Richter

Masterpieces in Process Chemistry II

OMe Me H Me Me OH H H Me Me Me OH O HO Me Me

1/11/06 Group Meeting

Selected Syntheses:
Vitamin D Analogs: Hoffmann-La Roche

Cholesterol Lowering Azetidinones: Schering Plough

F

N N Cl O OH OMe

Sch 48461 calcitriol

HO OH HO R

Sch 58053

R=H Ro 24-2090 R=OH Ro 23-7553

HIV Protease Inhibitors: DuPont-Merck

O N HO Ph N Ph OH H2N Ph N O N Ph NH2

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

HO

OH

HO

OH

DMP 323

DMP 450

Epilepsy Therapy: Eli Lilly

Me O O NAc N

Cholesterol Lowering: Sandoz

F

CO2Na N H2N Me Me OH OH

"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

LY300164

Lescol

Richter

Masterpieces in Process Chemistry II

1/11/06 Group Meeting

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 C. 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 C. 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.

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."

Richter

Masterpieces in Process Chemistry II

Me Me H Me H Me Me

1/11/06 Group Meeting

Me Me H Me Me Me

Common Process Reactor:

Mixer Drive

1. SO2 2. TBSCl 97%

TBSO

H SO2

Manway Top Head Nozzles Carbon Steel (Low Temp) Fin Baffle
HO

vitamin D2 expensive

safety, toxicity
1. O3, DCM/ MeOH, 10 C; NaBH4, 87% 2. I2/PPh3, imid, DCM, 71%
Me Me H I

Me Me H CO2Et

safety

NiCl2/Zn Pyridine
CO2Et

H SO2

Jacket

Impeller

SO2

83%
TBSO TBSO

Vitamin D Analogs:
Me Me H Me Me OH H H Me Me Me Me OH

1. NaHCO3, EtOH, 73% 2. SeO2, NMO, DCM, MeOH; chromatography TBSCl, imid., DCM, 41%
Me Me H CO2Et Me Me H Me Me OH H

1. MeMgBr, THF, 82% 2. TBAF, THF, 81% 3. h!, MeOH, 93% chromatography

calcitriol
HO OH HO R

R=H, Ro 24-2090 R=OH, Ro 23-7553

TBSO OTBS

HO

OH

calcitriol several batches 100g each 10 steps 9% overall

JOC, 1995, 60, 6574.

Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 89.

Richter

Masterpieces in Process Chemistry II

Synthesis of Ro 24-2090
Me O CHO Me H H OAc Me OH Me OTBS HO H H O Me Me Me Me Me Me OTBS Me Me

1/11/06 Group Meeting

Me O Me H H H Br

Original Med. Chem. route to Ro 24-2090 and Ro 23-7553.

O Me O Me O Me

toxicity
1. Ac2O, DCM, BF3OEt2 2. cyclohexane,
Br N O N Br AcO

3 steps
O

7 steps

cost

4 steps

Me Me Me OTBS

1. TBAF, THF 2. NaOMe, MeOH 3. TDSCl, imid., DCM, 44%

Me O

H OAc

1. EtPPh3Br, Tol., effective lower t-BuOK, 94% limit of cooling safety 2. Me2AlCl, hex., 55 C,
OTBS Me Me Me OH TDSO

Me H H

Ro 24-2090 / Ro 23-7553 Preparation of starting material for Ro 23-7553.

Me O Me H HO H H Me O

OHC

Me Me Me OTBS Me

Penicillium ATCC 12556

HO

HO

Me H

H H TDSO

1. 2. 3. 4.

toxicity NaH, THF, PhNCS Bu3SnH, hex., AIBN, 50 C TBAF, THF, 48% Ac2O, TEA, DMAP, DCM, 90%

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

Acetate required for subsequent crystallization.

AcO

Me H H

Me OAc Me

Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 89., JACS 1960, 82, 4026.

JOC 1995, 60, 767.

Richter

Masterpieces in Process Chemistry II

Me Me R' Me H H AcO H H Me Me R'

1/11/06 Group Meeting

Me

AcO

provitamin h!

lumi-isomer

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. *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.*
Me Me Me Me Me H Me OAc H Me Me OH

>305 nm
Me Me Me H RO

h!

>305 nm

R'

previtamin

h!

"

<270 nm
Me Me R' Me Me R'

NaOH, EtOH
AcO

91%

HO

photosensitized isomerization
AcO

Synthesis of Ro 23-7553 proceeded in an analogous manner albiet with lower yields.

AcO

Ro 24-2090 Must be stored in solution for stability 13 steps 6% overall 1 Chromatography

tachy-isomer

vitamin D
JOC 1995, 60, 767.

Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 89.

