Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
There are three different but complementary ways to explore medicinal chemistry, every
having its own constraints:
Discovery, hit-to-lead, and lead optimization: * rapidity
* development of a chemical library
Process chemistry and development: * scalable synthesis (yield optimization, ease of
purification, cost, safety) for bulk industrial
production
Isotopic labeling: * availability and price of labeled reagents
* reaction times for radiochemistry (tomography...)
Route
Discovery
Process
Labeling
Typical
scale
synthesis
1 mg < x < 1 kg
> 100 kg
~100 mg
Baran Lab GM 2011-11-19
Some data about some common radiolabels:
Isotope
Type
Decay
Half-life
Medical use
3T
natural
(trace)
3He,
β–
12.32 years
analytical
11C
artificial
11B,
β+
20.38 min
PET imaging
14C
natural
(trace)
14N,
β–
5,730 ± 40
years
analytical
13N
artificial
13C,
β+
<10 min
PET imaging
15O
artificial
15N,
β+
122 s
PET imaging
18F
artificial
18O,
β+
109.77 min
PET imaging
99mTc
artificial
99Tc,
γ
6.01 h
imaging
123I
artificial
123Te,
EC
13.3 h
SPECT
imaging
131I
artificial
131Xe,
β–
8.02 h
radiation
therapy
Isotopic labeling synthesis, a few definitions:
This technique is used for metabolic and pharmacological studies. Radiolabeled
compounds allow for measuring absorption, distribution, metabolism, and elimination of
compounds from the human body. Stable-labeled molecules often serve as internal
standards in mass spectrometry and NMR studies. Radioactive molecules are also used
in imaging and radiation therapy.
Radioactive isotopes: 3T, 11C, 14C, 13N, 15O, 18F, 35S, 124I, 131I...
Diagnostic medical imaging: 3 main techniques, all using gamma cameras
Stable isotopes: 2D, 13C, 15N, 17O, 18O...
Isotopomers or isotopic isomers: two molecules with the same number of each isotopic
atom but differing in their positions, e.g.:
2D
Me
2D
Me
Me
CH22D
Me
2D
OH
Me
Note: Radiography uses electromagnetic radiation (X-rays) and does not require any
radioactive molecules!
OH
Isotopologues: molecules only differing in their isotopic constitution, e.g.:
* Scintigraphy: 2D imaging
* SPECT (Single-photon emission computed tomography): 3D imaging by
reconstitution, directly detects gamma rays
* PET (Positron emission tomography): 3D imaging by reconstitution, detects gamma
rays produced by annihilation of a positron and an electron
H2O, H218O,
2D O...
2
1
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Baran Lab GM 2011-11-19
Production of small radioactive building blocks:
Small radioactive molecules (e.g. CO2) are produced in a cyclotron and chemically
transformed. Enzymatic transformations have also been developed. For example for 11C
labeling:
11CH SH
3
CuSO4
Na2S2O5
R3P
Pt, NH3
H
N
Cu11CN
H11CN
Br3
11CNBr
Fe/O2
11COCl
