Masterpieces in Process Chemistry · masterpieces in process chemistry. 2. Process syntheses are...
Transcript of Masterpieces in Process Chemistry · masterpieces in process chemistry. 2. Process syntheses are...
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Selected Syntheses Discussed:
OO
MeOH
Me
HO
MeOH
Me
Me
Me
OH
Me
O
Me
H
O
NH2
DiscodermolideNovartis
EGFR Irreversible InhibitorPfizer
N
N
HNHN
O
O
NO
F
Cl
NCO2H
O
H
KetorolacSyntex
O
S
ON
HOOH
ERa-SERMMerck
S
NHHN
O
CO2HH H
HBiotin
Tanabe Seiyaku Co.
O
OMe
MeOHO
OAc
CortisoneMerck
N
N O
NH
OMeH
F
O
O
LinezolidPharmacia
N
NN
OtBuHN
HN
O
OHPh
OH
IndinavirMerck
N
NHO
Me
MeF
CO2HO
HO
LipitorPfizer
NH
NMeHN
OO
ZomigAstraZeneca
CO2EtOMeMe
AcHNNH2•H3PO4
TamifluHoffmann-LaRocheF
MeO
OH
NH
NH
O
N
CN
MIV-105Chiron
NH
SMeHN
OO
MeN
AmergeGlaxoSmithKline
N
Cl
N
OO Me
N
Cl
NH
ClaritinSchering-Plough Clarinex
Schering-Plough
N OMeHN NCF3
O
CO2HHSB-273005GlaxoSmithKline
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Selected Syntheses Not Discussed:
Ecteinascidin 743Corey
N MeN
NH
SO
H
HH
OHH
HO
MeOO
AcOMe
OO
HOOMe
Me
N N
O
ON
CO2Me
CO2MeClOCF3
IndoxacarbDuPont
N
OH
Me
O
H
CO2–
NH3+
H
ThienamycinMerck
See Jeremy Richter, Baran Group Meeting, January 2004
NMe
O Cl
OH
HONMeN
FTI CandidatePfizer
F3C
O NHMe
ProzacEli Lilly
N
HN
S
N
NMe
Me
ZyprexaEli Lilly
OO
O
O
O
O
O
O
O OO
O
O
OO
O
H
Me
MeHH
H H
Me
Me
HO
HO
HOH
H
H
H
H
H
H
H
H
HH
H
H H H
H
H
HalichondrinKishi
Disclaimers:
1. This is by no means a comprehensive sampling of the many masterpieces in process chemistry.
2. 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 titles.
3. 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 time.
4. To give this topic the credit it deserves would require the publication of Classics in Process Chemistry.
5. 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 information.
Partial 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 bromination
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
OO
MeOH
Me
HO
MeOH
Me
Me
Me
OH
Me
O
Me
H
O
NH2
(–)-Discodermolide
1. 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 synthesis.3. Currently in phase I clinical trials.4. 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, 35.5. Novartis Process Synthesis: a. Drew heavily upon the Smith and Paterson approaches b. OPRD 2004, 8, 92-130
HOCO2Me
Me PMBO CCl3
NH
PPTS, DCM> 98%
PMBOCO2Me
Me
PMBOMe
LiBH4, THF
> 98%
OH
[LAH worked wellbut filtration = 24 hrs]
TEMPO, Bleach,
DCM100%
[Swern not amenablefor large scale – stench]
Bu2BOTf,TEA, > 75%
PMBOMe
O
N OMe
O O
Bn
[46-55% on20-25 kg scale]
PMBOMe
OH
Me
O
Xc
[First purification:crystallization]
i. LiOH, H2O2, MeOH
ii. (R)-PhenylethylaminePMBO
Me
OH
Me
O
O
NH3
Me
84%
i. HClii. iBuOCOCliii. MeNHOMe 75-80%
PMBOMe
OH
Me
O
MeN
N
N
N
Cl
OMeMeO
i. LiOH H2O2
ii.
