HO S GlaxoSmithKline OH O O Me Cortisone Cl N Merck N ERa-SERM O Cl Merck N O O N O Ph S N OH OH MeHN N H O N N N N N H N N O O O Me Amerge H F O O tBuHN O Claritin GlaxoSmithKline Indinavir Linezolid Me Schering-Plough Clarinex H Merck Pharmacia NH Schering-Plough 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Selected Syntheses Not Discussed: Me Me HO H H H H H H O O O H OMe O H NH Cl CO Me H MeO 2 O O O HO Me OCF3 HO O O O O O H H H H H H H AcO H O O S H HO H O O O Me N N Me H H N Me Me O N N HO H O O H O CO2Me H Halichondrin O H OH H Indoxacarb Kishi Ecteinascidin 743 DuPont Corey Disclaimers: OH NH + H 3 1. This is by no means a comprehensive sampling of the many O NHMe Me masterpieces in process chemistry. H N F3C O 2. Process syntheses are very difficult to locate and decipher, since most of – CO2 the relevant literature is burried in patents and the words "process scale" do not appear in the titles. Thienamycin Prozac Merck Eli Lilly 3. Some of the syntheses not discussed above were not done so because See Jeremy Richter, Baran they were either not actual process routes (Ecteinascidin 743, Halichondrin) Group Meeting, January 2004 or I was unable to locate the relevant literature in time.

4. To give this topic the credit it deserves would require the publication of Classics in Process Chemistry. OH H S Me 5. Many of the syntheses presented here are wonderfull full papers that N MeN N delineate the entire conception process along with problems encountered HO along the way. I recommend these papers for more information. N N Partial List of Transforms: Zhao olefination, Parikh-Doering oxidation, Still-Genari olefination, Nozaki- O N Cl Hiyama coupling, Evans-Saksena reduction, Kagan oxidation, Ullmann Me NMe Zyprexa reaction, Strecker reaction, Moffit oxidation, Fukuyama coupling, Wohl- FTI Candidate Eli Lilly Zeigler bromination Pfizer 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

(–)-Discodermolide NH Me Me Me HO Me PMBO CCl3 Me LiBH4, THF Me H HO PMBO CO Me CO Me > 98% O O OH O NH2 2 PPTS, DCM 2 Me Me > 98% [LAH worked well OH O Me Me but filtration = 24 hrs] OH Bn Me O 1. Non-taxane microtubule stabilizing agent (most potent known). TEMPO, N 2. Small amounts available naturally and must be harvested by manned Me Bleach, Me O submersibles. Fermentation has not been successful so all material O must come from total synthesis. PMBO OH PMBO O DCM Bu2BOTf, 3. Currently in phase I clinical trials. 100% TEA, > 75% 4. Previous syntheses: [Swern not amenable [46-55% on a. Schreiber, JACS 1993, 115, 12621; ibid. 1996, 118, 11054 for large scale – stench] 20-25 kg scale] b. Smith, JACS 1995, 117, 12011; OL 1999, 1, 1823; ibid. 2000, 2, 1983; JACS 2000, 122, 8654 Me c. Myles, JOC 1997, 62, 6098 d. Marshall, JOC 1998, 63, 7885 NH e. Paterson, ACIEE 2000, 39, 377; TL 2000, 41, 6935; JACS 2001, 3 123, 9535; OL 2003, 5, 35. 5. Novartis Process Synthesis: Me Me Me Me a. Drew heavily upon the Smith and Paterson approaches i. LiOH, H2O2, MeOH b. OPRD 2004, 8, 92-130 PMBO Xc PMBO O ii. (R)-Phenylethylamine OH O OH O "One major problem associated with a synthesis of this length is the proper laboratory 84% examination of the later reactions in a sequence. Initially, there are no answers to [First purification: these supply problems; one just has to run the small-scale reaction and hope that on Cl crystallization] i. HCl i. LiOH ii. transfer to larger scale the reaction proceeds as expected. . . . On a positive note, this ii. iBuOCOCl project was a first for Novartis, and its progress was avidly followed by the entire H O N N 2 2 iii. MeNHOMe department who were all interested in the "disco". The success of this project and its MeO N OMe chemistry paves the way for other, perhaps even more complex, natural products to 75-80% be prepared for early-phase clinical evaluations and sends a positive message to both the isolation and synthetic academic community and possibly other pharmaceutical companies that: "your work need not just be of academic interest" and it may be Me Me Me Me OMe MeNHOMe Me worth taking a few risks. A total of 43 chemists participated in the concept of the PMBO O N PMBO N synthesis, experimental design, and execution. . . . The hybridized Novartis–Smith– OMe Paterson synthetic route that resulted in the preparation of 60 g of a structurally 85% complex molecule containing 13 stereogenic centers is a crowning achievement to all OH O N N OH O those who participated in this endeavor. The option of optimizing the present synthesis further or replacing with a better one is a topic of our ongoing studies, and OMe we are confident of climbing this mountain as the situation demands." 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Me Me TBSOTf, Me Me Me Me Me Me PMBO NMeOMe 2,6-Lut., PMBO NMeOMe PMBO NMeOMe DDQ, Tol., NMeOMe