SPECT scanner
source: UCAIR website
http://www.ucair.med.utah.edu/
What_is_SPECT.html
PtCl4
2
CO2H
11CH
2
2)2
2D
2:
13C:
0.0156%
1.1%
15N: 0.00364%
18O: 0.00205%
17O: 0.00038%
Price examples of stable-labeled
building blocks (Sigma-Aldrich):
18F-Fluoro-Dopa
OMe
11CH
3NO2
Fe–Mo
cat
LiAlH4
11CO
MeLi
HI
3Li
3OH
H11CHO
K,
NH3
R11CH2OH
R11CHO
K11CN
R11CH3I
R11CH2Li
R11CH3SH
Stable isotope natural abundance:
NH2
N
N
13CH
3OH (99%): $167.00/1g
13C2D O2D (99%, 99.5%): $277.50/1g
3
13CH O (99%): $368.50/1g
2
H13CO2H (99%): $363.50/1g
13COCl (99%, 1M in benzene): $396.50/5mL
2
15NH
3
(98%): $432.00/1L
2D
O
18F
18F
Ni, H2
Zn
11CO
3I
AgNO2
Handbook of radiopharmaceuticals : radiochemistry and
applications / editors, Michael J. Welch, Carol S. Redvanly
Published !Chichester, England ; Hoboken, NJ : Wiley,
c2003
18F
MPPF
4
3IH
11CH
R11CH2NO2
HO
N
Cl2
n–BuLi
11CH
Me211CO
Common radiopharmaceuticals
for 18F PET:
N
4
NH3
11CO(NH
HO
11CCl
I2
11CH
11CH
PET principle
source Dr. Bernard Langlois Fluorine Chemistry
class
2O (99.994%): $12.40/1g
C2D3OH (99.8%): $39.90/1g
C2D3O2D (99.96%): $48.30/1g
C2D2O in 2D2O (98%): $19.83/1g
2DCO 2D in 2D O (99%): $42.00/1g
2
2
C62D6 (99.96%): $18.58/1g
H218O (99%): $992.00/1g
2D 18O (95%): $839.00/1g
2
CH318OH (95%): $993.00/1g
CH317OH (20%): $1,290.00/1g!!!
2
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Baran Lab GM 2011-11-19
Me
OH
Synthesis of small labeled molecules:
O
2 H2
Activity (A) = # decays per seconde
A(final product)
Radiochemical yield (RY): RY =
x100
A(starting material)
17O
H2
17O
N
Me
OH
17O
2
Me
O
Specific activity (SA): activity for one mole. Unit = Ci/mol with Ci = 3.7x1010 Bq = 37 GBq
17O
O
BH3
3
B
THF
8
13NH
8
3
NaOCl
3
8
13NH
+ H217O2
2 H2
2
N
O
Appl. Radiat. Isot. 43, 389
Me
J. Label. Compd. Radiopharm. 2010, 53, 78
K2PtI4
13NH
3
(13NH3)2PtI2
AgNO3
NaCl
(13NH3)2Pt(H2O)22+
(13NH3)2PtCl2
Cisplatin, RY: 27%
O
Me
J. Nucl. Med. 27, 399
O
11C
1. Me2NH2ClO4
O
N
R2
Zincke aldehyde
Br
J. Label. Compd. Radiopharm.
1999, 36, 33
HO
2. 11CH3NO2,
tBuOK
3. Na2S
Me
Me
NH2
R1
HCl gas
H218O
OH
H
N
Me
1.
Br
Br
OAc
OTf
O
AcO
AcO
OAc
OH
O
AcO
MeCN, 80°C, AcO
5 min
HCl
OAc
18F
O
18F
2,
3T
Pd/C
N
3T
EtOH
N
OH
O
3T
Me
3T
OH
OMe
[3T](R,R)–4–methoxyfenoterol
125I
chloramine-T
Na125I
NNa
S
OH
O
[125I]Melphalan
N
Cl
OH
O
3T
H2N
N
EtOH, pH = 7
CO2H
BrCH2CO2Me,
J. Label. Compd. Radiopharm.
2008, 51, 113
H
N
Pd/C
EtOH
J. Label. Compd. Radiopharm. 2010, 53, 68
ClH3N
O
OH
Cl
OH
3T
6N HCl
J. Label. Compd.
Radiopharm. 1995 26, 1077
2,
OMe
H2N
Cl
H
HO
Cl
O
HO
HO
O
3T
O
55%
(2 steps)
3T
J. Label. Compd. Radiopharm. 2010, 53, 68
2–deoxy–2–[18F]Fluoro–D–glucose prepared in ca. 50min
18FDP is commonly used for PET
J. Nucl. Med. 27, 235
N
OAc
Me
2. HCl
OH
K18F,
Kryptofix
2.2.2,
80°C, 87%
3T
R1
R2
18O
CH3ONa
Named reaction?
