Masterpieces in Process Chemistry
Richter
Selected Syntheses Discussed:
Me
HO
O
Me
OH
O
NH2
HN
O
Lipitor
Pfizer
H
S
O
Ketorolac
Syntex
NH
H
CO2H
F
O
N
H
N
OH
Me
MeHN
O
OH
O
Me
Tamiflu
Hoffmann-LaRoche
CN
N
O
N
CF3
O
MIV-105
Chiron
SB-273005
GlaxoSmithKline
OH
H
CO2H
O
O
ERa-SERM
Merck
Cortisone
Merck
N
O
N
N
O
N
H
N
O O
tBuHN
Me
NH
OH
Ph
H
N
N
O
O
Indinavir
Merck
Me
N
Cl
Cl
N
O
Linezolid
Pharmacia
NH2•H3PO4
N
H
OAc
Me
F
CO2Et
AcHN
O
H
Biotin
Tanabe Seiyaku Co.
EGFR Irreversible Inhibitor
Pfizer
S
Me
O
CO2H
N
HO
Me
O
H
O
HN
N
NH
N
Cl
N
O
Zomig
AstraZeneca
N
F
HN
N
H
Me
Discodermolide
Novartis
OH
O
O
Me
O
NMe
O
F
OH
Me
H
N
CO2
HO
Me
Me
HO
Me
Me
H
O
Me
11/3/04
Group Meeting
O
O
MeHN
OH
N
O
O
Me
Claritin
Schering-Plough
N
S
Amerge
GlaxoSmithKline
N
H
N
H
Clarinex
Schering-Plough
Masterpieces in Process Chemistry
Richter
11/3/04
Group Meeting
Selected Syntheses Not Discussed:
H
HO
MeO
O
AcO
Me
S H
O
H
OMe
NH
HO
Cl
Me
O
H
OH
N
CO2Me
O
H
NHMe
H
F3C
NH3+
H
Me
N
O
See Jeremy Richter, Baran
Group Meeting, January 2004
H
N
N
N
O
N
Me
FTI Candidate
Pfizer
O
O
H
H
Me H
H
H
O
H
H
O
O
H
H
O
H
O
H
O O
Me
O
Halichondrin
Kishi
H
O
H
O
H
H
1. This is by no means a comprehensive sampling of the many
masterpieces in process chemistry.
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.
OH
MeN
HO
H
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.
CO2–
Thienamycin
Merck
Prozac
Eli Lilly
Me
Disclaimers:
OH
O
O
H
HO
Indoxacarb
DuPont
Ecteinascidin 743
Corey
H
O
HO
HO
H
O
O
N N
Me
N
O
OCF3
O
H
N
H
CO2Me
Me
Cl
S
Me
N
NMe
Zyprexa
Eli Lilly
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, NozakiHiyama coupling, Evans-Saksena reduction, Kagan oxidation, Ullmann
reaction, Strecker reaction, Moffit oxidation, Fukuyama coupling, WohlZeigler bromination
Masterpieces in Process Chemistry
Richter
(–)-Discodermolide
Me
O
Me
H
Me
NH
Me
PMBO
Me
HO
O
Me
Me
Me
HO
Me
OH
OH
O
11/3/04
Group Meeting
NH2
CCl3
PMBO
PPTS, DCM
> 98%
CO2Me
LiBH4, THF
Me
[LAH worked well
but filtration = 24 hrs]
O
OH
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."
> 98%
CO2Me
Bn
Me
Me
PMBO
OH
O
N
TEMPO,
Bleach,
Me
DCM
100%
O
O
O
PMBO
Bu2BOTf,
TEA, > 75%
[Swern not amenable
for large scale – stench]
[46-55% on
20-25 kg scale]
Me
NH3
Me
Me
PMBO
Xc
OH
i. LiOH
H2O2
O
N
MeO
Me
OMe
Me
O
N
OMe
MeNHOMe
Me
Me
Me
N
PMBO
85%
OH
O
N
N
OMe
O
i. HCl
ii. iBuOCOCl
iii. MeNHOMe
75-80%
N
PMBO
O
OH
[First purification:
crystallization]
N
Me
PMBO
ii. (R)-Phenylethylamine
84%
Cl
ii.