OH O Tol., 0 ºC TBSO O OH O M.S., 0 ºC O O O 90% 61% [Chromatographic purification – 12 kg] [DIBAL-H reduction worked Red-Al, but –78 ºC was unacceptable] Tol., –20 ºC Bn OMe [Chromatography required] 68% i. TBSOTf, Me Me Me O 2,6-Lut, 100% N i. LAH, THF Name? ii. LiBH4, THF Me Me I Me Me –30 ºC to RT, O O OH O O ii. Bu2BOTf, TEA, PMBO NaHMDS, THF, PMBO 60% –78 ºC to –10 ºC, Me Bn I TBSO I TBSO O 85% Me O [Crystalline] N (15:1 cis:trans, 31%) Ph3P Me [Chromatography required] I OMe O O [No larger than 2.5 kg] Ph3P Me NaHMDS, I2

Me Me Me Me Me Me Me Me Me Me t PMBO NMeOMe i. H2, Pd/C, BuOH O NMeOMe OH I

TBSO O ii. TEMPO, PhI(OAc) TBSO O O O OTBS O O OTBS 2 Ph3P, I2, imid.,

i. MeMgBr Tol., RT, 90% Name? ii. SO , Py, [Chromatography 3 Required] DMSO OMe OMe

Me Me 24% overall Me NMeOMe

O TBSO O

66% overall [Chromatography Required] 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Me Me Me t i. BuLi, 9-MeOBBN, Me Me Me I THF, –78 ºC Me Me O ii. Cs2CO3, DMF, Me MeOMeN Me PMBO TBSO O O + Me I Pd(dppf)2Cl2, RT OTBS OCONH2 Me Me O TBSO O [Chromatography Me Me TBSO required] TBSO [problems with commercial (+)-DIP-Cl, TEA, 55% purity of (+)-DIP-Cl] OMe Me Me Me Me Me Me HO i. DIBAL–H, 92% PMBO Me Me Me ii. SO3, Pyr., Me MeOMeN OTBS OCONH2 DMSO, 93% OTBS O O Me Me Me Me O TBSO O TBSO 4:1 dr, recyclable TBSO [Chromatography required on reverse-phase silica]

Me Me Me Name? Me N+(OAc) BH, 73% i. CrCl , OMe 4 3 PMBO O 2 Me Name? Me Me Me Br OTBS OPMB HO Me Me TMS Me Me Me