O
O
J. Med. Chem. 1999, 42, 5235
S
O
NH
O
14CH
O
2–aminopyridine
[14C]Piroxicam
NH
OH
3I
S
O
N
14CH
O
3
3
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Temozolomide (Temodar, Merck):
O
* anticancer drug (astrocytoma (brain tumor) and melanoma)
* prodrug, DNA methylating agent
O
Me
N
N
3. 2-mercaptopyridineN-oxide,
Et3N, –15°C
O
O
N
O
N
O
N
N
Process route: JCS Chem. Commun. 1994,1687
N
N
Isotopic labeling route (2002): 11C
Isotopic labeling route: J. Med. Chem. 2002, 45, 5448
O
NH2
O
all three papers are from Malcolm F. G. Stevens
Me
CO2Et
1. dry HCl
EtOH:Et2O
> 0°C, 24h
H2N
CONH2
HN
HCl
H2N
N
H2O, pH = 4
rt, 90%
HN
N
N
1. aq NaNO2
1N HCl,
0°C, 70%
N
2. Methyl
isocyanate
DCM, dark, rt,
98%
Mechanism?
N
O
NH2
1.
N
O
Cl
H311C
O
Cl
11CH
2.
NH2
HN
NHCl
2. aq NaNO2
2N HCl, 0°C
72% (2 steps)
N
HCl
N
H2N
N2
H2NOC
N
CONH2
MeNH2
N
H2NOC
N
11COCl
N
55%
NH
HN
N
N
N
O
NH2
NH2
O
N
N
11C
N
N
Me
O
11COCl
2
11COCl
2
11CH
3I
+ MeN(SiMe3)2 –> MeN11CO + 2 MeSiCl or
+ MeNSO –> MeN11CO + SOCl2
+ AgOCN –>
11CH
3NCO
+ AgI
O
11C
NHCl
11 C
H2NOC
2. Me2CHCH2OCOCl,
NMO, DMF, –15°C
N
2
NH
H3
HN
1. 5N HCl, 45°C
N
N
3I
O
Ph
N
N
N
H2N
O
CONH2 1. EtO2CCH2NCO EtO C
2
DMSO, pyr, 20°C
N
N
N
CO
H 3N
N
N
N
N
O
MeN 1
N
1
CO
NH2
O
H2N
NH
radiosynthesis
time: ~47 min
SA = 64 GBq.µmol-1
N
N2
Process route (1984): avoiding the use of Methyl isocyanate (Bhopal disaster, 1984)
H2N
N
CONH2
and
O
N
PhN2Cl
HCOOH,
Pd/C 30%, H2,
H2O:2-Methoxyethanol
rt, P > 1 atm, 3-4h
then HCl reflux 15min, 71%
JACS, 1945 67, 1017
J. Biol. Chem. 1949, 181, 89
JOC 1959, 24, 256
TL, 1979, 4253
Me
O
O
2. sat. NH3
EtOH, rt, 5d
60% (2 steps)
Temozolomide
N
N
Discovery route (1984):
NC
NH2
O
Temozolomide
4. Bu3SnH, AIBN
(cat), DMF, hν, rt
21% (4 steps)
N
Discovery route: J. Med. Chem. 1984, 27, 196
N
Baran Lab GM 2011-11-19
N
N
11C
O
N
N
Me
radiosynthesis
time: ~50 min
SA = 52
GBq.µmol-1
4
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Brivanid (under evaluation, BMS):
EtO213C
* anticancer
* VEGFR-2 kinase inhibitor (tyrosine kinase vascular endothelial growth factor
receptor-2): slow down angiogenesis and tumor progression
H
N
Me
HO
N
O
N
F
H
13C
EtO2
2. HC(OEt)3,
p–TSA (cat),
Me2NC(O)Me,
73°C
EtO2C
N
Me
EtO2C
1. NaH, NH2Cl,
DMF, 0°C, 55%
CONH2
N
H
MeO2C
1. Ph2P(O)ONH2,
NaH, DMF
Me
N
NH
O
2. H14C(OEt)3, p–TSA
(cat), Me2NC(O)Me,73°C
N
N
15NH
MeO
45°C,