Me
i. LiOH, H2O2, MeOH
OH
O
OMe
Masterpieces in Process Chemistry
Richter
Me
Me
PMBO
NMeOMe
OH
Me
TBSOTf,
2,6-Lut.,
Me
PMBO
NMeOMe
Tol., 0 ºC
90%
O
Me
TBSO
Me
Me
PMBO
OH
Me
DDQ, Tol.,
NMeOMe
O
11/3/04
Group Meeting
NMeOMe
M.S., 0 ºC
61%
O
O
O
O
[Chromatographic
purification – 12 kg]
[DIBAL-H reduction worked
but –78 ºC was unacceptable]
[Chromatography required]
Me
Me
Name?
I
NaHMDS, THF,
PMBO
Me
TBSO
I
(15:1 cis:trans, 31%)
Ph3P
Me
I
TBSO
Me
TBSO
Me
Me
Bn
Me
OMe
N
O
O
O
OH
O
O
i. LAH, THF
ii. Bu2BOTf, TEA,
–78 ºC to –10 ºC,
O
Bn
Me
85%
[Crystalline]
I
Ph3P
Me
Me
Me
Me
NMeOMe
TBSO
Name?
O
O
O
O
Me
OTBS
I
Ph3P, I2, imid.,
O
O
OTBS
[Chromatography
Required]
OMe
24% overall
Me
NMeOMe
O TBSO
Me
Tol., RT, 90%
i. MeMgBr
ii. SO3, Py,
DMSO
Me
Me
OH
OMe
Me
O
O
Me
O
ii. TEMPO, PhI(OAc)2
N
OMe
Me
t
NMeOMe i. H2, Pd/C, BuOH
O
i. TBSOTf,
2,6-Lut, 100%
ii. LiBH4, THF
–30 ºC to RT,
60%
Me
NaHMDS, I2
Me
Me
PMBO
[Chromatography required]
[No larger than 2.5 kg]
PMBO
Red-Al,
Tol., –20 ºC
68%
O
66% overall
[Chromatography
Required]
Masterpieces in Process Chemistry
Richter
Me
Me
i. tBuLi, 9-MeOBBN,
THF, –78 ºC
ii. Cs2CO3, DMF,
Pd(dppf)2Cl2, RT
Me
I
PMBO
Me
TBSO
I
Me
O
O
Me
O
[problems with commercial
purity of (+)-DIP-Cl]
OMe
Me
i. DIBAL–H, 92%
ii. SO3, Pyr.,
DMSO, 93%
PMBO
Me
O
MeOMeN
Me
PMBO
Me
Me
Br
OTBS OPMB
Me
Me
Me
PMBO
iii. KHMDS, 18-c-6, 76%
O
F3CH2CO P
F3CH2CO
Name?
TBSO
CO2Me
Me
MeO2C
Me
Me
Me
Me
Me
TBSO
OTBS OH
Me
[Chromatography
required]
O
Me
Me
OTBS OCONH2
Me
TBSO
4:1 dr, recyclable
Me4N+(OAc)3BH, 73%
Name?
Me
Name?
HO
Me
Me
ii. KOH
i. DDQ, H2O, 88%
ii. PhI(OAc)2, TEMPO
O TBSO
Me
O
OMe
TMS
TBSO
Me
[Chromatography required
on reverse-phase silica]
i. CrCl2,
O
Me
MeOMeN
Me
O TBSO
TBSO
Me
(+)-DIP-Cl, TEA, 55%
HO
Me
Me
Me
Me
+
Me
Me
OTBS O
Me
Me
OTBS OCONH2
Me
[Chromatography
required]
TBSO
TBSO
Me
Me
Me
Me
Me
11/3/04
Group Meeting
MeOMeN
Me
OH
Me
Me
OTBS OCONH2
Me
[Chromatography
required]
Me
O TBSO
Me
Me
TBSO
HCl, MeOH
Me
Me
OTBS OPMB
Me
HO
81%
[Chromatography
required]
i. CCl3CONCO;
Na2CO3, MeOH, 100%
ii. DIBAL–H, DCM, –78 ºC
iii. PhI(OAc)2, TEMPO, 80%
O
O
Me
Me
OH
Me
Me
H
Me
Me
Me
OH
O
OH
NH2
O
discodermolide
[ > 60 g produced]