PMBOMe
OH
Me
O
O
N N
NOMe
OMe
MeNHOMe
85% OMe
"One major problem associated with a synthesis of this length is the proper laboratoryexamination of the later reactions in a sequence. Initially, there are no answers tothese supply problems; one just has to run the small-scale reaction and hope that ontransfer to larger scale the reaction proceeds as expected. . . . On a positive note, thisproject was a first for Novartis, and its progress was avidly followed by the entiredepartment who were all interested in the "disco". The success of this project and itschemistry paves the way for other, perhaps even more complex, natural products tobe prepared for early-phase clinical evaluations and sends a positive message to both the isolation and synthetic academic community and possibly other pharmaceuticalcompanies that: "your work need not just be of academic interest" and it may beworth taking a few risks. A total of 43 chemists participated in the concept of thesynthesis, experimental design, and execution. . . . The hybridized Novartis–Smith–Paterson synthetic route that resulted in the preparation of 60 g of a structurallycomplex molecule containing 13 stereogenic centers is a crowning achievement to allthose who participated in this endeavor. The option of optimizing the presentsynthesis further or replacing with a better one is a topic of our ongoing studies, andwe are confident of climbing this mountain as the situation demands."
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
PMBOMe
OH
Me
O
NMeOMeTBSOTf, 2,6-Lut.,
Tol., 0 ºC90%
PMBOMe
TBSO
Me
O
NMeOMe
Red-Al,Tol., –20 ºC68%
[Chromatographicpurification – 12 kg]
[DIBAL-H reduction workedbut –78 ºC was unacceptable]
[Chromatography required]
PMBOMe
TBSO
Me
O
NaHMDS, THF,
Ph3P Me
I
NaHMDS, I2Ph3P Me
I
I
PMBOMe
TBSO
Me
Me
I
(15:1 cis:trans, 31%)[Chromatography required]
[No larger than 2.5 kg]
Name?
PMBOMe
TBSO
Me
O
NMeOMe i. H2, Pd/C, tBuOH
ii. TEMPO, PhI(OAc)2
OMe
TBSO
Me
O
NMeOMe
i. MeMgBrii. SO3, Py, DMSO
Me
TBSO
Me
O
NMeOMeMe
O
[Chromatography Required]
66% overall
PMBOMe
OH
Me
O
NMeOMe DDQ, Tol.,
M.S., 0 ºC61%
Me
O
Me
O
NMeOMe
O
OMeMe
O
Me
OHO
OMe
i. LAH, THFii. Bu2BOTf, TEA, –78 ºC to –10 ºC,
Me
O
N O
O
Bn
N
O
MeO
O
Bn85%
[Crystalline]
i. TBSOTf, 2,6-Lut, 100%ii. LiBH4, THF –30 ºC to RT, 60%
Me
O
Me
OTBSO
OMe
MeOH
[Chromatography Required]
Ph3P, I2, imid.,
Tol., RT, 90%
Me
O
Me
OTBSO
OMe
MeI
24% overall
Name?
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Me
O
Me
TBSO O
OMe
MeI
MeTBSO
Me
Me
I
i. tBuLi, 9-MeOBBN, THF, –78 ºCii. Cs2CO3, DMF, Pd(dppf)2Cl2, RT
Me
O
Me
OTBS O
OMe
Me
MeTBSO
Me
Me
i. DIBAL–H, 92%ii. SO3, Pyr., DMSO, 93%
Me
OPMB
Me
OTBS
Me
MeTBSO
Me
Me
O i. CrCl2,
ii. KOH
Br
TMS
Me
OPMB
Me
OTBS
Me
MeTBSO
Me
Me
PMBO
PMBO
PMBO
PMBO
81%[Chromatography
required]
Name?
i. DDQ, H2O, 88%ii. PhI(OAc)2, TEMPO
iii. KHMDS, 18-c-6, 76%
PO
CO2MeF3CH2CO
F3CH2CO
Me
OH
Me
OTBS
Me
MeTBSO
Me
Me
MeO2C
Name?
i. CCl3CONCO; Na2CO3, MeOH, 100%
ii. DIBAL–H, DCM, –78 ºCiii. PhI(OAc)2, TEMPO, 80%[Chromatography
required]
Me
OCONH2
Me
OTBS
Me
MeTBSO
Me
Me [Chromatographyrequired]
OMe
TBSO
Me
O
MeOMeN Me
O+
(+)-DIP-Cl, TEA, 55%
Me
OCONH2
Me
OTBS
Me
MeTBSO
Me
Me
HOMe
TBSO
Me
O
MeOMeN
O 4:1 dr, recyclable[Chromatography required
on reverse-phase silica]
Me4N+(OAc)3BH, 73%
[problems with commercialpurity of (+)-DIP-Cl]
Name?
