Masterpieces in Process Chemistry - The Scripps Research Institute

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

Richter
Selected Syntheses Not Discussed:
HO
MeO
Me
F 3C
O
O
AcO
O
O
H
NH
HO
H
S H
N
OH
Ecteinascidin 743
Corey
Masterpieces in Process Chemistry
N Me
H
OMe
O NHMe
Prozac
Eli Lilly
MeN
HO
OH
O N
Cl
Me
FTI Candidate
Pfizer
N
Me
Cl
Me
H
O
CO 2Me
O
N N
O
Indoxacarb
DuPont
OH
H
N
CO 2 –
N
CO 2Me
Thienamycin
Merck
See Jeremy Richter, Baran
Group Meeting, January 2004
H
N
N
Zyprexa
Eli Lilly
S
N
Me
NMe
OCF 3
NH 3 +
HO
HO
HO
H
Disclaimers:
O
H
O
H
Me H
Me
Me
H H H H H H
O O O
O
H
Halichondrin
Kishi
O
H H
O
O
O
11/3/04
Group Meeting
O O
H
O
Me
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
H
H
H
H
H
O
O
H
O
H
H

Richter
(–)-Discodermolide
O
Me
O
HO
OH
H
Me
Masterpieces in Process Chemistry
Me
OH
Me
Me
OH
Me
Me
O
Me
O
NH 2
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
"One major problem associated with a synthesis of this length is the proper laboratory
examination of the later reactions in a sequence. Initially, there are no answers to
these supply problems; one just has to run the small-scale reaction and hope that on
transfer to larger scale the reaction proceeds as expected. . . . On a positive note, this
project was a first for Novartis, and its progress was avidly followed by the entire
department who were all interested in the "disco". The success of this project and its
chemistry paves the way for other, perhaps even more complex, natural products to
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
worth taking a few risks. A total of 43 chemists participated in the concept of the
synthesis, experimental design, and execution. . . . The hybridized Novartis–Smith–
Paterson synthetic route that resulted in the preparation of 60 g of a structurally
complex molecule containing 13 stereogenic centers is a crowning achievement to all
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
we are confident of climbing this mountain as the situation demands."
HO
PMBO
PMBO
i. LiOH
H 2O 2
PMBO
Me PMBO CCl 3
CO 2Me
Me
Me
Me
OH
ii.
MeO
OH
OH
Me
N
Me
NH
PPTS, DCM
> 98%
TEMPO,
Bleach,
DCM
100%
[Swern not amenable
for large scale – stench]
O
O
Cl
N
X c
N
O
OMe
PMBO
PMBO
i. LiOH, H 2O 2, MeOH
ii. (R)-Phenylethylamine
84%
[First purification:
crystallization]
N OMe
N N
OMe
MeNHOMe
85%
Me
Me
PMBO
11/3/04
Group Meeting
CO 2Me
O
PMBO
LiBH 4, THF
> 98%
[LAH worked well
but filtration = 24 hrs]
Me
N O
Bn
Me
O
O
Bu2BOTf, TEA, > 75%
[46-55% on
20-25 kg scale]
Me
OH
Me
Me
O
NH 3
O
i. HCl
ii. i BuOCOCl
iii. MeNHOMe
75-80%
OH
Me
O
Me
N
OMe