TBSO ii. KOH MeOMeN OTBS OCONH2 Me Me [Chromatography O TBSO OH TBSO Me Me Me required] i. DDQ, H2O, 88% PMBO HCl, MeOH ii. PhI(OAc)2, TEMPO Me OTBS OPMB Me Me Me iii. KHMDS, 18-c-6, 76% Me Me 81% HO Name? O TBSO Me [Chromatography H F3CH2CO P CO2Me required] O O OH O NH2 F3CH2CO Me Me Me Me Me i. CCl CONCO; OH O 3 Me Me Na2CO3, MeOH, 100% discodermolide MeO2C Me OH [ > 60 g produced] OTBS OH ii. DIBAL–H, DCM, –78 ºC Me Me iii. PhI(OAc)2, TEMPO, 80% 39 steps, 17 chromatographic purifications, 20 months TBSO [Chromatography 7 problematic steps identified and being optimized required] 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

EGFR Irreversible Inhibitor F O F N OH HN Cl O HN Cl t O2N KO Bu, THF N HN 98% N [83% after recrystallization] O N O N Combined 3 operations N N O into one pot, 95% O

F 1. Treatment of solid tumors. Ra-Ni, THF 2. Inhibits Epidermal Growth Factor Tyrosine Kinase. 3. Process synthesis – Rober Hughes, Pfizer, Gordon Research H , 99% HN Cl Conference Presentation. 2 [Observed losses to dechlorination] H2N N Initial Route Problems Improved Route 1% Pt/C, THF, H2 O N i. 65% HNO / 80% from EtOH O 3 N NH H SO , 70 ºC, 81% < 0.2% deschloro CO H •AcOH 2 4 2 [Material still lost in cyrstalization] O H NH2 NH ii. HOAc, 57% F NH F N 2 CH3OCH2CH2OH [Yield loss] F 98% Used DMF instead of COCl HOAc for Recrystallization O 74% HN Cl TEA, EtOAc, HN 51% N F [2 recrystallizations] O O N i. SOCl2, 98% Last step was optimizable, but for O2N i HN Cl legal reasons they had to develop: NH ii. TEA, PrOH, N O2N F N i. Ac2O, 85% O F N 86% ii. 1.5% Pt/C, H2, THF, 99% H N Cl Final: [6.5:1 regioselectivity] 2 F N COCl Cl 8 steps (3 pots) Could not improve iii. TEA, THF, 0 ºC; NaOH, 80% 55% overall yield produced multikilo's iv. MeSO3H/AcOH/THF; NaOH, 90% 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Ketorolac 2nd Generation Route

O O O H Br2 H DMF, 80 ºC N H N N Br CO2H 0 ºC O O

Br O O 1. Non-steroidal antiinflammatory drug (NSAID). 2. Powerful antiinflammatory and analgesic activity. 3. 10 mg equiefficacious with morphine (10 mg) for post-operative pain. O 4. 10 mg equiefficacious with aspirin (650 mg) for postpartumpain. O 5. 10 mg equiefficacious with acetaminophen (1 g) or acetominophen O (600 mg)/codein (60 mg) combination. O 6. Syntex development: Muchowski, Adv. Med. Chem. 1992, 1, 109. O O i. MeOH, HCl st N N CO2Me 1 Generation Route Br ii. NaH, DMF, 75 ºC CO2Me H i. NCS, DMS H PhCONMe2 Br Br N DCM, –30 ºC N POCl3, DCE SMe ii. D, 60% D i. HO– Mechanism? ii. H2, Pd/C, Ketorolac, O O 47% from benzoyl pyrrole H NaH, DMF; O MgO racemic N O iii. HCl SMe 55 ºC, O O O O 3rd Generation Route O O N Begins from Pyrrole and proceeds in 45% overall yield: SMe See US Patent 6,197,976

MeO2C New Chemistry Discovered: CO2Me i. NaH, DMF, 85 ºC 1. Selective substitution of pyrrole at C–3 when protected as N–Silyl. i. mCPBA O ii. NaOH 2. Acid induced isomerization of C–2 substituted pyrroles to C–3. 3. New routes to pyrrole-2-carboxaldehydes. ii. MeOH, HCl N 4. New routes to acylpyrroles. SO2Me 5. Mild reduction of acylpyrroles to alkylpyrroles. Ketorolac, 6. Conversion of acylpyrroles to acylpyrrolidines. 21% from pyrrole 7. First reported intramolecular carbenoid addition to a pyrrole nucleus. racemic 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