pressure tube
OMe
4OH,
99%
Cl
O
H3
O
O
13C
13C
13C
13C
H2
O
MeO
OMe
OEt
H3
p–TSA (cat),
80°C
O
15NH
15NH
2
2
HCl
O
13C
13C
13C
13C
Me2N
13C
EtO2
13C 13C
15NH
15N
OEt
AcOH
rt 18h
then
100°C
6h
H313C
O
H313C
13C
2. 4-Fluoro-2-methyl13 13
1H-indol-5-ol, DMF, EtO2 C C
K2CO3, rt, 66%
N
15N
15N
13C
13C
13C
N
H
N
O
H313C
Me
O
OEt
F
Me
3. Et3N, LiCl, Me
EtOH, 58%
O
H
N
Me
1. POCl3, DIEA,
toluene, 110°C,
98%
2. 50% H2O2, BF3OEt2,
CH2Cl2, 68%
O
H215N
NMe2
NH
14C
1. LiCl, CH3MgBr,
THF/Toluene (1:1), 56%
J. Label. Compd. Radiopharm. 2006, 49, 139
O
O
H313C
O
N
CO2Me 2. HCONH Δ
2,
N
H
N
Me
Me
Synthesis of the pyrrolotriazine core in the isotopic labeling route: 13C, 15N
O
15N
Completion of 13C, 15N-labeled Brivatid synthesis with the discovery route:
1. TosMIC, NaH, MeO2C
DMSO:THF
2. AlCl3,
CCl3COCl,
then NaOMe,
MeOH
Named reaction for 1.?
15NH
H
Bioorg. Med. Chem. Lett. 2005, 15, 1429
CO2Me
13C 13C
The same synthesis has been used to do a 14C-labeling of the core:
Synthesis of the pyrrolotriazine core in the discovery route:
Me
O
H313C
1. NaH, NH2Cl,
DMF, 0°C, 55%
CO15NH2
15N
30%
Process route and isotopic labeling
route: J. Label. Compd. Radiopharm.
2011, 54, 324
O
Me
(R)
3
13C13C
Discovery route: J. Med. Chem. 2006,
49, 2143
Me
13CH
Baran Lab GM 2011-11-19
13C
O
HO
13C
15N
15N
F
overall yield for
the 5 steps: 14%
N
What about the process route?
13C, 15N-labeled Brivatid has also been synthesized from the same core intermediate
15NH
HCl
with the process route. This route is somehow similar to its precedent, with some
15NH
H215N
2
optimized conditions, one supplementary protection/deprotection sequence and the
oxidative decarbonylation of the pyrrole moiety being done prior to the indole arylation.
O
O
Overall yield for the 7 steps: 24%!
5
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Baran Lab GM 2011-11-19
Tipranavir (Aptivus, Boehringer-Ingelheim (Pharmacia & Upjohnʼs))
1. TiCl4, DCM, –78°C
2.DIEA
* combination therapy to treat HIV infection
* inhibits the replication of viruses
Discovery route: J. Med. Chem. 1998,
41, 3467
Me
OH
H
N
3α
(R)
Me
(R)
6
Ph
CF3
N
O
O
Process route: JOC 1998, 63, 7348
OMe
3.
XA
Ph
Me
4. aq. HClO4
95% (4 steps)
65%, 25:1 dr
1. KOtBu, THF, 0°C
2.H2, Pd/C,
MeOH:EtOAc
N(Bn)2
Et
O
OH
Me
O
O
O
N(Bn)2
Me
O
Isotopic labeling route: J. Label.
Compd. Radiopharm. 2008, 51, 314
S
O
3.