39 steps, 17 chromatographic purifications, 20 months
7 problematic steps identified and being optimized
Masterpieces in Process Chemistry
Richter
EGFR Irreversible Inhibitor
O
N
HN
1. Treatment of solid tumors.
2. Inhibits Epidermal Growth Factor Tyrosine Kinase.
3. Process synthesis – Rober Hughes, Pfizer, Gordon Research
Conference Presentation.
F
NH2
NH
NH2
N
[Observed losses to dechlorination]
1% Pt/C, THF, H2
O2N
NH
F
N
[6.5:1 regioselectivity]
80% from EtOH
< 0.2% deschloro
N
O
HN
O2N
Cl
N
F
COCl
TEA, EtOAc,
51%
O
HN
HN
Last step was optimizable, but for
legal reasons they had to develop:
O
i. Ac2O, 85%
ii. 1.5% Pt/C, H2, THF, 99%
N
COCl
iii. TEA, THF, 0 ºC; NaOH, 80%
iv. MeSO3H/AcOH/THF; NaOH, 90%
Cl
N
[2 recrystallizations]
Cl
Could not improve
N
F
86%
Cl
O
[Yield loss]
i. SOCl2, 98%
ii. TEA, iPrOH,
H2N
Cl
N
[Material still lost in cyrstalization]
Used DMF instead of
HOAc for Recrystallization
74%
F
HN
H2N
ii. HOAc, 57%
F
O
F
H2, 99%
i. 65% HNO3/
H2SO4, 70 ºC, 81%
O
F
O
Ra-Ni, THF
Improved Route
•AcOH
CH3OCH2CH2OH
98%
N
into one pot, 95%
O
H
N
Combined 3 operations
N
Cl
N
O
[83% after recrystallization]
N
Problems
O2N
KOtBu, THF
98%
Cl
N
O
CO2H
OH
HN
HN
NH
F
O
F
Initial Route
11/3/04
Group Meeting
N
N
O
Final:
8 steps (3 pots)
55% overall yield
produced multikilo's
Masterpieces in Process Chemistry
Richter
11/3/04
Group Meeting
2nd Generation Route
Ketorolac
O
O
N
O
Br2
H
N
H
CO2H
DMF, 80 ºC
H
N
Br
0 ºC
O
O
Br
1.
2.
3.
4.
5.
Non-steroidal antiinflammatory drug (NSAID).
Powerful antiinflammatory and analgesic activity.
10 mg equiefficacious with morphine (10 mg) for post-operative pain.
10 mg equiefficacious with aspirin (650 mg) for postpartumpain.
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.
O
O
Br
i. NCS, DMS
DCM, –30 ºC
H
N
PhCONMe2
POCl3, DCE
H
N
i. HO–
ii. H2, Pd/C,
Mechanism?
O
NaH, DMF;
55 ºC,
SMe
O
O
O
O
O
O
O
O
N
SMe
MeO2C
i. mCPBA
ii. MeOH, HCl
ii. NaH, DMF, 75 ºC
Br
D
H
N
N
CO2Me
CO2Me
Br
SMe
ii. D, 60%
O
O
i. MeOH, HCl
N
1st Generation Route
O
O
O
O
O
CO2Me
O
i. NaH, DMF, 85 ºC
ii. NaOH
N
SO2Me
Ketorolac,
21% from pyrrole
racemic
MgO
iii. HCl
Ketorolac,
47% from benzoyl pyrrole
racemic
3rd Generation Route
Begins from Pyrrole and proceeds in 45% overall yield:
See US Patent 6,197,976
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.
Masterpieces in Process Chemistry
Richter
11/3/04
Group Meeting
ERa-SERM
HO
BnO
S
OH
S
O
O
HCl, 92%
O
N
OBn
O
I
S
OBn
BH3•THF
10 ºC
88%, 99% ee
Name?