ERa-SERM

BnO S BnO S HO S OBn PhPOCl2 OBn OH O MeCN, 90% O O OH N I I O

– 1. SERM = selective estrogen receptor modulator. D-DIPT O i BnO S+ 2. Potentially useful for the treatment of bone loss, cartilage degeneration, Ti(O Pr)4 BH3•THF endometriosis, uterine fibroid disease, hot flashes, increased levels of OBn low-density lipoprotein cholesterol, cardiovascular disease, obesity, Cumene O 10 ºC incontinence and cancer. 88%, 99% ee 3. Synthesis: Merck, PNAS, 2004, 101, 5776. hydroperoxide Name? I Mechanism? i. BnBr, NaI, O HO (H2N)2CS, S K2CO3, 84% O CuI, K2CO3, HCl, 92% O BnO S 2,2'-bipyridyl, 140 ºC O ii. NaOH OBn Mechanism? O MgBr N Me OMe I OH N BnO SH + O OH I BnO S BnO OBn TMSI O 81% N 92% O + – Br OBn PhMe3N Br3 OBn 88% HO S O DME, 100% O OH

I I O ERa-SERM 8 steps 80% N O 37% overall yield 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Biotin O O DCC, O DMF, 90 ºC; TFA, Pyr., O S NBn BnN NBn BnN NBn H HCl, 90 ºC 10–60 ºC HN NH H H H H NHBn 95% 93% CO2H H H SH S O CO2H H2NOC S H

1. Important in human nutrition and animal health. CO2Et 2. > 80 tons produced synthetically anually. I Name? 3. Synthesis: Tanabe Seiyaku Co., Chem. Eur. J. 2004, ASAP. Zn 4. For a comprehensive review of Biotin syntheses see: Ryan Shenvi, Baran Lab Group Meeting, July 2003. O CO2Et IZn BnN NBn i. PhOCOCl, NaOH, O Pd/C, THF, i. NaBH4, H2SO4, H H HS NH2•HCl H O, Tol., RT 2 THF, D Tol, DMF CO2Et H S NBn S CO2H ii. BnCl, NaOH, H ii. DCC, TFA, Pyr., 94% DMSO, H2O, RT CO2H DMSO, EtOAc, 83%, >99% ee 50 ºC O Name? i. H2 (0.9 MPa), Pd(OH)2/C, Name? HN NH MeOH, H2O; O O O H H i. NaHSO3, EtOAc CO2H ii. BnNH2, DCM; NaOH, 90% S S NBn S NHBn + S NHBn ii. MeSO3H, mesitylene, 74% H H NaCN, 8–20 ºC; H H biotin O NaHSO , NaCN NHBn NHBn 3 12 steps, 86%, >99% ee NC NC 100% 39% overall 11:1 syn/anti

O O O i. H2O2, K2CO3, DMSO/DCM S NBn + S NHBn DMF BnN NBn H H 120 ºC H H ii. H2O, filter NHBn NHBn iii. HCl S O H2NOC H2NOC 93% 7% 91% 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Cortisone Me Me OH OAc Me Me i. HBr, O CO2Me CHCl3 CO2Me Me Me Me O OH ii. H O, Me 2 O HO CHCl3