Richter
PMBO
PMBO
PMBO
Me
OH
Me
TBSO
Me
O
Me
NMeOMe
Masterpieces in Process Chemistry
Me
(15:1 cis:trans, 31%)
[Chromatography required]
[No larger than 2.5 kg]
Me
TBSO
Me
O
I
TBSOTf,
2,6-Lut.,
Tol., 0 ºC
90%
[Chromatographic
purification – 12 kg]
PMBO
Me
TBSO
[DIBAL-H reduction worked
but –78 ºC was unacceptable]
[Chromatography required]
NaHMDS, THF,
I
Name?
Ph 3P Me
NMeOMe i. H 2, Pd/C, t BuOH
ii. TEMPO, PhI(OAc) 2
I
PMBO
Me
Me
TBSO
NaHMDS, I 2 Ph 3P Me
Me
O
I
Me
TBSO
Name?
Me
O TBSO
O
NMeOMe
Red-Al,
Tol., –20 ºC
68%
Me
Me
O
O
NMeOMe
i. MeMgBr
ii. SO 3, Py,
DMSO
Me
O
66% overall
[Chromatography
Required]
NMeOMe
PMBO
O
Me
OH
Me
O
i. TBSOTf,
2,6-Lut, 100%
ii. LiBH 4, THF
–30 ºC to RT,
60%
Me
O
OMe
Me
Me
OTBS
NMeOMe DDQ, Tol.,
O
OH
Me
[Chromatography
Required]
O
OMe
Me
M.S., 0 ºC
61%
OH
Bn
Me
O
N
85%
[Crystalline]
Ph 3P, I 2, imid.,
Tol., RT, 90%
O
O
O
O
Me
11/3/04
Group Meeting
O
OMe
Me
Me
O
NMeOMe
i. LAH, THF
ii. Bu 2BOTf, TEA,
–78 ºC to –10 ºC,
O
OMe
Bn
Me
Me
O
N
Me
OTBS
24% overall
O
I
O

Richter
PMBO
PMBO
Me
Me
Name?
MeO 2C
TBSO
TBSO
Me
Me
I
I
Me
Masterpieces in Process Chemistry
Me
Me
Me
TBSO O O
i. DIBAL–H, 92%
ii. SO 3, Pyr.,
DMSO, 93%
Me
Me
Me
OTBS OPMB
Me
i. DDQ, H 2O, 88%
ii. PhI(OAc) 2, TEMPO
iii. KHMDS, 18-c-6, 76%
O
F3CH2CO F3CH2CO P CO2Me Me
TBSO
Me
Me
Me
O
PMBO
Me
OMe
Me
PMBO
Me
TBSO
OTBS OH
Me
[Chromatography
required]
i. t BuLi, 9-MeOBBN,
THF, –78 ºC
ii. Cs 2CO 3, DMF,
Pd(dppf) 2Cl 2, RT
TBSO
Me
Me
i. CrCl 2,
Br
TMS
ii. KOH
Me
Me
Me
Me
OTBS O O
Me
Name?
Me
Me
OTBS OPMB
Me
81%
[Chromatography
required]
i. CCl 3CONCO;
Na 2CO 3, MeOH, 100%
OMe
ii. DIBAL–H, DCM, –78 ºC
iii. PhI(OAc) 2, TEMPO, 80%
O
Me
TBSO
Me
Me
Me
[problems with commercial
purity of (+)-DIP-Cl]
MeOMeN
MeOMeN
O
Me
Me
O TBSO
Me
O TBSO
O
HO
OH
H
Me
+
OTBS OCONH2 Me
[Chromatography
required]
HO
Me
HO
Me
Me
Me
(+)-DIP-Cl, TEA, 55%
Me
11/3/04
Group Meeting
Me
O TBSO
Me
MeOMeN Me
Me
Me
OTBS
Me
Me
OCONH 2
O TBSO 4:1 dr, recyclable
[Chromatography required
on reverse-phase silica]
Name?
Me
OH
Me
OH
TBSO
Me
Me 4N + (OAc) 3BH, 73%
Me
HCl, MeOH
Me
OH
Me
Me
Me
OTBS
Me
Me
O
discodermolide
[ > 60 g produced]
Me
O
Me
OCONH 2
O
[Chromatography
required]
NH 2
39 steps, 17 chromatographic purifications, 20 months
7 problematic steps identified and being optimized