BnO
Mechanism?
CuI, K2CO3,
2,2'-bipyridyl, 140 ºC
O
BnO
OBn
O
i. BnBr, NaI,
K2CO3, 84%
ii. NaOH
I
S+
BnO
Cumene
hydroperoxide
MgBr
OMe
S
O–
D-DIPT
Ti(OiPr)4
Mechanism?
Me
BnO
I
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.
HO
PhPOCl2
MeCN, 90%
N
O
(H2N)2CS,
OBn
O
OH
O
O
S
N
OH
I
SH
+
O
OH
I
BnO
BnO
S
OBn
TMSI
O
81%
OBn
PhMe3N+Br3–
DME, 100%
O
I
80%
Br
92%
O
OBn
88%
O
I
HO
S
OH
O
O
N
ERa-SERM
8 steps
37% overall yield
N
Masterpieces in Process Chemistry
Richter
Biotin
O
S
NH
H
H
S
1.
2.
3.
4.
NBn
HCl, 90 ºC
H
95%
NHBn
O
i. PhOCOCl, NaOH,
NH2•HCl
H2O, Tol., RT
H
S
NBn
H
ii. BnCl, NaOH,
DMSO, H2O, RT
CO2H
83%, >99% ee
S
NBn
H
O
86%, >99% ee
i. H2O2, K2CO3,
DMSO/DCM
Pd/C, THF,
ii. DCC, TFA, Pyr.,
DMSO, EtOAc,
50 ºC
94%
Name?
i. H2 (0.9 MPa), Pd(OH)2/C,
MeOH, H2O;
ii. H2O, filter
iii. HCl
S
NaCN, 8–20 ºC;
NaHSO3, NaCN
O
NHBn +
H
NHBn
NC
O
S
NHBn
H
NHBn
NC
100%
11:1 syn/anti
O
O
NBn
+
H
NHBn
H2NOC
93%
S
DMF
NHBn
H
120 ºC
NHBn
H2NOC
7%
BnN
NBn
H
H
S
91%
O
O
CO2Et
BnN
NBn
H
H
Tol, DMF
CO2Et
S
O
NaOH, 90%
ii. MeSO3H, mesitylene, 74%
HN
NH
H
H
S
H
S
Name?
Zn
i. NaBH4, H2SO4,
THF, D
O
i. NaHSO3, EtOAc
ii. BnNH2, DCM;
S
CO2H
SH
NBn
H
CO2Et
I
Name?
O
BnN
10–60 ºC
93%
H
H
IZn
CO2H
NBn
H
H2NOC
CO2H
Important in human nutrition and animal health.
> 80 tons produced synthetically anually.
Synthesis: Tanabe Seiyaku Co., Chem. Eur. J. 2004, ASAP.
For a comprehensive review of Biotin syntheses see:
Ryan Shenvi, Baran Lab Group Meeting, July 2003.
HS
BnN
O
DCC,
TFA, Pyr.,
DMF, 90 ºC;
O
HN
O
11/3/04
Group Meeting
H
biotin
12 steps,
39% overall
CO2H
O
Masterpieces in Process Chemistry
Richter
Cortisone
OH
OAc
O
Me
O
Me
Me
Me
Me
OH
O
Br
O
i. Br2, CHCl3
O
Me
Me
i. PhMgCl
CO2Me
Me
ii. Na2Cr2O7
CrO3, acetone
CO2Me
Me
ii. H2O,
CHCl3
HO
Synthesis at the time was meant to provide large quantities to test.
Starting material readily available from cow bile.
Work done in the early 1950's without modern spectroscopy.
Work done in less than 2 years.
Process synthesis: Merck, OPRD, 2004, 8, 708.
Me
i. HBr,
CO2Me
CHCl3
Me
1.
2.
3.
4.
5.
11/3/04
Group Meeting
ii. HOAc, D
75.5%
61.6% from SM
O
Me
OH
Me
OH
Me
CO2H
Me
MeOH
CO2Me
95.5%
iii.
OH
Me
CO2H i. MeOH,
91%
HO–;
H+
ii. H2, Pt0
HO
iv.