Richter

Masterpieces in Process Chemistry II

Initial Process Route to DMP 323: safety NH2 1. CbzCl, 95%
Ph OH

1/11/06 Group Meeting

waste stream

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 HO Ph N Ph OH H2N Ph N O N

cost (unnatural)

2. NaOCl, NaBr TEMPO, 90%

Ph

NHCbz O

Zn/Cu, VCl3 50%

O CbzHN NHCbz Ph

1. TESCl, imid. 2. H2, Pd/C 3. CDI 4. HCl, MeCN, H2O, 78%

Ph

HN

NH Ph

HO

OH

HO

OH

Ph

NH2 Ph HO OH

DMP 323 Med. Chem. Route:

DMP 450

HO

OH

safety
NH2 Ph OH

epimerize & polymerize

Ph NHCbz O

waste stream
Zn/Cu, VCl3 55%

Avoid protecting group switch

C(CH3)2(OMe)2, pTsOH, DMF 95%

1. CbzCl, 95% 2. Swern, 84% 78 C, stench

cost (unnatural)

O atom economy 1. KOtBu, THF, 91% HN NH OTr

CbzHN Ph

contains carcinogenic impurity 1. MEMCl, 81% 2. H2, Pd/C NHCbz 3. CDI, DCM, 76%
OH Ph

DMP 323 8 steps 27% overall No chromatography required

Cl

Ph

2. HCl, MeOH, Tol., H2O, 92%

O Me

O Me

Ph

HO

4. NaH,
OTHP Cl

need crystallinaty protecting groups

unstable, allowed monoalkylation

Rational for necessity of acetonide to favor bis-alkylation:

OR

5. HCl, 80% chromatography

O

Bn R

DMP 323 8 steps 23% Overall HO final de of 99.5+% Used for 5 kg in the kilo lab

N Ph

N O Ph OH R

Bn N N Bn OR

VS

O R

N N Bn

OR OR

HO

OH

Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 201-219.

JOC 1996, 61, 444.

Richter

Masterpieces in Process Chemistry II

Process Route to DMP 450: 1. MeOH, H+ 2. C(CH3)2(OMe)2 CSA, Tol., 85 C, 85% 3. DIBAL-H, Tol., 40 C; i-PrOH, 10 C; H2NNMe2, 5 C, 85%
NH2 Ph NH2 Ph

1/11/06 Group Meeting

HIV Protease Inhibitors (Continued):

Studies to solve the cyclization problem: 1. C(CH3)2(OMe)2 2. H2, Pd/C, 90%
Ph HO OH Ph

Me2N

CbzHN

NHCbz

CDI, MeCN 15%

NMe2

MeO2C HO

CO2Me OH

O Me O

O Me

O Me

O Me

pyrophoric
NH

NH2 Ph

NH2

1. CDI, DCM
O Me O Me Ph

HN Ph

2. TCE, 147 C 67%

O Me O

O Me

required high dilution of high-boiling Ph chlorinated solvents

NH HN

1. Tol., s-BuLi, THF; H2O, 90% flammable 2. Ra Ni, MeOH, 100 C, 250 psi H2, 85% 1. TEA, Tol., 80 C
O2N CHO

NH2 Ph

NH2 Ph

NH2 Ph

NH2 Ph

CDI, TEA, MeCN 92%

Ph

HN

NH Ph

O O

O O

trioxepane is thermally unstable and releases 2 equivalents of formaldehyde

O2N

Ph

O Me

O Me

Ph NO 2

2. NaBH(OAc)3, AcOH, 35 C, 96%

O Me

O Me

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.
N H2N Ph

toxic 1. COCl2, PhCl, TEA, 125 C; MeOH, PhCl, H2SO4, 88% 2. Pd/C, MeSO3H, i-PrOH, H2O, H2, 90%
O N Ph NH2

DMP 450 12 steps (5 isolated intermediates) 36% Overall Used for 20 kg in the pilot plant

HO

OH

DMP 450
Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 201-219.

Richter

Masterpieces in Process Chemistry II

Me O O NAc N

1/11/06 Group Meeting

Epilepsy Therapy:

Initial Process Route to LY300164:

O O O Me O O O OH Me

waste
KMnO4, 0 C, 70%

racemic

1. H2NNHAc P 2. DIAD, PPh3

H2N

purification
NO2 NO2 O O O O Me

LY300164 Slightly Modified Med. Chem. Route:

O O O Me

Process Route to LY300164:

O O O Me O O Me

1. NaBH4 2. p-NO2PhCHO, HCl

1. Z. rouxii, XAD-7 2. p-NO2PhCHO, HCl, 87%

47% yield, Cr waste 1. CrO3, H2SO4 2. HBF4OMe2 strong acid

Me O O NH N

NO2 Me O O+BF4O NAc N Me

1. air, NaOH, DMSO 2. H2NNHAc 3. MsCl, TEA, 75%

O

NO2

rocket fuel
1. H2NNH2 2. BH3DMS,
Ph Me Ph OH Me NH2

O O

Me OMs N NHAc

1. NaOH, EtOH 2. KO2CH, Pd/C 91%

O2N

NO2

56% yield stoichiometric auxiliary (expensive)

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 263282.