Me
OCONH2
Me
OTBS
Me
MeTBSO
Me
Me
HOMe
TBSO
Me
O
MeOMeN
OH
HCl, MeOH
[Chromatographyrequired]
OO
MeOH
Me
HO
MeOH
Me
Me
Me
OH
Me
O
Me
H
O
NH2
discodermolide[ > 60 g produced]
39 steps, 17 chromatographic purifications, 20 months7 problematic steps identified and being optimized
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
EGFR Irreversible Inhibitor
1. Treatment of solid tumors.2. Inhibits Epidermal Growth Factor Tyrosine Kinase.3. Process synthesis – Rober Hughes, Pfizer, Gordon Research Conference Presentation.
Initial Route Problems Improved Route
N
N
HNHN
O
O
NO
F
Cl
CO2H
NH2F
•AcOH
CH3OCH2CH2OH
H NH2
NH
NF
NH
O i. 65% HNO3/ H2SO4, 70 ºC, 81%
ii. HOAc, 57%
98%
NF
NH
OO2N
i. SOCl2, 98%ii. TEA, iPrOH,
H2N
F
Cl NF
N
HNO2N
F
Cl
86%
ON OH
KOtBu, THF98%
[83% after recrystallization] N
N
HNO2N
O
NO
F
Cl
Ra-Ni, THF
H2, 99%
N
N
HNH2N
O
NO
F
Cl
[Observed losses to dechlorination]
TEA, EtOAc,51%
[2 recrystallizations]
COCl
[Yield loss]
N
N
HNHN
O
O
NO
F
ClUsed DMF instead of
HOAc for Recrystallization74%
[6.5:1 regioselectivity]
Could not improve
Combined 3 operations
into one pot, 95%
1% Pt/C, THF, H2
80% from EtOH< 0.2% deschloro
[Material still lost in cyrstalization]
Last step was optimizable, but forlegal reasons they had to develop:i. Ac2O, 85%ii. 1.5% Pt/C, H2, THF, 99%
iii. TEA, THF, 0 ºC; NaOH, 80%iv. MeSO3H/AcOH/THF; NaOH, 90%
Cl COCl Final:8 steps (3 pots)55% overall yieldproduced multikilo's
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Ketorolac
1. Non-steroidal antiinflammatory drug (NSAID).2. Powerful antiinflammatory and analgesic activity.3. 10 mg equiefficacious with morphine (10 mg) for post-operative pain.4. 10 mg equiefficacious with aspirin (650 mg) for postpartumpain.5. 10 mg equiefficacious with acetaminophen (1 g) or acetominophen (600 mg)/codein (60 mg) combination.6. Syntex development: Muchowski, Adv. Med. Chem. 1992, 1, 109.
NCO2H
O
H
HN
1st Generation Route
i. NCS, DMS DCM, –30 ºC
ii. D, 60%
HN
SMe
PhCONMe2POCl3, DCE
D
HN
O
SMe
NaH, DMF;
55 ºC,
O OO O
N
O
SMe
OO
OO
i. mCPBA
ii. MeOH, HCl N
O
SO2Me
CO2MeMeO2C
i. NaH, DMF, 85 ºCii. NaOH
Ketorolac,21% from pyrrole
racemic
2nd Generation Route
3rd Generation Route Begins from Pyrrole and proceeds in 45% overall yield: See US Patent 6,197,976
HN
OBr2
0 ºC
HN
O
Br
Br
DMF, 80 ºC
O OO O
N
O
Br
OO
OO
Br
i. MeOH, HCl
ii. NaH, DMF, 75 ºCN
CO2Me
O
CO2Me
Br
i. HO–
ii. H2, Pd/C,
MgOiii. HCl
Ketorolac,47% from benzoyl pyrrole
racemic
New Chemistry Discovered:1. Selective substitution of pyrrole at C–3 when protected as N–Silyl.2. Acid induced isomerization of C–2 substituted pyrroles to C–3.3. New routes to pyrrole-2-carboxaldehydes.4. New routes to acylpyrroles.5. Mild reduction of acylpyrroles to alkylpyrroles.6. Conversion of acylpyrroles to acylpyrrolidines.7. First reported intramolecular carbenoid addition to a pyrrole nucleus.