H+
SeO2 worked in 1 step
but needed in Korean
War electronics
Me
Me
HO
i. Br2, MeOH/PhH
ii. NaOAc, DMF
Me
Me
O
Ph
O
Ph
87%
Me
i. HBr
Me
Me
Me
CO2Me
Me
Me
i. Na2Cr2O7,
H2SO4
Me
Ph
hn; D
Name?
Ph
92.7%
AcO
O
NBS, PhH,
Me
Me
Ph
ii. Ac2O
Br
Me
EtO2CO
O
94%
HO
ii. CrO3
Me
Me
HO
i. EtOCOCl, Pyr.
O
CO2Me
H2SO4
O
Me
Me
Br
Me
Ph
ii. Zn, HOAc
87.4%
AcO
Me
"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
O
DNBS, Ac2O;
Me
MPPA; NaOH
AcO
92%
[DNBS = dinitrobenzenesulfonic acid]
[MPPA = monoperphthalic acid]
Masterpieces in Process Chemistry
Richter
Me
O
OH
Me
HO
AcO
O
Me
i. Br2, MeOH, PhH
ii. KOAc, HOAc, NaI
iii. DDH, acetone
iv. Zn, HOAc
94%
O
Me
O
Linezolid
OH
Me
O
N
O
86%
52.6% from ether
[DDH = dibromodimethylhydantoin]
O
F
N
"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!"
AcO
i. Br2, CHCl3,
HOAc
Me
O
H2NCONHNH2
Me
ii. NaBr,
acetone
O
Me
H2NOCHNN
F
95%
[step 2 used to convert O
all side products to the
Br
desire product]
"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."
Me
AcO
O
O
OH
O
NH
"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."
K2CO3
F
HO H
N
i. Cl
F
ii. KOtBu
iii. LDA
NHCbz
CbzCl,
N
O
OH
O
ii. Pd/C,
H2
NO2
O
92%
87.4% from triketone
28.3% overall
NH
i.
F
Me
HCl
CHCl3
Me
Me
H
O
AcO
O O
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
OH
11/3/04
Group Meeting
NH2
O
OH
90% Overall
N
F
O
N
H
O
OH
O
N
O
TEA,
F
N
NsCl
85% Overall H
O
i. NH4OH,
MeOH, 45 ºC
ii. Ac2O, 85%
ONs
linezolid
9 steps
65% overall yield
Masterpieces in Process Chemistry
Richter
i. tBuOAc,
H2SO4, 90%
Indinavir
N
OH
tBuHN
CN
O
O
i. pyroglutamic acid resolution
with recycle, 47%
HN
N
OH
H
N
N
N
N
Ph
NH
ii. H2, Pd(OH)2,
95%
Me Me
Ph
1. HIV Protease Inhibitor.
2. Synthesis: Merck, Chimia, 1997, 51, 306.
Narendra Ambhaikar, Baran Group Meeting, July 2004.
11/3/04
Group Meeting
O
CONHtBu
ii. Boc2O, KOH, 80%
BocN
i. MeOH, D
ii. HCl(g)
O
N
N
O
O
tBuHN
(S,S)-MnII(salen)Cl
NaOCl, P3NO
Mechanism?
87% ee
N
Oleum,
tBuHN
94%
99% ee
Cl
iPrOAc,
NH2
NaOH, 70 ºC;
NH2
base
MsOH, 35 ºC,
Me
Me Me
Ph
N
Me Me
Ph
O
N
Br
88%
H2SO4
OH
99% ee
>50% yield
N
O
N
Tartaric acid,
OH
OAc
OH
O
O
OH
COCl
H
N
N
MeCN,
H2O
OH
enzyme
Ph
OH
LHMDS,
–15 ºC
94%
O
i. NIS, H2O,
NaHCO3, 91%
ii. NaOMe, 100%
Ph
H
N
N
N
O
OH
tBuHN
O
O
indinavir
75% over 3 steps
>32% overall
OH
O
Masterpieces in Process Chemistry
Richter
OH
Lipitor
HO
HO
CO2
HO
O
CO2K
CaCO3,
K2CO3
HO
OH
N
OH
Me
Hypolipidemic.