H2N

NO2

1. Ac2O 2. H2, Pd/C

LY300164 7 steps 3 isolated intermediates 55% overall 99.9% ee

Richter

Masterpieces in Process Chemistry II

First Process Route:
F Cl F

1/11/06 Group Meeting

Cholesterol Lowering Drug:

AlCl3
COCl

Cl

PhNHiPr, EtOH;
O

ZnCl2, EtOH, 99%

CO2Na N Me Me OH OH

"Since a 2-formylation of indoles had previously not been reported, we had to invent it."
F F

New Reaction POCl3

O

Lescol Med. Chem. Route:

Br F

1. NaH, BuLi, THF, MeOAcAc 2. Et3B, NaBH4

N Me Me CHO 3. NaOH, H O, 2

dangerous
Me

N Me

Me2N

CHO

90 C MeOH

EtOAcAc
F F

PhN2

CO2Et

Me cost - 67% of

total for route

expensive

CO2Et N H F

toxicity 1. NaH, DMA, MeI

2. DIBAL-H 3. MnO2, Et2O dangerous
N Me

CHO

pyrophoric, waste, expensive 1. BuLi, Bu3SnCH=CHOEt

2. MeOAcAc

spontaneously flammable Lescol toxic, removing B to 10 ppm freeze too low temperature drying poor selectivity (8:2)
F

POCl3, MeCN, 75%

F N Me O O N Me Me PhMeN CHO N Me Me CHO

MeO2C

poor de 1. t-BuNH2BH3 2. NaOH

O

N Me

OH

3. 4. heat

H+

SDZ 61-983 11 steps Very low yeilding

OH

Lescol 6 steps 54% overall

1. t-BuOAcAc, THF BuLi, hex., NaH 2. NaBH4, THF Et2BOMe, MeOH; H2O2, 73% 3. NaOH, EtOH, H2O

Repic, Oljan. Principles of Process Research and Chemical Development in the Pharmaceutical Industry.

JOC, 1992, 57, 3250.

Richter

Masterpieces in Process Chemistry II

O HO F Xc OH Ar (CH2)3Ph N N O Cl O OH OMe O O Xc

1/11/06 Group Meeting

(EtO)2POCl, 50% NaOH PTC, 85%

Cholesterol Lowering Drug:

OMe

1. LiOH, H2O2 THF, H2O 2. p-anisidine, HOBT, DCC DCM, 80%

ArHN

OH Ar (CH2)3Ph

still required 1 Sch 48461 chromatography 5 steps 53% overall

TiCl4, DIPEA, 20 C; 65%,
(CH2)3Ph
N OMe

Sch 48461

Sch 58053

TEA, DMAP;
NH

Ph(CH2)4COCl Process Route to Sch 48461:

O O O Xc

BuLi, THF;
NH

pyrophoric, expensive, safety issues Bu BOTf, 2 DIPEA, 78 C;

(CH2)3Ph

Ph O Xc NHAr Ar (CH2)3Ph

BSA; TBAF (cat.); MeOH 85%

Sch 48461 3 steps 55% overall

MeO

Ph(CH2)4COCl
Bn

p-anisaldehyde 85% toxic

Bu3P, DEAD, 80%

Process Route to Sch 58053:

O O O OEt

HO O

Ar OEt

O Xc

OH Ar (CH2)3Ph

1. LiOH, H2O2 2. p-anisidine, HOBT, DCC 80%

ArHN

OH Ar (CH2)3Ph

1. LDA, TMSCl, 95% 2. 4-BnOC6H4CHO, A; TBAF, 90%

O O O O

required 2 chromatographies (on one step)

Sch 48461 5 steps 54% overall >99.9% ee TiCl4, TEA, TMEDA, 20 C;

i-Pr
ArO2SN

A
O O

B H

1. 4-FC6H4NH2, Me3Al 2. (EtO)2POCl, 50% NaOH, PTC, 59% 1. 4-ClC6H4MgBr, 80 C, 90% 2. 10% Pd/C, ZnBr2, 70%
O Ar N O Ar'

TEA, DMAP;
NH Xc

Ph(CH2)4COCl
Bn

(CH2)3Ph

p-anisaldehyde 78%

Sch 58053 6 steps 32% overall

expensive (unnatural)
Gadamasettie, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 221 242.