F
Richter
EGFR Irreversible Inhibitor
Masterpieces in Process Chemistry
HN
O
O
1. Treatment of solid tumors.
2. Inhibits Epidermal Growth Factor Tyrosine Kinase.
3. Process synthesis – Rober Hughes, Pfizer, Gordon Research
Conference Presentation.
O 2N
Initial Route Problems Improved Route
F
CO 2H
NH 2
O
N
NH
[6.5:1 regioselectivity]
Could not improve
NH
H NH 2
•AcOH
CH3OCH2CH2OH 98%
N
HN
F
N
i. SOCl 2, 98%
ii. TEA, i PrOH,
H 2N
F
N
O
O
N
F
Cl
O 2N
NH
i. 65% HNO 3/
H 2SO 4, 70 ºC, 81%
ii. HOAc, 57%
[Yield loss]
HN
Cl F N
Used DMF instead of
HOAc for Recrystallization
74%
N
F
Cl
86%
O
N OH
KOtBu, THF
98%
O2N [83% after recrystallization] O N
Combined 3 operations
into one pot, 95%
Ra-Ni, THF
H 2, 99%
[Observed losses to dechlorination]
1% Pt/C, THF, H 2
80% from EtOH
< 0.2% deschloro
[Material still lost in cyrstalization]
COCl
TEA, EtOAc,
51%
[2 recrystallizations]
Last step was optimizable, but for
legal reasons they had to develop:
i. Ac 2O, 85%
ii. 1.5% Pt/C, H 2, THF, 99%
H 2N
O
HN
COCl
Cl
iii. TEA, THF, 0 ºC; NaOH, 80%
iv. MeSO3H/AcOH/THF; NaOH, 90%
O
O
N
N
HN
N
HN
N
11/3/04
Group Meeting
N
HN
N
O
N
O
N
O
F
F
Cl
Cl
F
Cl
Final:
8 steps (3 pots)
55% overall yield
produced multikilo's

Richter
Ketorolac
Masterpieces in Process Chemistry
O
N
CO 2H
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.
1 st Generation Route
H
N
O
i. mCPBA
ii. MeOH, HCl
i. NCS, DMS
DCM, –30 ºC
ii. D, 60%
Mechanism?
H
N
SMe
O
H
N
NaH, DMF;
H
SMe
55 ºC,
O O
MeO 2C
N
O O
CO 2Me
SO 2Me
PhCONMe 2
POCl 3, DCE
O
D
O
N
O
SMe
i. NaH, DMF, 85 ºC
ii. NaOH
O
O
Ketorolac,
21% from pyrrole
racemic
2 nd Generation Route
O
O
H
N
O
N
Br
i. HO –
ii. H 2, Pd/C,
MgO
iii. HCl
O
Br
Br 2
0 ºC
O
O
i. MeOH, HCl
3 rd Generation Route
Begins from Pyrrole and proceeds in 45% overall yield:
See US Patent 6,197,976
O
ii. NaH, DMF, 75 ºC
H
N
Ketorolac,
47% from benzoyl pyrrole
racemic
Br
Br
11/3/04
Group Meeting
O
DMF, 80 ºC
O O
N
O O
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.
Br
CO 2Me
CO 2Me

Richter
ERa-SERM
HO
S
O
Masterpieces in Process Chemistry
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
Me OMe
N
O
O
O
80%
(H 2N) 2CS,
HCl, 92%
Mechanism?
I BnO
I
+
OBn
MgBr
HO
PhMe 3N + Br 3 –
DME, 100%
OH
O
Br
O
S
O
N
O
I
i. BnBr, NaI,
K 2CO 3, 84%
ii. NaOH
OBn
BnO SH
88%
OH
BnO
BnO
S
O
OH
D-DIPT
Ti(O i Pr) 4
Cumene
hydroperoxide
Name?
HO
S
O
S
O
TMSI
81%
BnO
OBn
I
OBn
I
OH
O
PhPOCl 2
MeCN, 90%
O –
S +
O
BnO
OBn
CuI, K 2CO 3,
2,2'-bipyridyl, 140 ºC
BnO
N
N
I
OH
S
O
92%
11/3/04
Group Meeting
S
O
BH 3•THF
10 ºC
88%, 99% ee
Mechanism?
OBn
O
ERa-SERM
8 steps
37% overall yield
N
OBn
I