Number one selling drug of all time (Natural product inspired).
Synthesis: Bruce Roth, Pfizer, Prog. Med. Chem. 2002, 40, 1.
Largest competitors:
HO
Me
Me
Mevacor
HO
Me
Me
O
O
H2, Ra-Ni,
CO2tBu
NC
HO
H
O
Me
Me
HO
Me
O
Me
H
CONHPh
Me
Me
Me
Me
O
HO
Zocor
Pravacol
HO
F
Me
Me
O
O
CO2tBu
H2N
Mechanism?
Me Me
MeOH, 95%
CO2Na
O
O
O
CO2tBu
iii. TBAF, HOAc, THF
or:
3 equiv. LiCH2CO2tBu
ii. Me2C(OMe)2,
MeSO3H, 65%
Me
O
NC
i. NaBH4, Et2BOMe,
MeOH, –90 ºC
H
OH
Mg(O2CCH2CO2tBu)2
O
O
i. TBSCl, imid.,
4-DMAP
ii. NaCN, DMSO
CO2Me
O
O
CO2Me
Br
i. NaOH
ii. CDI,
OTBS
NC
OH
H2,
Pd/C
Br
O
Me
CO2Me
Br
NH
Me
MeOH
OH
Me
F
O
HBr,
HOAc,
OH
H2O2,
O
HO
1.
2.
3.
4.
11/3/04
Group Meeting
Bn
N+ Cl–
S
F
O
Me
TEA
O
O
Me
CONHPh
Masterpieces in Process Chemistry
Richter
F
O
+
Me
Me
O
O
Me
O
Zomig
NMe
O
O
pivalic acid
1:4:1 Tol.:heptane:THF
D, 75%
Me
H
N
CO2tBu
H2N
Me
CONHPh
O
CO2tBu
Me
O
N
H
1. Used to treat migraine headaches.
2. Synthesis: AstraZeneca, US Patent 6084103, 6160123,
Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
i. Na2CO3, H2O, EtOAc; ClCO2Bu
ii. H2, 5% Pd/C, EtOAc, BuOH, 30–50 ºC
ClH•H2N
MeO2C
NO2
Me
F
11/3/04
Group Meeting
N
iii. NaBH4, BuOH, 35 ºC
iv. NaOMe, MeOH, BuOH, 85 ºC
Me
NH
i. NaNO2, HCl, 0 ºC
ii. Na2SO3, H2O, 0–60 ºC
O
iii. reflux, 3 hr
OEt
EtO
NMe2
CO2
HO
Me
F
N
Me
NH
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."
H
N
NMe2
O
O
N
H
No yields given
One-pot procedure
O
O
iv. 10% EtOH/EtOAc
HO
H
N
NH2
precipitated upon cooling
Masterpieces in Process Chemistry
Richter
Tamiflu
MIV-105
Me
F
Me
O
N
H
1. Potent inhibitor of influenza neuraminidase at nanomolar concentrations.
2. Synthesis: Hoffmann-LaRoche, Chimia, 2004, 58, 621.
1. Non-nucleoside reverse transcriptase inhibitor.
2. Synthesis: Chiron, OPRD, 2004, 8, 353.
i. SOCl2, DEA,
0 ºC, 86%
3 steps
CO2H
70–80%
Me
HO
CO2Et i. Et3SiH, TiCl4
O
OH
ii. BuMgNiPr2, THF, D;
I2, THF, 5 ºC, 56%
5 steps
HO
Me
O
OH
Me
i. NaN3, NH4Cl,
DMF, 85 ºC
Me
Me
O
ii. Ac2O, Pyr.
35%
i. NaN3, NH4Cl,
CO2Et
EtOH, 65 ºC
HN
ii. PMe3,
MeCN, RT
iii. MeI, K2CO3, 97%
iv. (CH2OH)2, pTSA,
PhH, 86%
Me
O
iii. HCl, 78%
iv. TsOH, EtOH,
D, 93%
O
i. EtCOCl, Pyr., 100%
ii. AlCl3, 88% Mechanism?
