Masterpieces in Process Chemistry II
Richter
Selected Syntheses:
Cholesterol Lowering Azetidinones: Schering Plough
Vitamin D Analogs: Hoffmann-La Roche
Me
Me
Me
H
Me OH
N
Me
H
Me OH
H
R=H Ro 24-2090
R=OH Ro 23-7553
calcitriol
OH
HO
R
HIV Protease Inhibitors: DuPont-Merck
O
N
HO
Ph
O
N
HO
OH
N
Ph
OH
H2N Ph
HO
DMP 323
Epilepsy Therapy:
Eli Lilly
N
OH
Ph
NH2
DMP 450
Cholesterol Lowering: Sandoz
F
Me
N
NAc
N
CO2Na
N
H2N
LY300164
Me
OH
Me
O
OH
OMe
Sch 58053
Informative Books on Process Chemistry:
– Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical
Industry. Marcel Dekker, Inc. New York: 1999.
– Anderson, Neal G. Practical Process Research & Development.
Academic Press. San Diego: 2000.
– Repic, Oljan. Principles of Process Research and Chemical
Development in the Pharmaceutical Industry. John Wiley & Sons, Inc.
New York: 1998.
"The mission of process chemistry in the pharmaceutical industry is to
provide documented, controlled synthetic processes for the manufacture
of supplies to support the development programs and future commercial
requirements for an active pharmaceutical ingredient (API) or the drug.
The mission represents a tremendous challenge to the synthetic skills of
the process scientists as the requirements for drug supply progress from
milligrams to metric ton quantities."
– Kumar Gadamasetti
"The ideal chemical process is that which a one-armed operator can
perform by pouring the reactants into a bath tub and collecting pure product
from the drain hole."
– Sir John Cornforth
O
O
Cl
O
Sch 48461
HO
F
HO
OMe
Me
Me
1/11/06
Group Meeting
OH
Lescol
"Graduate school research in organic synthesis resembles chemical
development much more than it resembles medicinal chemistry: Given a
target molecule, one must design the synthesis and discover and develop
all reaction conditions to obtain a reasonable yield of the target molecule."
– Oljan Repic
"Thus, early on in a project, 'Make stuff!' wins out over 'Learn to make it
better!'"
– Richard Mueller
Richter
Masterpieces in Process Chemistry II
Practical Considerations for Process Research:
Solvents and Drying:
– Avoid using solid dessicants, azeotrope instead.
– "In general, small, unlike molecules form azeotropes."
– Concentration to dryness is rarely performed, normally solvents are
chased out azeotropically.
– Consider using excess reagent to dry the solvents.
– Decanting and siphoning are difficult to perform on scale.
– Solvents avoided: pentane, Et2O, HMPA (use NMP instead), hexane,
PhH, CHCl3, CCl4, DCM, DCE, ethylene glycol, DME, dioxane, NH3.
– In general, avoid solvents with flash points below 15 ºC.
– Commonly used solvents: MTBE, heptane, H2O, MeOH, EtOH, AcOH,
n-BuOH, i-PrOH, MeCN, DMSO, DMF, Acetone, MIBK (good for
extractive workups and azeotroping), EtOAc (i-PrOAc is better), THF (2MeTHF allows extractions), PhCl, Tol., TEA, Cyclohexane.
– Stirrability (viscosity) needs to be considered.
– Don't be afraid of multiple solvent systems.
– It is best to use solvents that do not require distillation or purification.
– Optimal concentration is >10%.
Running Reactions:
– To remove oxygen: sparge with N2 or reflux under N2.
– Liquids are easier to transfer than solids.
– Acceptable temperature range: –40 to 120 ºC.
– If adding neat liquids to a cooled reaction, the liquid may freeze on the
surface, so add as a solution or subsurface.
– Many factors need to be considered when monitoring a reaction: is it a
representative sample? Did the sampling and prep time affect the
result? Does the temperature increase matter? Determine endpoint
based on two samples.
– Reactions requiring anything "rapid" are difficult to perform.
– Be aware of potential exotherms and plan accordingly. May require
slower additions, or reflux to absorb the exotherm.
– Consider the following things when choosing reagents: toxicity, side
reactivity, expense, availability,consistency between lots, stability,
robustness, work-up/quench issues, specialized equipment, solubility.
– Sequence and duration of reagent addition can dramatically affect the
outcome.
Anderson, Neal G. Practical Process Research & Development.
1/11/06
Group Meeting
– To mimic reactions on scale, extend reaction times in the hood.
– Use reagents of low purity before moving to high purity.