Me O Br Me O i. Br2, CHCl3 i. PhMgCl 1. Synthesis at the time was meant to provide large quantities to test. CO2Me 2. Starting material readily available from cow bile. Me 3. Work done in the early 1950's without modern spectroscopy. ii. Na2Cr2O7 ii. HOAc, D O 75.5% 4. Work done in less than 2 years. CrO3, acetone 61.6% from SM 5. Process synthesis: Merck, OPRD, 2004, 8, 708. Me Me Br Me Me Me Me OH OH O O Me Me Me i. HBr Me Ph Ph Ph Ph Me CO2H MeOH Me CO2Me O ii. Ac O 87% 2 H SO AcO 92.7% 2 4 94% HO HO Me Br Me Me i. Na Cr O , O i. Br2, MeOH/PhH O 2 2 7 Me NBS, PhH, H SO i. EtOCOCl, Pyr. ii. NaOAc, DMF Me 2 4 Ph Ph Me CO2Me hn; D ii. CrO iii. HO–; iv. H+ ii. Zn, HOAc 3 Name? 87.4% SeO2 worked in 1 step AcO 95.5% but needed in Korean Me EtO2CO War electronics O Me "As interesting as was the O DNBS, Ac O; Me Me 2 O OH kinetics of acetic acid formation Me Me Me during enol acetylation or MPPA; NaOH peracid uptake during the + Me CO2H i. MeOH, H Me CO2Me oxidation and despite the nice 92% data plots, they taught little AcO about minor byproducts or over- ii. H , Pt0 91% 2 reaction." [DNBS = dinitrobenzenesulfonic acid] HO HO [MPPA = monoperphthalic acid] 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Me AcO O O Linezolid Me Me O OH i. Br2, MeOH, PhH O OH Me ii. KOAc, HOAc, NaI Me O N iii. DDH, acetone O 94% HO iv. Zn, HOAc O 86% F N [DDH = dibromodimethylhydantoin] 52.6% from ether O O "With benzene, we actually considered it beneficent in that carbon tetrachloride was a Me H known liver toxin. Little did we know at the time that we were exchanging it for what NH would many years later be labeled a carcinogen!" AcO 1. Active against gram-positive and gram-negative bacteria with potency O in the 2-4 mg/mL. i. Br2, CHCl3, Me HOAc O OH H NCONHNH 2. Synthesis: Pharmacia/Pfizer, ACIEE, 2003, 42, 2010, 2 2 US Patent: 5837870. Me ii. NaBr, O acetone O 95% F i. NH CbzCl, [step 2 used to convert O N all side products to the Br desire product] F NO2 ii. Pd/C, K2CO3 "A great deal of development was still required as the demonstration with an H2 F NH2 incompletely developed process was initiated in the new plant. Some improvements were made on an ad-hoc basis, at times prematurely, with production at sub-optimal performance better than no production at all. For better and for worse, such a modus O HO H O operandi is no longer practiced, courtesy of FDA and cGMP regulations." N i. Cl OH N AcO AcO O O O t Me Me F NHCbz ii. KO Bu F N O OH O OH iii. LDA O Me HCl Me 90% Overall H OH CHCl3 O H2NOCHNN O 92% N 87.4% from triketone O i. NH OH, 28.3% overall 4 TEA, MeOH, 45 ºC linezolid F N "Product elegance has long been an ethereal objective of ethical pharmaceutical O 9 steps companies; it is sometimes an expensive one. Planning for the last step has to include NsCl ii. Ac2O, 85% 65% overall yield concerns of color and appearance as well as chemical purity. It is annoying to some H synthetic chemists to see a difficultly won, elegant, white crystalline material subjected 85% Overall ONs by pharmacists to granulation, sometimes coloration, and compression to an unnatural form." 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

t Indinavir i. BuOAc, i. pyroglutamic acid resolution N HN Ph H2SO4, 90% with recycle, 47% N OH OH N NH H N N ii. H2, Pd(OH)2, ii. Boc2O, KOH, 80% N CN CONHtBu 95% O tBuHN O Me Me Ph 1. HIV Protease Inhibitor. O i. MeOH, D BocN O 2. Synthesis: Merck, Chimia, 1997, 51, 306. N ii. HCl(g) N Narendra Ambhaikar, Baran Group Meeting, July 2004. O O tBuHN O (S,S)-MnII(salen)Cl NaOCl, P3NO Mechanism? Ph 87% ee N OH OH Oleum, H N N MeCN, OH O enzyme H2O tBuHN O OH 94%