Ph
O
OMe
1. NaH (2 eq),
nPr
THF
Ph
2. NaOH then
H3O+
72% (2 steps)
O
OH
Me
1. H2, Pd/C,
MeOH, 92%
2. HPLC chiral
resolution of Cbz
derivative
3. A, pyr, DCM
O
N
Tipranavir Cl
S
O
O
O
N
Ph
O
1. CuBr Me2S, B
THF, 0°C
Et
2. Na2CO3, BnBr,
H2O:DCM
78% (2 steps)
JACS 1997, 119, 3627
2. NaOH, MeOH, 95%
(2 steps)
O
nPr
A
OPOM
nPr
O
2. TEMPO, NaOCl,
78%
HO
Et
nPr
OH
Ph
OPOM
Ph
Et
O
OH
1. DIBAL–H
POMCl, DIEA,
76%
OPOM
Ph
isopropenyl acetate
NO2 Amano P30 lipase
Et
AcO
~50% conversion
N(Bn)2
O
nPr
Ph
H
The first asymmetric synthesis:
O
Me
THF
OH
cocrystallization
O with norephedrine
27%
CF3
This route allows for diversity at C3α, C6 and sulfonamide
O
OH
OLi
O
Me
Ph
O
Tipranavir
This synthesis actually allowed for the elucidation of
the absolute streochemistry of Tipranavir
1.
nPr
Ph
2. AlEt3, CuBr Me2S
THF, 80% (2 steps)
O
NO2
O
O
Ph
The process route:
1. AlCl3,
m–nitrobenzaldehyde
THF
Me
OH
XA
O
Me
Me
3. A, pyr, DCM
54% (3 steps)
The discovery route:
O
1. Ti(OnBu)Cl3,
DCM, –78°C
2.DIEA
O
Et
O
Et
NO2
+ HO
NO2
N
Et
Ph
Cl
BrMg
B
NO2
O
N(TMS)2
POMCl
MeO2C
1. MsCl
2. NaC7H11O4
3. 6N HCl
4. HCl, MeOH
6
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Et
OH
Et
NaHMDS, 90%
NO2
Ph
MeO2C
H
O
POMO
CO2Me
nPr
H
Et
H
O
N
Nu
O
Ar
R
Me
Tipranavir
2. A, pyr, DCM,
78% (2 steps)
nPr
Ph
Mo
1. H2, Pd/C,
MeOH
NO2
3. NaOH, MeOH,
75% (3 steps)
N
ACIEE 2002, 41, 1929
N
OC
Ph
OH
1. PCC
2. H2SO4
CO
O
NO2
nPr
O
17 steps, 2
resolutions
A more academic route? The use of DYKAT (Dynamic kinetic asymmetric transformation)
Me
OPMB
Me
Cl
Me
PMBOH, Et3B, 1 mol %
Pd2(dba)3 CHCl3, 3 mol
% (S,S)–L1 1 mol %
O
OPMB
L1
O
O
Et
NH HN
(S,S)
3. DMP, DCM, rt
4. Ph3P=CH2, THF,
reflux,
86% (4 steps)
PPh2
Me
OPMB
Ph
2. DMP, DCM, rt,
88% (two steps).
NO2
Et
B
PMBO
Ph2P
1. Catechol
borane, 1 mol %
(Ph3P)3RhCl, THF Me
then 3 N NaOH,
30% H2O2, rt.
+
2. DMP, DCM, rt,
(89% two steps)
MeO2C
Ph
CHO
L
O
1. CAN, MeCN/H2O, 88%.
2. NaOH, MeOH, 4°C, 77%
(97% brsm).
3. 5 mol % Pd/C, H2,
MeOH, rt
L
OPMB
Ph
14C
OH
Ph
sodiomalonate, THF,
reflux, 94%, 96% ee.
3. NaCl, 150 °C,
20:1 DMSO/H2O,100%.
Me
NO2
OH
Et
NO2
O
O
NH HN
(R,R)
N
NO2
nPr
Ph
O
O
nPr
O
14C
3. 90% HNO3
72% (3 steps)
L2
MeO2C
OH
1. SOCl2
2. Cd(Et)2
O
NO2
18 steps, overall yield: 25%!