Mechanism?
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
ERa-SERM
1. SERM = selective estrogen receptor modulator.2. 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 cancer.3. Synthesis: Merck, PNAS, 2004, 101, 5776.
O
S
ON
HOOH
O
O
(H2N)2CS,
HCl, 92%
HO
O
SO
i. BnBr, NaI, K2CO3, 84%
ii. NaOH
BnO SH
OHO
NMe OMe
I BnO
MgBr
O
I
OBn PhMe3N+Br3–
DME, 100%
80%
O
I
OBn
O
I
OBnS
OH
BnO
88%
PhPOCl2
MeCN, 90% O
S
I
BnOOBn
D-DIPTTi(OiPr)4
Cumenehydroperoxide
O
S+
I
BnOOBn
O–
Name?
BH3•THF
10 ºC88%, 99% ee
O
S
I
BnOOBn
CuI, K2CO3,2,2'-bipyridyl, 140 ºC
NOH
O
S
ON
BnOOBn
O
S
ON
HOOH
TMSI
81%92%
ERa-SERM8 steps
37% overall yield
+
Mechanism?
Mechanism?
Br
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Biotin
1. Important in human nutrition and animal health.2. > 80 tons produced synthetically anually.3. Synthesis: Tanabe Seiyaku Co., Chem. Eur. J. 2004, ASAP.4. For a comprehensive review of Biotin syntheses see: Ryan Shenvi, Baran Lab Group Meeting, July 2003.
S
NHHN
O
CO2HH H
H
NH2•HClHS
CO2HH
i. PhOCOCl, NaOH, H2O, Tol., RT
ii. BnCl, NaOH, DMSO, H2O, RT
NBnS
CO2HH
O i. NaBH4, H2SO4, THF, D
ii. DCC, TFA, Pyr., DMSO, EtOAc, 50 ºC83%, >99% ee
NBnSH
O
O86%, >99% ee
i. NaHSO3, EtOAcii. BnNH2, DCM;
NaCN, 8–20 ºC; NaHSO3, NaCN
NBnSH
O
NHBnH2NOC
100%11:1 syn/anti
NHBnSH
O
NHBnH2NOC
+i. H2O2, K2CO3, DMSO/DCM
ii. H2O, filteriii. HCl
NHBnSH
O
NHBnNC
NHBnSH
O
NHBnNC
+
DMF
120 ºCS
NBnBnN
O
H H
O
NBnSH
O
NHBnH2NOC
DMF, 90 ºC;
HCl, 90 ºC95%
91%93% 7%
SHCO2H
NBnBnN
O
H H
DCC, TFA, Pyr.,
10–60 ºC 93%
S
NBnBnN
O
H H
O
ICO2Et
Zn
IZnCO2Et
Pd/C, THF,
Tol, DMFS
NBnBnN
O
H HCO2Et
94%
i. H2 (0.9 MPa), Pd(OH)2/C, MeOH, H2O;
NaOH, 90% ii. MeSO3H, mesitylene, 74% S
NHHN
O
CO2HH H
H
biotin12 steps,
39% overall
Name?Name?
Name?
O
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Cortisone
1. Synthesis at the time was meant to provide large quantities to test.2. Starting material readily available from cow bile.3. Work done in the early 1950's without modern spectroscopy.4. Work done in less than 2 years.5. Process synthesis: Merck, OPRD, 2004, 8, 708.