COCl 99% ee Cl i PrOAc, NH2 NH2 N NaOH, 70 ºC; Tartaric acid, OH OH H2SO4 MsOH, 35 ºC, base OAc 99% ee >50% yield Ph Me N OH OH H N N Me Me Me Me N Ph Ph O O O i. NIS, H O, tBuHN O N N 2 Br NaHCO3, 91% O O indinavir LHMDS, ii. NaOMe, 100% 75% over 3 steps –15 ºC >32% overall 88% 94% 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Lipitor OH HO OH HBr, HO O H2O2, HOAc, CO2 O HO CO2K HO HO CaCO3, MeOH OH OH K2CO3

F Me N OH OH i. TBSCl, imid., Me H2, 4-DMAP Br CO2Me Br CO2Me NH Pd/C ii. NaCN, DMSO Br O

i. NaOH 1. Hypolipidemic. OTBS ii. CDI, OH O t 2. Number one selling drug of all time (Natural product inspired). NC CO2Me NC CO2 Bu 3. Synthesis: Bruce Roth, Pfizer, Prog. Med. Chem. 2002, 40, 1. Mg(O CCH CO tBu) 4. Largest competitors: 2 2 2 2 iii. TBAF, HOAc, THF HO O or: 3 equiv. LiCH CO tBu O 2 2 O i. NaBH , Et BOMe, Me Me 4 2 H2, Ra-Ni, Me O MeOH, –90 ºC O O H Me Me t MeOH, 95% NC CO2 Bu ii. Me2C(OMe)2, MeSO3H, 65% Me Me Me

Mevacor CO2Na O O t HO O HO CO2 Bu Mechanism? H2N O HO O O Bn Me N+ Cl– CONHPh Me O Me O F H H Me S O Me Me Me Me Me HO Me Me F TEA Me HO O O O Me Zocor Pravacol CONHPh 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Zomig Me Me F O + O O H NMe N Me t CO2 Bu O H2N O Me O N CONHPh H pivalic acid 1. Used to treat migraine headaches. 1:4:1 Tol.:heptane:THF 2. Synthesis: AstraZeneca, US Patent 6084103, 6160123, D, 75% Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.

Me O CO tBu Me 2 i. Na2CO3, H2O, EtOAc; ClCO2Bu ClH•H2N O ii. H2, 5% Pd/C, EtOAc, BuOH, 30–50 ºC MeO2C NO 2 iii. NaBH4, BuOH, 35 ºC F Me iv. NaOMe, MeOH, BuOH, 85 ºC N Me

NH i. NaNO2, HCl, 0 ºC H O ii. Na2SO3, H2O, 0–60 ºC N O O iii. reflux, 3 hr NH OEt 2 EtO NMe2 precipitated upon cooling HO iv. 10% EtOH/EtOAc CO2 HO