Richter
Biotin
HN
Masterpieces in Process Chemistry
O
S
NH
H H
H
CO 2H
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.
HS
S
O
NH2•HCl H
CO 2H
NBn
H
O
86%, >99% ee
i. H 2O 2, K 2CO 3,
DMSO/DCM
ii. H 2O, filter
iii. HCl
i. PhOCOCl, NaOH,
H 2O, Tol., RT
ii. BnCl, NaOH,
DMSO, H 2O, RT
i. NaHSO 3, EtOAc
ii. BnNH 2, DCM;
NaCN, 8–20 ºC;
NaHSO 3, NaCN
S
O
H 2NOC
Name?
NBn +
H
NHBn
S
O
S NBn
i. NaBH4, H2SO4, THF, D
H ii. DCC, TFA, Pyr.,
CO2H DMSO, EtOAc,
83%, >99% ee 50 ºC
Name?
O
S
O
H
93% 2NOC
7%
NHBn +
H
NHBn
NC
S
O
NC
100%
11:1 syn/anti
NHBn DMF
H
NHBn
120 ºC
BnN
NHBn
H
NHBn
O
S
91%
NBn
H H
O
S
O
DMF, 90 ºC;
NBn
H HCl, 90 ºC
NHBn 95%
H 2NOC
I
IZn
Zn
Pd/C, THF,
Tol, DMF
94%
CO 2Et
CO 2Et
i. H 2 (0.9 MPa), Pd(OH) 2/C,
MeOH, H 2O;
NaOH, 90%
ii. MeSO 3H, mesitylene, 74%
BnN
O
NBn
H H
Name?
SH CO 2H
BnN
O
S
NBn
H H
HN
O
S
NH
H H
H
biotin
12 steps,
39% overall
DCC,
TFA, Pyr.,
10–60 ºC
93%
11/3/04
Group Meeting
CO 2Et
CO 2H
BnN
O
S
NBn
H H
O

Richter
Cortisone
O
Masterpieces in Process Chemistry
O
Me
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.
HO
HO
Me
Me
OH
Me
i. EtOCOCl, Pyr.
ii. CrO 3
Me
O
EtO 2CO
Me
Me
91%
Me
CO 2H MeOH
Me
H 2SO 4
O
OAc
Me
Me
O
OH
HO
CO 2H i. MeOH, H +
ii. H 2, Pt 0
Me
Me
OH
Me
CO 2Me
i. Br 2, MeOH/PhH
ii. NaOAc, DMF
CO2Me iii. HO – ; iv. H +
95.5%
SeO2 worked in 1 step
but needed in Korean
War electronics
HO
Me
94%
Me
OH
Me
CO 2Me
HO
Me
i. Br 2, CHCl 3
Me
OH
Me
ii. Na 2Cr 2O 7
CrO 3, acetone
O
Me
O
NBS, PhH,
hn; D
Name?
Me
Me
Ph
CO 2Me
Ph
O
Me
O
i. HBr,
CHCl 3
ii. H 2O,
CHCl 3
Me
Br
Me
i. HBr
CO 2Me
75.5%
61.6% from SM
Me
O
Me
11/3/04
Group Meeting
Me
Me
i. PhMgCl
ii. HOAc, D
Me
Br
Me
CO 2Me
ii. Ac
87% 2O
AcO
92.7%
AcO
"As interesting as was the
kinetics of acetic acid formation
during enol acetylation or
peracid uptake during the
oxidation and despite the nice
data plots, they taught little
about minor byproducts or overreaction."
O
Me
AcO
Me
Br
Me
Ph
87.4%
O
Me
Ph
Me
Me
O
92%
O
Ph
i. Na 2Cr 2O 7,
H 2SO 4
ii. Zn, HOAc
DNBS, Ac 2O;
MPPA; NaOH
Ph
[DNBS = dinitrobenzenesulfonic acid]
[MPPA = monoperphthalic acid]