O
OMe
MeOHO
OAc
HO
Me
MeMe
OH
CO2H MeOH
H2SO4HO
Me
MeMe
OH
CO2Me
i. EtOCOCl, Pyr.
ii. CrO3
EtO2CO
Me
MeMe
O
CO2Me
i. Br2, MeOH/PhHii. NaOAc, DMF
iii. HO–; iv. H+
HO
Me
MeMe
O
CO2H i. MeOH, H+
ii. H2, Pt0HO
Me
MeMe
OH
CO2Me
SeO2 worked in 1 stepbut needed in Korean
War electronics
HO
Me
MeMe
OH
CO2Mei. HBr, CHCl3
ii. H2O, CHCl3
Me
MeMe
CO2Me
i. Br2, CHCl3
ii. Na2Cr2O7 CrO3, acetone O
Me
MeMe
CO2Me
BrO
94%
95.5%
91%
75.5%61.6% from SM
i. PhMgCl
ii. HOAc, D
O
Me
MeMe
O
PhPh i. HBr
ii. Ac2O
Me
MeMe
O
PhPh
Br
AcO
NBS, PhH,
hn; DMe
MeMe
O
PhPh
Br
AcO
i. Na2Cr2O7, H2SO4
ii. Zn, HOAc
Me
MeMe
OO
AcO
DNBS, Ac2O;
MPPA; NaOH
[DNBS = dinitrobenzenesulfonic acid][MPPA = monoperphthalic acid]
"As interesting as was thekinetics of acetic acid formationduring enol acetylation orperacid uptake during theoxidation and despite the nicedata plots, they taught littleabout minor byproducts or over-reaction."
Name?
87% 92.7%
87.4%
92%
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Linezolid
1. Active against gram-positive and gram-negative bacteria with potency in the 2-4 mg/mL.2. Synthesis: Pharmacia/Pfizer, ACIEE, 2003, 42, 2010, US Patent: 5837870.
N
N O
NH
OMeH
F
O
O
F
F NO2
i.
ii. Pd/C, H2
ONH
N
NH2F
O CbzCl,
K2CO3
N
NHCbzF
O
90% Overall
i.
ii. KOtBuiii. LDA
Cl OHHHO
N
N O
H
F
O
O
OH
TEA,
NsCl
N
N O
H
F
O
O
ONs85% Overall
i. NH4OH, MeOH, 45 ºC
ii. Ac2O, 85%
linezolid9 steps
65% overall yield
Me
MeMe
OO
HO
OH i. Br2, MeOH, PhHii. KOAc, HOAc, NaI
iii. DDH, acetoneiv. Zn, HOAc
[DDH = dibromodimethylhydantoin]
Me
MeO
O
O
OH
"With benzene, we actually considered it beneficent in that carbon tetrachloride was a known liver toxin. Little did we know at the time that we were exchanging it for whatwould many years later be labeled a carcinogen!"
94%86%
52.6% from ether
i. Br2, CHCl3, HOAc
ii. NaBr, acetone
Me
MeO
O
O
OH
Br[step 2 used to convertall side products to the
desire product]
H2NCONHNH2
Me
MeO
O
H2NOCHNN
OH
HCl
CHCl3O
OMe
MeOHOAcO
AcO
AcO
AcO
"A great deal of development was still required as the demonstration with anincompletely developed process was initiated in the new plant. Some improvementswere made on an ad-hoc basis, at times prematurely, with production at sub-optimalperformance better than no production at all. For better and for worse, such a modus operandi is no longer practiced, courtesy of FDA and cGMP regulations."
"Product elegance has long been an ethereal objective of ethical pharmaceuticalcompanies; it is sometimes an expensive one. Planning for the last step has to include concerns of color and appearance as well as chemical purity. It is annoying to somesynthetic chemists to see a difficultly won, elegant, white crystalline material subjectedby pharmacists to granulation, sometimes coloration, and compression to an unnaturalform."
95%
92%87.4% from triketone
28.3% overall
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Indinavir
1. HIV Protease Inhibitor.2. Synthesis: Merck, Chimia, 1997, 51, 306. Narendra Ambhaikar, Baran Group Meeting, July 2004.
N
NN
OtBuHN
HN
O
OHPh
OH
(S,S)-MnII(salen)ClNaOCl, P3NO
enzymeOH
OH
O
Oleum,
MeCN, H2O
NH2
OH
87% ee
99% ee
99% ee>50% yield
Tartaric acid,
base
NH2
OH
iPrOAc, NaOH, 70 ºC;
MsOH, 35 ºC,
COCl
Me
OAc
N
O
OPh
88%
NN
CN
MeMe
LHMDS,–15 ºC94%
BrN
O
OPh
MeMe
i. NIS, H2O, NaHCO3, 91%
ii. NaOMe, 100%
i. tBuOAc, H2SO4, 90%
ii. H2, Pd(OH)2, 95%
HNNH
CONHtBu
i. pyroglutamic acid resolution with recycle, 47%
ii. Boc2O, KOH, 80%
BocNN
OtBuHN
N
O
OPh
MeMei. MeOH, Dii. HCl(g)
NN
OtBuHN
HN
O
OHPh
OH
94%
N
Cl
H2SO4
N
NN
OtBuHN
HN
O
OHPh
OH
indinavir75% over 3 steps
>32% overall
Mechanism?