H NMe N 2 F Me O N O N Me H NH No yields given One-pot procedure O

"...produced stereochemically pure atorvastatin calcium in a convergent, commercially viable manner which accomplished the original vision for the synthesis developed in discovery chemistry, but was reduced to practice in chemical development." 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Tamiflu MIV-105 CN F O Me Me O CO Et N N N 2 H H OH AcHN Me NH2•H3PO4 O 1. Non-nucleoside reverse transcriptase inhibitor. 1. Potent inhibitor of influenza neuraminidase at nanomolar concentrations. 2. Synthesis: Chiron, OPRD, 2004, 8, 353. i. HNO , D, 92% 2. Synthesis: Hoffmann-LaRoche, Chimia, 2004, 58, 621. 3 i. SOCl2, DEA, ii. IPA, BnHN Ph 3 steps 0 ºC, 86% HO CO2H Me NEt2 70–80% CO2H I iii. HCl, 78% ii. BuMgNiPr , THF, D; HO Me 2 O iv. TsOH, EtOH, O CO Et i. Et SiH, TiCl I2, THF, 5 ºC, 56% OH 2 3 4 D, 93% ii. NaHCO3 F OH O F i. EtCOCl, Pyr., 100% HO CO2H 80% Me ii. AlCl , 88% Mechanism? 5 steps OMs 3 I CO2Et HO OMe 40–45% iii. MeI, K2CO3, 97% O OH OH Me iv. (CH2OH)2, pTSA, Me Me PhH, 86% O Me Me F i. BuLi, THF, –78 ºC i. NaN3, NH4Cl, i. NaN , NH Cl, ii. ZnBr , –65 ºC 3 4 i. HCl, dioxane, H O 2 DMF, 85 ºC O CO2Et EtOH, 65 ºC O CO2Et 2 ii. LiOH, MeOH, H O CO2Et 2 iii. Pd(OAc) , (ArO) P, iii. HCl 2 3 ii. Ac2O, Pyr. ii. PMe3, OMe –65 ºC, 85% 35% HN MeCN, RT O O Me Name? O CN Me Me Me Me F F O O CO Et O CO Et 2 i. Lindlar, H2 2 i. TEA, EtOCOCl CO2H N N N ii. NaN3; D H H AcHN ii. H3PO4, 80% AcHN OMe OMe CN N NH •H PO Me iii. Me BCl3, DCM, 52% 3 2 3 4 O O [A series of studies was undertaken to improve the H2N N efficiency and safety of this route, through the Tamiflu 35% from Shikimic acid MIV-105 replacement of the azide chemistry, as well as 27% overall yield beginning with more cost effective starting materials.] 20% from Quinic acid 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

Amerge Claritin and Clarinex Me N Cl Cl O O S N N MeHN

N H N N H 1. Used to treat migraine headaches. O O Me 2. Synthesis: GlaxoSmithKline, J. Med. Chem. 1995, 38, 3566, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004. 1. Antihistamines. 2. Synthesis: Schering-Plough, J. Org Chem. 1989, 54, 2242, Me O O Li, J.J. Contemporary Drug Synthesis, Wiley, 2004. NMe N S i. MeHN Br i. tBuOH, H SO i. POCl , 89% O Pd(OAc)2, (o-tolyl)3P, 2 4 3 Me 75 ºC, 97% Cl ii. BrMg NMe N KOH, IMS, Br TEA, DMF, 85 ºC H n O THF, 50 ºC; D, 94% ii. HCl, 89% N CN ii. BuLi, THF, N N HCl, RT, 89% H –40 ºC, NaBr NHtBu Cl Me Me Cl N N

O O H2, Pd/C, O O Cl S S Cl MeHN DMF, H O, MeHN O i. HF, BF3, 92% 2 N ii. TEA, Tol., MeOH, 90% N N N H H 80 ºC, 73% Amerge Me O 75% overall yield N COCl N Me O O Me Cl claritin N 52% overall yield KOH, H2O clarinex 47% overall yield EtOH, D, 91% N H 11/3/04 Richter Masterpieces in Process Chemistry Group Meeting

SB-273005

CF3 MeHN N O N O

H CO2H 1. Vitronectin receptor antagonist. 2. Synthesis: GlaxoSmithKline, OPRD. 2004, 8, 738.

i. Br , DCM, 65% HO 2 HO O ii. itaconic acid, TEA, O

Pd(OAc)2, (o-tolyl)3P, Bu NBr, MeCN, 80% 4 HO2C CO2H OMe HO DCA, [RuCl2(R-BINAP)]2, OMe H2SO4,

TEA, H2, 60 ºC, MeOH, D, MeOH, H2O, 84% 86% HO2C CO2H H

HO i. ZnCl , MeCN, D, CF3 O 2 HO N ClH•H N CF 2 3 O

MeO C ii. NaBH(OAc)3, DMA 2 CO2Me CO2Me iii. TFA, Tol., D, 72% H H

MeHN N OH CF3 MeHN N O N O i. PPh3, DIAD, TBME CO H SB-273005 H 2 ii. LiOH, H2O, THF, 18% overall yield 50 ºC, 66% Last Reaction = 50 kg