Richter
HO
O
Me
Me
Me
Masterpieces in Process Chemistry
O
OH i. Br 2, MeOH, PhH
ii. KOAc, HOAc, NaI
iii. DDH, acetone
iv. Zn, HOAc
[DDH = dibromodimethylhydantoin]
"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 what
would many years later be labeled a carcinogen!"
i. Br 2, CHCl 3,
HOAc
ii. NaBr,
acetone
[step 2 used to convert
all side products to the
desire product]
H 2NOCHNN
94%
O
Me
O
AcO
Br
Me
O
Me
O
OH
AcO
Me
95%
HCl
CHCl 3
O
OH
O
O
O
Me
Me
O
OH
86%
52.6% from ether
H 2NCONHNH 2
O
Me
AcO
"A great deal of development was still required as the demonstration with an
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
operandi is no longer practiced, courtesy of FDA and cGMP regulations."
AcO
Me
O
OH
92%
87.4% from triketone
28.3% overall
"Product elegance has long been an ethereal objective of ethical pharmaceutical
companies; 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 some
synthetic chemists to see a difficultly won, elegant, white crystalline material subjected
by pharmacists to granulation, sometimes coloration, and compression to an unnatural
form."
Linezolid
O
N
F
N
11/3/04
Group Meeting
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.
O
TEA,
NsCl
F
F NO 2
N
F
90% Overall
O
N
F
NHCbz
85% Overall
N
i.
O
NH
ii. Pd/C,
H 2
H
i.
H
ii. KO t Bu
iii. LDA
O
O
O
O
HO H
Cl OH
O
ONs
O
NH
N
F
Me
O
i. NH 4OH,
MeOH, 45 ºC
ii. Ac 2O, 85%
N
F
NH 2
N
CbzCl,
K 2CO 3
H
O
O
linezolid
9 steps
65% overall yield
OH

Richter
Indinavir
N
N
tBuHN
Masterpieces in Process Chemistry
1. HIV Protease Inhibitor.
2. Synthesis: Merck, Chimia, 1997, 51, 306.
Narendra Ambhaikar, Baran Group Meeting, July 2004.
N
O
(S,S)-Mn II (salen)Cl
NaOCl, P 3NO
enzyme
i PrOAc,
NaOH, 70 ºC;
MsOH, 35 ºC,
OAc
Me
Me Me
Ph
O
N
O
88%
COCl
99% ee
>50% yield
Br
LHMDS,
–15 ºC
94%
OH
NH 2
OH
Ph
O
H
N
87% ee
OH
99% ee
O
OH
OH
Tartaric acid,
Ph Me Me
O
N
base
O
Mechanism?
Oleum,
MeCN,
H 2O
NH 2
i. NIS, H 2O,
NaHCO 3, 91%
ii. NaOMe, 100%
OH
N
O
CN
N
i. t BuOAc,
H 2SO 4, 90%
ii. H 2, Pd(OH) 2,
95%
Ph Me Me
O
N
O
N
HN
N
tBuHN
N
tBuHN
11/3/04
Group Meeting
NH
CONHt i. pyroglutamic acid resolution
with recycle, 47%
ii. Boc2O, KOH, 80%
Bu
i. MeOH, D
ii. HCl (g)
N
O
N
O
OH
94%
OH
Ph
O
N
H2SO4 Ph
O
indinavir
75% over 3 steps
>32% overall
H
N
Cl
H
N
BocN
tBuHN
OH
OH
N
O