F
40–45%
OH
Me
F
80%
OMs
i. HNO3, D, 92%
ii. IPA, BnHN
Ph
NEt2
I
ii. NaHCO3
OH
CO2H
HO
N
Me
O
NH2•H3PO4
CO2H
N
H
OH
AcHN
HO
CN
O
CO2Et
11/3/04
Group Meeting
O
i. HCl, dioxane, H2O
ii. LiOH, MeOH, H2O
iii. HCl
O
Me
i. BuLi, THF, –78 ºC
ii. ZnBr2, –65 ºC
CO2Et
iii. Pd(OAc)2, (ArO)3P,
–65 ºC, 85%
OMe
O
CO2Et
O
F
CO2Et
I
OMe
Name?
Me
O
Me
Me
O
AcHN
Me
CO2Et
O
i. Lindlar, H2
ii. H3PO4, 80%
F
Me
CO2Et
CO2H
NH2•H3PO4
Tamiflu
35% from Shikimic acid
20% from Quinic acid
O
Me
H2N
N
H
N
N
H
N
OMe
CN
iii.
CN
O
i. TEA, EtOCOCl
ii. NaN3; D
OMe
AcHN
N3
[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.]
F
O
Me
BCl3, DCM, 52%
MIV-105
27% overall yield
Masterpieces in Process Chemistry
Richter
Amerge
11/3/04
Group Meeting
Claritin and Clarinex
Me
N
Cl
O
MeHN
N
S
N
N
H
N
1. Used to treat migraine headaches.
2. Synthesis: GlaxoSmithKline, J. Med. Chem. 1995, 38, 3566,
Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
O
Me
N
NMe
Br
i.
MeHN
KOH, IMS,
D, 94%
Br
O
S
TEA, DMF, 85 ºC
ii. HCl, 89%
Me
N
MeHN
H2, Pd/C,
O
N
H
Me
N
CN
DMF, H2O,
MeOH, 90%
MeHN
ii. nBuLi, THF,
–40 ºC, NaBr
i. POCl3, 89%
Cl ii. BrMg
O
N
NMe
THF, 50 ºC;
HCl, RT, 89%
NHtBu
Cl
Cl
Cl
O
O
Me
i. tBuOH, H2SO4
75 ºC, 97%
Me
N
S
O
1. Antihistamines.
2. Synthesis: Schering-Plough, J. Org Chem. 1989, 54, 2242,
Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
N
H
O
N
H
O
Pd(OAc)2, (o-tolyl)3P,
O
N
H
Cl
O
S
N
i. HF, BF3, 92%
ii. TEA, Tol.,
O
N
H
Amerge
75% overall yield
Cl
N
80 ºC, 73%
Me
N
Me
O
COCl
N
O
Cl
N
KOH, H2O
clarinex
47% overall yield
EtOH, D, 91%
N
H
O
Me
claritin
52% overall yield
Masterpieces in Process Chemistry
Richter
SB-273005
MeHN
N
O
CF3
N
O
CO2H
H
1. Vitronectin receptor antagonist.
2. Synthesis: GlaxoSmithKline, OPRD. 2004, 8, 738.
HO
i. Br2, DCM, 65%
ii. itaconic acid, TEA,
O
HO
Pd(OAc)2, (o-tolyl)3P,
Bu4NBr, MeCN, 80%
O
HO2C
CO2H
OMe
DCA, [RuCl2(R-BINAP)]2,
HO
TEA, H2, 60 ºC,
MeOH, H2O, 84%
OMe
MeOH, D,
86%
HO2C
H
HO
i. ZnCl2, MeCN, D,
O
ClH•H2N
MeO2C
H
MeHN
N
CO2Me
H2SO4,
CO2H
HO
CF3
O
ii. NaBH(OAc)3, DMA
iii. TFA, Tol., D, 72%
N
O
N
CF3
O
i. PPh3, DIAD, TBME
ii. LiOH, H2O, THF,
50 ºC, 66%
CO2Me
H
OH
MeHN
CF3
N
SB-273005
18% overall yield
Last Reaction = 50 kg
H
CO2H
11/3/04
Group Meeting