Tipranavir
The isotopic labeling route: 14C and 13C
Pd
CO2Me
OPMB
Ph
4. 5-(Trifluoromethyl)-2pyridinesulfonyl chloride,
DCM, pyr, DMSO, -25 °C,
92%.
JACS 1998, 120, 12702
1. Boc2O, DCM, Et3N,
DMAP, rt, 98%
2. 10 mol %
Mo(CO)3(C7H8), 15 mol
% (R,R)–L2, dimethyl
HO
OH
Me
69%, 98% ee.
2. 1N NaOH,
Et2O, 25°C, 86%
(two steps)
1. PhI, 10 mol %
Pd(OAc)2, 40 mol %
P(o-Tol)3, toluene,
Et3N, reflux
2. 5 mol % Pd/C, H2,
MeOH, Pyr, rt
Me
1. NaHMDS,
THF, -78°C
NO2
O
Me
O
CHO
Trost, JACS 2002, 124, 14320
1.CH2CHMgBr,
THF, 0 °C
Baran Lab GM 2011-11-19
1.
O
O
Ph
Et
TiCl4, pyr, THF
2. [((R,R)–MeDuPHOS)Rh(cod)]BF4,
H2, (80 PSI), 57°C
63% (2 steps)
1. H2, Pd/C,
MeOH
2. A, PhNMe2, BHT,
DCM, 58% (2
steps)
[14C]Tipranavir
7 steps (25%), SA = 54
mCi/mmol
13C
N
Synthesis of [13C6]Tipranavir with the same route starting with:
13C
13C
13C
CO2H
13C
13C
7
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
BMS-644950 (in clinical development)
The process route goals:
more convergence, no chromatographies, avoiding production of MeSH (in synthesis of
triazole D), highly flammable and toxic gas, avoiding epimerization at C5.
* anticholesterol, statin type
* Inhibits cholesterol synthesis
HO
F
Me
N
N
CHO
Process route: OPRD, 2010, 14, 441
Me
Isotopic labeling route: J. Label. Compd.
Radiopharm. 2011, 54, 72
H2N
The discovery route:
CO2Et Me
NH
2
Me
Me
N
Me
O
Me
O
Me
N
N
O
O
H2N
Ph
S
O
O
O
1. KOtBu, D,
THF:DMF, rt F
2. (MeO)2CO,
DABCO
CO2Me Me
Me
N
N
HO
N
Cl
O
OtBu
BMS-644950
ammonium salt
SMe
NH
H2SO4
MeNHNH2
then HCO2H
NH2
N
N
N
D
Me
+ MeSH
Me
Me
3. DIBAL–H,
toluene
80% (3 steps)
N
NMe
N
NMe
N
1. LiHMDS, D (2.5 eq),
–60°C
BMS-644950
sodium salt
2. LiHMDS, MeI
3. aq. HCl, THF
4. NaOH, THF
70% (4 steps) 7 steps from
C
N
N
Named reaction?
then work-up and
crystallisation,
88%
2. POCl3, 95%
Bioorg. Med. Chem. 1997, 5, 437
SO2Me
Me
NH
35% overall yield!!!
similar steps to the
discovery route, but
improved
New synthesis of aminotriazole D:
MeO
N
C
NH2
N
C
N
NH2
N
MeNHNH2
NMe2
known pyrimidine,
30–40°C
MeOH,
N N
Me2N
42% overall yield MeO
D
0°C–10°C
Me
(20% real overall
yield)
The isotopic labeling route, an adaptation of the process route: 14C
Named reaction for 3.?
N
N
CO2tBu
F
3. LiHMDS, C, THF,
–78°C,
60% (3 steps)
N
HN
SO2Me
Me
Me
CO2Et Me
2. DDQ/, DCM
3. m–CPBA,
48% (3 steps)
O
1 step from
commercially available
compounds
NH2
1. CuCl2 (0.01 eq.),
K2CO3 (0.1 eq.),
F
tBuOOH (2.2 eq),
DCM, 40°C
F
Me
2. Cool to 20°,
crystallization, 85%
Me
First oxidation conditions were 65% HNO3, but... "If this reaction were to reach >40°C,
then it would become unstoppable until all the reagents are consumed".