Workup:
– Take advantage of natural phase separations.
– Determine the required number and amounts of washes, extractions, etc.
– Be aware of potential quench exotherms.
– Use the smallest number of vessels as possible.
– Add cosolvents (EtOAc, Tol.) or change the pH or electrolyte content to
destroy emulsions.
– Consider using activated carbon plugs to remove polar impurities.
– Metals must be removed to cGMP levels.
Cystallizations:
– Each 1% of impurity holds back 1-2% of product.
– Optimize to decrease the nuber of crops required.
– Precipitation is different than crystallization and rarely purifies product.
– Ways to increase crystallization pressure: cool a warmed solution,
increase concentration, increase antisolvent, increase ionic strength,
control pH.
– Seeding helps crystallization.
Asymmetric Synthesis on Scale:
– Need greater than 98% ee.
– Resolutions (chiral salts, covalent modification, kinetic, enzymatic,
recycling, Preferential Crystallization).
– Chiral pool (consider that the SM may not be high ee)
– Asymmetric induction (metal based, chiral auxiliary, enzymatic): consider
recycling, cost, toxicity, synthesis of ligands.
– If a reaction is not enantiospecific or stereospecific, it should be placed at
the beginning of a synthetic sequence.
Miscellaneous
– Avoid using protecting groups.
– Avoid excessive oxidation state manipulations.
– Every impurity present in 0.1% or greater amount must be fully
characterized and analyzed for toxicity. For this reason it is a good idea
to freeze the final steps and purity profile of a process early.
– Each operation on scale generally requires twice as long as in the hood.
– Ideally the API should be producted at lower than $1000/kg.
– As a process chemist, it may be necessary to "make a reaction work
instead of "trying something else."
Masterpieces in Process Chemistry II
Richter
Me
Common Process Reactor:
Me
Me
Me
H
H
Me
Me
Me
vitamin D2
expensive
Manway
Top Head
Nozzles
Fin Baffle
SO2
safety, toxicity
1. O3, DCM/
MeOH, – 10 ºC;
NaBH4, 87%
2. I2/PPh3, imid,
DCM, 71%
TBSO
Me
Me
Me
Me
H
CO2Et
safety
NiCl2/Zn
Pyridine
H
SO2
Impeller
H
2. TBSCl
97%
HO
Carbon Steel
(Low Temp)
Jacket
Me
1. SO2
H
CO2Et
H
I
H
SO2
83%
TBSO
TBSO
1. NaHCO3, EtOH, 73%
2. SeO2, NMO, DCM, MeOH; chromatography
TBSCl, imid., DCM, 41%
Vitamin D Analogs:
Me
Me
Me
Me
Me
H
Me OH
Me
Me
Me
Me
Me
H
H
Me OH
H
HO
R
Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 – 89.
H
CO2Et
1. MeMgBr, THF, 82%
TBSO
OTBS
HO
H
Me
Me OH
H
2. TBAF, THF, 81%
3. h!, MeOH, 93%
chromatography
R=H, Ro 24-2090
R=OH, Ro 23-7553
calcitriol
OH
Me
Me
Mixer Drive
HO
1/11/06
Group Meeting
OH
calcitriol
several batches
100g each
10 steps
9% overall
JOC, 1995, 60, 6574.
Masterpieces in Process Chemistry II
Richter
Original Med. Chem. route to Ro 24-2090 and Ro 23-7553.
Synthesis of Ro 24-2090
Me O
Me
O
Me
Me O
3 steps
Me
7 steps
H
H
O
O
Me
CHO
H
OAc
toxicity
H
Me
Me
Me
O
Me
Me OTBS
H
Me
Me OTBS
N
H
OAc
Me
Me O
H
HO
HO
Penicillium
H
cost
ATCC 12556
Me
Me
H
H
H
HO
H
H
1. TBAF, THF
2. NaOMe, MeOH
3. TDSCl, imid.,
DCM, 44%
Me O
Me
H
TDSO
OH
Me
Me O
Br
H
OTBS
Me
Me
OHC
Preparation of starting material for Ro 23-7553.
H
Br
1. EtPPh3Br, Tol., effective lower
t-BuOK, 94% limit of cooling
safety 2. Me2AlCl, hex., – 55 ºC,
Ro 24-2090 / Ro 23-7553
Me
AcO
Me
4 steps
H
O
Me
OH
H
H
N
Me
Me
Me
Br
O
OTBS
Me O
1. Ac2O, DCM,
BF3•OEt2
2. cyclohexane,
HO
Me
1/11/06
Group Meeting
Me
OTBS
Me
1.