Richter
Lipitor
Masterpieces in Process Chemistry
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:
Me
Me
Me
O
Me
O
HO
H
F
Zocor
Me
Me
O
Me
Me
O
O
HO
O
N
HO
HO
H
O
Mevacor
Me
Me
Me
NH
O
Me
Me
HO
CO 2
O
O
O
H
HO
Pravacol
HO
Me
CO 2Na
HO
Br
NC
HO
OH
OH
Br
O
OTBS
OH
CONHPh
Me
O
O
CO 2Me
CO 2Me
i. NaBH 4, Et 2BOMe,
MeOH, –90 ºC
ii. Me 2C(OMe) 2,
MeSO 3H, 65%
Me
H 2O 2,
CaCO 3,
K 2CO 3
H 2,
Pd/C
i. NaOH
ii. CDI,
F
HO
O
Br
OH
OH
Mg(O t
2CCH2CO2 Bu)2
iii. TBAF, HOAc, THF
or:
3 equiv. LiCH t
2CO2 Bu
NC
HO
Me
Me
O O
Mechanism?
Me
S
Bn
N +
TEA
Cl –
OH
CO 2 t Bu
F
CO 2K
CO 2Me
NC
H 2N
11/3/04
Group Meeting
HBr,
HOAc,
MeOH
i. TBSCl, imid.,
4-DMAP
ii. NaCN, DMSO
OH O
H 2, Ra-Ni,
MeOH, 95%
O
Me
Me
O O
O
Me
CONHPh
CO 2 t Bu
Me
CO 2 t Bu

Richter
F
O
F
F
Masterpieces in Process Chemistry
O
Me
CONHPh
Me
Me
Me
+
O
N
HO
N
H 2N
O
O
HO
Me
Me
O O
pivalic acid
1:4:1 Tol.:heptane:THF
D, 75%
O
Me
Me
NH
CO 2 t Bu
CO 2 t Bu
"...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."
Me
Me
NH
CO 2
Zomig
O
H
N
NMe
O
N
H
1. Used to treat migraine headaches.
2. Synthesis: AstraZeneca, US Patent 6084103, 6160123,
Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
ClH•H 2N
O
MeO 2C
H
N
NO 2
i. NaNO 2, HCl, 0 ºC
ii. Na 2SO 3, H 2O, 0–60 ºC
iii. reflux, 3 hr
OEt
EtO
NMe2 iv. 10% EtOH/EtOAc
O
N
H
No yields given
One-pot procedure
11/3/04
Group Meeting
i. Na 2CO 3, H 2O, EtOAc; ClCO 2Bu
ii. H 2, 5% Pd/C, EtOAc, BuOH, 30–50 ºC
iii. NaBH 4, BuOH, 35 ºC
iv. NaOMe, MeOH, BuOH, 85 ºC
NMe 2
O
H
N
O
NH 2
precipitated upon cooling

Richter
Tamiflu
Me
Masterpieces in Process Chemistry
O
AcHN
Me
CO 2Et
NH 2•H 3PO 4
1. Potent inhibitor of influenza neuraminidase at nanomolar concentrations.
2. Synthesis: Hoffmann-LaRoche, Chimia, 2004, 58, 621.
Me
HO
HO
HO
HO
OH
OH
CO 2H
OH
CO2H i. NaN 3, NH 4Cl,
DMF, 85 ºC
ii. Ac 2O, Pyr.
35%
O
AcHN
Me
N 3
3 steps
70–80%
5 steps
40–45%
Me
CO 2Et
O
HN
Me
Me
O
O
Me
CO 2Et
i. Lindlar, H 2
ii. H 3PO 4, 80%
OMs
CO 2Et
i. NaN 3, NH 4Cl,
EtOH, 65 ºC
ii. PMe 3,
MeCN, RT
Me
[A series of studies was undertaken to improve the
efficiency and safety of this route, through the
replacement of the azide chemistry, as well as
beginning with more cost effective starting materials.]
O
AcHN
Me
Me
i. Et 3SiH, TiCl 4
ii. NaHCO 3
80%
O
O
Me
CO 2Et
NH 2•H 3PO 4
CO 2Et
Tamiflu
35% from Shikimic acid
20% from Quinic acid
MIV-105
O
F
OH
Me
1. Non-nucleoside reverse transcriptase inhibitor.
2. Synthesis: Chiron, OPRD, 2004, 8, 353.
F
CO 2H
OH
i. HCl, dioxane, H 2O
ii. LiOH, MeOH, H 2O
iii. HCl
O
F
OMe
Me
i. SOCl 2, DEA,
0 ºC, 86%
ii. BuMgN i Pr 2, THF, D;
I 2, THF, 5 ºC, 56%
N
H
O
i. EtCOCl, Pyr., 100%
ii. AlCl3, 88% Mechanism?
iii. MeI, K 2CO 3, 97%
iv. (CH 2OH) 2, pTSA,
PhH, 86%
CO 2H
O
F
O
OMe
Me
I
N
H
O
CO 2Et
i. TEA, EtOCOCl
ii. NaN 3; D
iii.
H 2N
N
CN
O
F
O
F
N
O
CN
NEt 2
OMe
Me
11/3/04
Group Meeting
i. HNO3, D, 92%
ii. IPA, BnHN Ph
Me
iii. HCl, 78%
iv. TsOH, EtOH,
D, 93%
i. BuLi, THF, –78 ºC
ii. ZnBr 2, –65 ºC
iii. Pd(OAc) 2, (ArO) 3P,
–65 ºC, 85%
OMe
Me
Name?
N
H
O
I
N
H
MIV-105
27% overall yield
N
CO 2Et
CN
BCl 3, DCM, 52%