SMe
HMPA
CO2MeMe
O
H2SO4
1.
1. DIBAL–H, DCM
2. TEMPO, NaOCl,
EtOAc
1. CuCl (0.01 eq.),
F
H2SO4 (0.1 eq.), MeOH,
reflux
Me
O
H2N
N
Me
F
O
+
Discovery route: J. Med. Chem. 2008, 51, 2722
N
N
MeO
OH
Me
N
F
CO2H
5
Baran Lab GM 2011-11-19
H2N
14C
O
NH2
+ Me2NH
Ar
N
is used in the first step, ultimately leading to
MeN
Het
14C
R
N
SA = 21.8 mCi/mmol
iPr
8
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Baran Lab GM 2011-11-19
HN
Dasatanib (Sprycel, BMS)
HN
14C
S
Me
O
14C
H2N
* antileukemia
* Src tyrosine kinase inhibitor
O
HN
O
NH
Me
NH
OH
Cl
Cl
N
N
N
Discovery route: J. Med. Chem. 2004,
47, 6658
(see also, J. Med. Chem. 2006, 49,
6819)
NH
S
O
Cl
N
Cl
Cl
N
H
N
Me
N
N
H2N
14C
Isotopic labeling route: J. Label.
Compd. Radiopharm. 2008, 51, 41
Me
O
S
N
Cl
NH
HN
Me
N
NaOtBu
14C
O
S
N
THF, 82%
Cl
OMe
1. n–BuLi, 2–chloro–6–
methylphenyl isocyanate,
THF, –78 °C, 86%
Me
Cl 2. NaH, 4–methoxybenzyl
chloride, THF, 95%
S
1. NaH, 4–amino–6–
chloro–2–
methylpyrimidine,
THF, reflux, 83%
N
Cl
1–(2–hydroxyethyl)piperazine,
DIEA, nBuOH
N
N
N
H
N
N
H
S
Cl O
N
Me
2. HCl, Et2O,
MeOH,
91% (two steps)
Cl
The isotopic labeling route: 14C, 18F
O
N
1. 1–(2–
hydroxyethyl)piperazine,
1,4–dioxane, reflux
Me
Me
H2N
Dasatanib
chloride salt
O
Cl
NH
THF:H2O
98%
Cl
Mechanism?
O
[18F]Dasatanib
analog
18F
RA = 25.1 ± 5.8%
average SA = 2560 mCi/µmol
OTf
K18F, Kryptofix 2.2.2,
K2CO3, o–dichlorobenzene,
105°C, 10 min
Br
18F
Me
NBS
O
18F
Br
NaI, Cs2CO3
DMF:MeCN 1:1,
140 °C, 40 min
or TsO
DMSO, 160 °C,
30 min.
6 steps, 61%
overall yield!
Br
N
S
O
Br
NH2
NH
H
N
S
14C
N
N
Cl O
Me
SA = 18.3 mCi
Me
Cl
S
[14C]Dasatanib
66%
2. TfOH, TFA:DCM
(1:1), 99%
N
Me
NH
The discovery route:
N
Me
OH
N
Me
O
S
NH
OH
Cl
TsO
OTs
K18F, Kryptofix 2.2.2,
K2CO3, MeCN, 110°C, 10 min
TsO
18F
9
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Baran Lab GM 2011-11-19
Me
O
LY2784544 (human clinical trials phase, Lilly)
N
* anti myeloproliferative diseases
* JAK2 protein tyrosine kinase inhibitor
O
N
N
H
N
79%
PMB
Me
N
BocHN
The discovery route:
OMe
N
cyclopentyl
methyl ether,
90°C, 77%
Cl
N
N
NMe2
O
Cl
Cl
SOCl2, hex:MeOH
Cl
NPhth
PhthN
CO2H
AgNO3, TFA,
Cl
(NH4)2S2O8,
N
N
N
Me
MeCN:H2O,
70°C, 57%
O
Phth = Phthalimide
Cl
F
N
N
F
O
N
N
N
Me
NH2
HCl
F
+
tBuHN
NH2
O
N
N
Me
O
O
Et3SiH (6 eq)
TFA (11 eq)
85°C, 94%
F
Cl
Me
N
Cl
N
N
Cl
CN
Cl
N
1.