2.
3.
4.
toxicity
NaH, THF, PhNCS
Bu3SnH, hex., AIBN, 50 ºC
TBAF, THF, 48%
Ac2O, TEA, DMAP, DCM, 90%
TDSO
Me
*Note: Fortunately the activity of these compounds is so great that only
several hundred grams are required at peak production, allowing more
flexibility in scale-up operations, specifically in regards to purification and
difficult reaction sequences.*
Me
Me
Acetate required for
subsequent crystallization.
H
H
Me
OAc
Me
AcO
Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 – 89., JACS 1960, 82, 4026.
JOC 1995, 60, 767.
Masterpieces in Process Chemistry II
Richter
Me
Me
Me
R'
Me
Me
R'
Me
H
H
H
AcO
H
AcO
provitamin
lumi-isomer
h!
h!
>305 nm
Me
Caveats of running the Reaction:
1. If using mercury lamp with quartz immersion well and optically inactive
solvent, tachy is the major product, with less than 15% vitamin D form
after thermal isomerization.
2. If using benzene instead, the yield jumps to 15-40%, because the
benzene filters out the shorter wavelengths.
3. Use of 305-320 nm light promotes closure to form the pro- and lumiisomers.
4. Use of 250 nm light then 350 nm light can preferentially form the
previtamin, however the specialized equipment is not readily available
for scale-up.
Optimized Reaction Conditions:
1. Used a standard 450 W low pressure mercury vapor lamp
2. Irradiate in TBME with ethyl-4-dimethylaminobenzoate for 8 hrs (1:3:2:0)
3. Insert a Uranium filter with 9-acetylanthracene (1:5:<0.1:0)
4. Flash Chromatography
5. Reflux in EtOAc 4 hours to give product below in 39% yield.
>305 nm
Me
1/11/06
Group Meeting
R'
Me
*NOTE: In previous Med. Chem. syntheses this step proceeded in 15-30%
on milligram scale with very difficult HPLC separation to give an oil. This
process route produced the first crystals.*
H
RO
previtamin
Me
<270 nm
Me
H
Me
R'
Me
H
Me OAc
H
91%
Synthesis of Ro 23-7553 proceeded in an
analogous manner albiet with lower yields.
AcO
Me OH
HO
H
photosensitized
isomerization
tachy-isomer
Me
NaOH,
EtOH
R'
AcO
AcO
Me
Me
"
h!
Me
Me
Me
Ro 24-2090
Must be stored in
solution for stability
13 steps
6% overall
1 Chromatography
vitamin D
Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 – 89.
JOC 1995, 60, 767.
Masterpieces in Process Chemistry II
Richter
HIV Protease Inhibitors:
– Very interesting story about how structure based drug design has led to
a very potent molecule to inhibit the HIV protease. (Patrick Lam, et.al.
J. Med. Chem. 1996, 39, 3514.
O
N
N
Ph
OH
cost (unnatural)
O
N
Initial Process Route to DMP 323:
safety
NH2
1. CbzCl, 95%
Ph
HO
OH
OH
Ph
H2N Ph
DMP 323
Med. Chem. Route:
safety
NH2
Ph
cost (unnatural)
CbzHN
Ph
HO
2. Swern, 84%
–78 ºC, stench
OH
Ph
epimerize &
polymerize
Ph
Ph
OH
need crystallinaty protecting groups
NHCbz
O
Zn/Cu, VCl3
50%
HO
OH
Ph
1. TESCl, imid.
2. H2, Pd/C
3. CDI
4. HCl, MeCN,
H2O, 78%
waste stream
NHCbz
O
Ph
Ph
HN
NH
HO
OH
Ph
C(CH3)2(OMe)2,
pTsOH, DMF
95%
Avoid protecting
group switch
Zn/Cu, VCl3
O
atom economy
1. KOtBu, THF, 91%
HN
NH
55%
OTr
contains carcinogenic impurity
1. MEMCl, 81%
2. H2, Pd/C
NHCbz
3. CDI, DCM, 76%
Ph
NHCbz
NH2
DMP 450
1. CbzCl, 95%
OH
HO
waste stream
O
N
CbzHN
HO
2. NaOCl, NaBr
TEMPO, 90%
1/11/06
Group Meeting
DMP 323
8 steps
27% overall
No chromatography required
Cl
Ph
O
2. HCl, MeOH,
Tol., H2O, 92%
Me
Ph
O
Me
4. NaH,
OTHP
Cl
unstable, allowed
monoalkylation
Rational for necessity of acetonide to favor bis-alkylation:
5. HCl, 80%
chromatography
OR
O
DMP 323
8 steps
23% Overall
HO
final de of 99.5+%
Used for 5 kg in the kilo lab
N
Bn
N
N
N
O
Ph
HO
OH
Ph
OH
Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 201-219.