Richter
Amerge
Masterpieces in Process Chemistry
O O
S
MeHN
N
H
Me
N
1. Used to treat migraine headaches.
2. Synthesis: GlaxoSmithKline, J. Med. Chem. 1995, 38, 3566,
Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
Br
O O
S
MeHN
N
H
O
NMe
KOH, IMS,
D, 94%
N
H
Me
N
Br
H 2, Pd/C,
DMF, H 2O,
MeOH, 90%
N
H
Me
N
i.
O O
S
MeHN
O O
S
MeHN
Pd(OAc) 2, (o-tolyl) 3P,
TEA, DMF, 85 ºC
ii. HCl, 89%
N
H
Amerge
75% overall yield
Me
N
Claritin and Clarinex
N
N
O O Me
1. Antihistamines.
2. Synthesis: Schering-Plough, J. Org Chem. 1989, 54, 2242,
Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
N
N
Me
CN
N
Me
O
i. t BuOH, H 2SO 4
75 ºC, 97%
ii. n BuLi, THF,
–40 ºC, NaBr
Cl
Cl
clarinex
47% overall yield
N
Cl
Cl
N
i. HF, BF 3, 92%
ii. TEA, Tol.,
N
H
80 ºC, 73%
Me O
COCl
Cl
N
O
NH t Bu
N
H
KOH, H 2O
N
EtOH, D, 91%
11/3/04
Group Meeting
Cl
N
Cl
i. POCl3, 89%
ii. BrMg NMe
THF, 50 ºC;
HCl, RT, 89%
O O Me
Cl
claritin
52% overall yield

Richter
SB-273005
Masterpieces in Process Chemistry
1. Vitronectin receptor antagonist.
2. Synthesis: GlaxoSmithKline, OPRD. 2004, 8, 738.
HO
MeHN N O
N
O
DCA, [RuCl 2(R-BINAP)] 2,
HO
TEA, H 2, 60 ºC,
MeOH, H 2O, 84%
MeO 2C
MeHN
H
O
CO 2Me
N OH
i. PPh 3, DIAD, TBME
ii. LiOH, H 2O, THF,
50 ºC, 66%
i. Br 2, DCM, 65%
ii. itaconic acid, TEA,
H
Pd(OAc) 2, (o-tolyl) 3P,
Bu 4NBr, MeCN, 80%
HO
HO 2C
i. ZnCl 2, MeCN, D,
ClH•H 2N CF 3
OMe
H
ii. NaBH(OAc) 3, DMA
iii. TFA, Tol., D, 72%
CF 3
O
OMe
CO 2H
CO 2H
HO
HO 2C
H 2SO 4,
O
MeOH, D,
86%
HO N
MeHN N O
N
SB-273005
18% overall yield
Last Reaction = 50 kg
H
H
CO 2H
CF 3
O
CF 3
O
CO 2Me
CO 2H
11/3/04
Group Meeting