O
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Lipitor
1. Hypolipidemic.2. Number one selling drug of all time (Natural product inspired).3. Synthesis: Bruce Roth, Pfizer, Prog. Med. Chem. 2002, 40, 1.4. Largest competitors:
N
NHO
Me
MeF
CO2HO
HO
O
HO
MeH
O
Me
O
MeMe
O
Mevacor
O
HO
MeH
O
Me
O
MeMe
O
Me
Zocor
MeH
O
HO
O
MeMe
CO2Na
HO
HO
Pravacol
FO
CONHPh
OMe
Me
O
OHHO
HOOH
OH2O2,
CaCO3, K2CO3
CO2KHOOH
OH
HBr, HOAc,
MeOH
CO2MeBrOH
Br
H2,
Pd/CCO2MeBr
OH i. TBSCl, imid., 4-DMAP
ii. NaCN, DMSO
CO2MeNCOTBS
i. NaOHii. CDI,
Mg(O2CCH2CO2tBu)2
iii. TBAF, HOAc, THF
NCOH O
CO2tBu
i. NaBH4, Et2BOMe, MeOH, –90 ºC
ii. Me2C(OMe)2, MeSO3H, 65%
NCO O
CO2tBu
H2, Ra-Ni,
MeOH, 95%
MeMe
O OCO2
tBu
MeMe
or:3 equiv. LiCH2CO2
tBu
TEA
S
N+
HO
MeBn
F
OCONHPh
Me
MeO
Cl–
Mechanism? H2N
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Zomig
1. Used to treat migraine headaches.2. Synthesis: AstraZeneca, US Patent 6084103, 6160123, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
NH
NMeHN
OO
ClH•H2N
MeO2CNO2
i. Na2CO3, H2O, EtOAc; ClCO2Buii. H2, 5% Pd/C, EtOAc, BuOH, 30–50 ºC
iii. NaBH4, BuOH, 35 ºCiv. NaOMe, MeOH, BuOH, 85 ºC
NH2
HN
OO
i. NaNO2, HCl, 0 ºCii. Na2SO3, H2O, 0–60 ºC
iii. reflux, 3 hr
iv. 10% EtOH/EtOAcEtO
OEtNMe2
NH
NMe2HN
OO
No yields givenOne-pot procedure
precipitated upon cooling
O OCO2
tBu
MeMeF
OCONHPh
Me
MeO
N
NHO
Me
MeF
CO2tBu
O
O
+
pivalic acid1:4:1 Tol.:heptane:THF
D, 75%
N
NHO
Me
MeF
CO2HO
HO
Me
Me
"...produced stereochemically pure atorvastatin calcium in a convergent, commercially viable manner which accomplished the original vision for the synthesis developed indiscovery chemistry, but was reduced to practice in chemical development."
H2N
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
Tamiflu
1. Potent inhibitor of influenza neuraminidase at nanomolar concentrations.2. Synthesis: Hoffmann-LaRoche, Chimia, 2004, 58, 621.
CO2EtOMeMe
AcHNNH2•H3PO4
HO
HO
CO2H
OH
HO
HO
CO2H
OH
OH
O
O
CO2Et
OMs
Me
Me
i. Et3SiH, TiCl4ii. NaHCO3
80%
CO2EtOMe
Me
3 steps
70–80%
5 steps
40–45%
O
i. NaN3, NH4Cl, EtOH, 65 ºC
ii. PMe3, MeCN, RT
CO2EtOMe
Me
HN
i. NaN3, NH4Cl, DMF, 85 ºC
ii. Ac2O, Pyr. 35%
CO2EtOMe
AcHNN3
i. Lindlar, H2
ii. H3PO4, 80%
CO2EtOMeMe
AcHNNH2•H3PO4
Me
Tamiflu35% from Shikimic acid20% from Quinic acid
[A series of studies was undertaken to improve theefficiency and safety of this route, through thereplacement of the azide chemistry, as well asbeginning with more cost effective starting materials.]