R
Bn
R
VS
O
N
N
OR
OR
R
Bn
OR
Bn
JOC 1996, 61, 444.
Masterpieces in Process Chemistry II
Richter
HIV Protease Inhibitors (Continued):
Process Route to DMP 450:
Studies to solve the cyclization problem:
CbzHN
NHCbz
HO
OH
NH2
NH2
1. C(CH3)2(OMe)2
Ph
2. H2, Pd/C, 90%
Ph
O
Ph
O
CDI,
MeCN
Ph
MeO2C
15%
HO
CO2Me
NH2
Ph
O
O
Ph
2. TCE, 147 ºC
67%
Ph
Me
Me
NH
O
O
Me
N
N
O
O
Me
NMe2
Me
pyrophoric
HN
1. CDI, DCM
Me2N
3. DIBAL-H, Tol., –40 ºC;
i-PrOH, –10 ºC;
H2NNMe2, –5 ºC, 85%
OH
Me
Me
1. MeOH, H+
2. C(CH3)2(OMe)2
CSA, Tol., 85 ºC, 85%
O
NH2
1/11/06
Group Meeting
1. Tol., s-BuLi, THF;
H2O, 90%
flammable 2. Ra Ni, MeOH, 100 ºC,
250 psi H2, 85%
required high
dilution of
high-boiling
Ph chlorinated
solvents
Me
NH
HN
O
O
1. TEA, Tol., 80 ºC
NH2
NH2
O
NH2
Ph
O
NH2
O
O
HN
CDI, TEA,
MeCN
Ph
92%
Ph
NH
O
O
Ph
trioxepane is
thermally
unstable and
releases 2
equivalents of
formaldehyde
O2N
Ph
Me
Me
O2N
CHO
2. NaBH(OAc)3,
AcOH, 35 ºC, 96%
Ph
O
Me
O
Me
toxic
1. COCl2, PhCl, TEA, 125 ºC;
MeOH, PhCl, H2SO4, 88%
2. Pd/C, MeSO3H, i-PrOH,
H2O, H2, 90%
O
Concurrently, studies were in progess for a more efficient synthesis of the
pinacol product.
At this time, DMP 323 was canceled and DMP 450 was chosen for
development, necessitating an expedient preparation of this compound.
O
N
H2N
Ph
HO
N
OH
DMP 450
Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 201-219.
Ph NO
2
Ph
NH2
DMP 450
12 steps (5 isolated intermediates)
36% Overall
Used for 20 kg in the pilot plant
Ph
Masterpieces in Process Chemistry II
Richter
Epilepsy Therapy:
Me
Initial Process Route to LY300164:
O
Me
O
NAc
N
O
1/11/06
Group Meeting
O
O
waste
O
O
OH
KMnO4,
racemic
Me
O
1. H2NNHAc
P
2. DIAD, PPh3
0 ºC, 70%
purification
H2N
NO2
NO2
LY300164
Process Route to LY300164:
Slightly Modified Med. Chem. Route:
Me
O
O
O
1. NaBH4
Me
O
2. p-NO2PhCHO,
HCl
O
47% yield, Cr waste 1. CrO3, H2SO4
2. HBF4OMe2
strong acid
Me
O
NO2
NH
N
O
1. H2NNH2
2. BH3•DMS,
Ph
Me
O
Me
O
O+BF4-
NAc
N
O
1. NaOH, EtOH
O
OMs
N
Ph
2. KO2CH, Pd/C
91%
OH
Me
O2N
O
NO2
Me
Me
O
rocket fuel
O
2. p-NO2PhCHO, HCl, 87%
1. air, NaOH,
DMSO
2. H2NNHAc
3. MsCl, TEA,
75%
Me
O
1. Z. rouxii, XAD-7
O
O
O
O
Me
O
NH2
NO2
56% yield
stoichiometric auxiliary (expensive)
1. Ac2O
2. H2, Pd/C
LY300164
8 steps
14% overall
73% ee (raised to 96% w/ recrystallization)
"The most significant issues [with this synthesis] were symptoms of an overall
strategic problem which centered on excessive manipulation of oxidation state"
Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 263–282.