F
NaOH 2N
90°C, 86%
N
Me
N
tBu
NH2
Pd2(dba)3, Xantphos
NaOH, xylenes:H2O, reflux
2. TFA:H2O (1:5), reflux,
66% (2 steps)
N
4. TFA, PMHS, PhMe, 80°C
5. 6N HCl, PhMe
45% (5 steps)
PHMS = Polymethylhydrosiloxane
F
obtained with
a similar
synthesis to
the discovery
route, with
optimizations
Cl
EtOH, 40°C, 80%
O
F
NH2
N
N
Cl
N
PMB
NMO (10 eq)
Me VO(acac)2 (20 mol%)
Me
120°C
68%
1. AcOH, HCl, 100°C
2. NaBH4, MeOH, 5°C
O
3. Cl
Cl Cl
K2CO3
N
N
HCl, dioxane
reflux, 68%
N
O
Cl
NaOH workup
70%
Cl
N
Me
O
F
NH
2 HCl
N
DMF
Cl
H2N
Me
CN
PMB
The process route:
OMe
NH2 Me2N
14 steps, 4.3% yield
over the longest linear
sequence
O
1. p-anisaldehyde
EtOH, reflux
NH2
LY2784544
79%
2. H2 (15 psi), Pd/C
EtOH, 10–20°C
3. AcCl, MeOH, 40–
50°C, 68% (3 steps)
Me
TFA,
anisole
Me
N
N
Pyrazole synthesis:
Cl
N
N
H
Cl
Process route: OPRD, ASAP,
doi:10.1021/op200229j
F
N
N
F
Isotopic labeling route: coming soon???
Cl
N
N
Discovery route: U.S. Pat. Appl. Publ. US
20100152181 A1 20100617
N
HN
Me
PMB
Pd2(dba)3, Xantphos
NaOH, PhMe:H2O
N
Me
N
NH2
N
Me
LY2784544
8 steps, 35% yield over
N
N
tBu
NH2
the longest linear
sequence!!!
10
Short Stories in Pharmaceutical Discovery,
Process and Isotopic Labeling
Q. Michaudel
Baran Lab GM 2011-11-19
CO2H
Cl
Other examples:
O
Cl
O
OC2D
3
Me
O
Me
H
N
N
H
O
OH
O
N
H
N
N
H
Ph
Me
Me
Me
S
OMe
BMS-587101
Discovery route: J. Med. Chem. 2006, 49, 6946
N
N
Me
N
Process route: OPRD 2010, 14, 553
N
Me
Isotopic labeling route: J. Label. Compd.
Radiopharm. 2009, 52, 236
14CN
O
Atazanavir (Reyataz, BMS)
Discovery route: J. Med. Chem. 1998, 41, 3387
Process route: OPRD 2002, 6, 323
Isotopic labeling route: J. Label. Compd.
Radiopharm. 2005, 48, 1041
HO
H2N
14C
14C
N
O
N
Saxagliptin (Onglyza, BMS and AstraZeneca)
Discovery route: J. Med. Chem. 2005, 48, 5025
Process route: OPRD 2009, 13, 1169
Isotopic labeling route: J. Label. Compd.
Radiopharm. 2007, 50, 1224
Automated system for the radiosynthesis of [3–N–11C-methyl]temozolomide from [11C]iodomethane via
[11C]methyl] methyl isocyanate
J. Med. Chem. 2002, 45, 5448
11