MIV-105
1. Non-nucleoside reverse transcriptase inhibitor.2. Synthesis: Chiron, OPRD, 2004, 8, 353.
F
MeO
OH
NH
NH
O
N
CN
CO2H
i. SOCl2, DEA, 0 ºC, 86%
ii. BuMgNiPr2, THF, D; I2, THF, 5 ºC, 56%
IO
NEt2
i. HNO3, D, 92%ii. IPA,
iii. HCl, 78%iv. TsOH, EtOH, D, 93%
Ph
Me
BnHN
CO2EtI
F
OH
i. EtCOCl, Pyr., 100%ii. AlCl3, 88%
iii. MeI, K2CO3, 97%iv. (CH2OH)2, pTSA, PhH, 86%
F
OMeO
OMe
i. BuLi, THF, –78 ºCii. ZnBr2, –65 ºC
iii. Pd(OAc)2, (ArO)3P, –65 ºC, 85%
F
MeOMe
CO2Et
O
O
i. HCl, dioxane, H2Oii. LiOH, MeOH, H2Oiii. HCl
F
MeOMe
CO2H
O
i. TEA, EtOCOClii. NaN3; D
iii.
NH2N
CN
F
MeO
OMe
NH
NH
O
N
CN
BCl3, DCM, 52%
MIV-10527% overall yield
Name?
Mechanism?
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
NH
SMeHN
OO
MeN
Amerge
1. Used to treat migraine headaches.2. Synthesis: GlaxoSmithKline, J. Med. Chem. 1995, 38, 3566, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
NH
Br
KOH, IMS, D, 94%
NMe
O
NH
Br
MeN
i. Pd(OAc)2, (o-tolyl)3P,
TEA, DMF, 85 ºCii. HCl, 89%
SMeHNOO
NH
SMeHN
OO
MeN
H2, Pd/C,
DMF, H2O, MeOH, 90% N
H
SMeHN
OO
MeN
Amerge75% overall yield
Claritin and Clarinex
1. Antihistamines.2. Synthesis: Schering-Plough, J. Org Chem. 1989, 54, 2242, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
N
Cl
N
OO Me
N
Cl
NH
N
Me
CN
i. tBuOH, H2SO4 75 ºC, 97%
ii. nBuLi, THF, –40 ºC, NaBr
ClCl
N
Cl
O
NHtBu
i. POCl3, 89%ii.
THF, 50 ºC; HCl, RT, 89%
NMeBrMg
N
Cl
O
NMe
i. HF, BF3, 92%ii. TEA, Tol.,
80 ºC, 73%
N
Cl
N
OO Me
OMe COCl
KOH, H2O
EtOH, D, 91%
N
Cl
NH
claritin52% overall yield
clarinex47% overall yield
Masterpieces in Process ChemistryRichter 11/3/04 Group Meeting
SB-273005
1. Vitronectin receptor antagonist.2. Synthesis: GlaxoSmithKline, OPRD. 2004, 8, 738.
N OMeHN NCF3
O
CO2HH
HOO
i. Br2, DCM, 65%ii. itaconic acid, TEA,
Pd(OAc)2, (o-tolyl)3P, Bu4NBr, MeCN, 80%
HOO
CO2HHO2C
DCA, [RuCl2(R-BINAP)]2,
TEA, H2, 60 ºC, MeOH, H2O, 84%
HOOMe
CO2HHO2C
H
OMe
H2SO4,
MeOH, D, 86%
HOO
CO2MeMeO2C
H
i. ZnCl2, MeCN, D,
ii. NaBH(OAc)3, DMAiii. TFA, Tol., D, 72%
ClH•H2N CF3HO N
CF3
O
CO2MeH
i. PPh3, DIAD, TBME
ii. LiOH, H2O, THF, 50 ºC, 66%
N OHMeHNN OMeHN N
CF3
O
CO2HHSB-27300518% overall yield
Last Reaction = 50 kg