H2N
LY300164
7 steps
3 isolated intermediates
55% overall
99.9% ee
NO2
NHAc
Masterpieces in Process Chemistry II
Richter
Cholesterol Lowering Drug:
First Process Route:
F
F
Cl
F
Cl
AlCl3
1/11/06
Group Meeting
PhNHiPr, EtOH;
COCl
ZnCl2, EtOH, 99%
O
"Since a 2-formylation of indoles had previously not been reported, we had
to invent it."
CO2Na
N
Me
F
OH
F
OH
Me
Lescol
POCl3
Med. Chem. Route:
O
Br
F
2. DIBAL-H
3. MnO2, Et2O
dangerous
total for route
Me
O
OH
3.
4. heat
CHO 3. NaOH, H O,
2
MeOH
Me
spontaneously flammable
Lescol
toxic, removing B to 10 ppm
freeze
too low temperature
drying
poor selectivity (8:2)
F
F
CHO
N
Me
2. MeOAcAc
POCl3, MeCN, 75%
F
PhMeN
N
poor de
1. t-BuNH2•BH3
2. NaOH
H+
–90 ºC
N
Me cost - 67% of
Me
pyrophoric,
waste, expensive
1. BuLi,
Bu3SnCH=CHOEt
toxicity
1. NaH, DMA,
MeI
MeO2C
N
Me
CHO
F
CO2Et
F
PhN2
Me2N
N
+
CO2Et
F
N
H
dangerous
Me
EtOAcAc
F
expensive
1. NaH, BuLi,
THF, MeOAcAc
2. Et3B, NaBH4
New Reaction
Me
CHO
N
Me
Me
O
O
N
Me
SDZ 61-983
11 steps
Very low yeilding
OH
Repic, Oljan. Principles of Process Research and Chemical Development in the Pharmaceutical Industry.
Lescol
6 steps
54% overall
CHO
Me
1. t-BuOAcAc, THF
BuLi, hex., NaH
2. NaBH4, THF
Et2BOMe, MeOH;
H2O2, 73%
3. NaOH, EtOH, H2O
JOC, 1992, 57, 3250.
Masterpieces in Process Chemistry II
Richter
Cholesterol Lowering Drug:
O
F
HO
OMe
1. LiOH, H2O2
THF, H2O
OH
Xc
Ar
2. p-anisidine,
HOBT, DCC
DCM, 80%
(CH2)3Ph
O
Ar
still required 1
Sch 48461
chromatography 5 steps
53% overall
Cl
N
Sch 48461
O
O
OH
Sch 58053
OMe
O
O
O
BuLi, THF;
O
NH
Xc
Ph(CH2)4COCl
OH
Xc
Ar
(CH2)3Ph
O
1. LiOH, H2O2
2. p-anisidine,
HOBT, DCC
80%
p-anisaldehyde
85%
toxic
(CH2)3Ph
Bn
O
pyrophoric,
expensive,
safety issues Bu BOTf,
2
DIPEA, –78 ºC;
OH
ArHN
Bu3P,
DEAD,
Ar
(CH2)3Ph
required 2
chromatographies
(on one step)
80%
Sch 48461
5 steps
54% overall
>99.9% ee
Xc
NH
O
NH
TiCl4, TEA,
TMEDA, –20 ºC;
O
TEA, DMAP;
Xc
Ph(CH2)4COCl
Bn
(CH2)3Ph
p-anisaldehyde
78%
expensive (unnatural)
Gadamasettie, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 221 – 242.
OMe
(CH2)3Ph
Ph
O
Xc
N
BSA;
TBAF (cat.);
NHAr
Ar
MeOH
85%
(CH2)3Ph
Sch 48461
3 steps
55% overall
MeO
Process Route to Sch 58053:
O
HO
OEt
O
2. 4-BnOC6H4CHO, A;
TBAF, 90%
O
i-Pr
ArO2SN
Ar
1. LDA, TMSCl, 95%
OEt
O
A
O
TiCl4, DIPEA,
–20 ºC; 65%,
O
TEA, DMAP;
Ph(CH2)4COCl
Process Route to Sch 48461:
PTC,
85%
(CH2)3Ph
N
O
(EtO)2POCl,
50% NaOH
OH
ArHN
1/11/06
Group Meeting
O
B
H
O
Sch 58053
6 steps
32% overall
O
O
1. 4-FC6H4NH2,
Me3Al
2. (EtO)2POCl,
50% NaOH,
PTC, 59%
Ar
1. 4-ClC6H4MgBr,
80 ºC, 90%
2. 10% Pd/C,
ZnBr2, 70%
Ar'
N
O
O