richter masterpieces in process chemistry ii group … masterpieces in process chemistry ii1/11/06...

Masterpieces in Process Chemistry IIRichter1/11/06

Group Meeting

Selected Syntheses:

Me

OH

Me

OHMe

MeH

H

HO

Vitamin D Analogs: Hoffmann-La Roche

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

Me

Me

H

HO

Me

Me OH

R

HIV Protease Inhibitors: DuPont-Merck

NN

O

PhHO OH

PhHO OH

NN

O

PhHO OH

PhH2N NH2

DMP 323 DMP 450

Cholesterol Lowering Azetidinones: Schering Plough

O

O N

NAc

H2N

Me

Epilepsy Therapy:Eli Lilly

LY300164

N

MeMe OH

OH

CO2Na

F

Cholesterol Lowering: Sandoz

Lescol

"The ideal chemical process is that which a one-armed operator canperform by pouring the reactants into a bath tub and collecting pure product from the drain hole." – Sir John Cornforth

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.

"Graduate school research in organic synthesis resembles chemicaldevelopment much more than it resembles medicinal chemistry: Given atarget molecule, one must design the synthesis and discover and developall reaction conditions to obtain a reasonable yield of the target molecule." – Oljan Repic

NO

OMe

OMe

N

O

FHO

OH

Cl

Sch 48461 Sch 58053

"The mission of process chemistry in the pharmaceutical industry is toprovide documented, controlled synthetic processes for the manufactureof supplies to support the development programs and future commercialrequirements for an active pharmaceutical ingredient (API) or the drug.The mission represents a tremendous challenge to the synthetic skills ofthe process scientists as the requirements for drug supply progress frommilligrams to metric ton quantities." – Kumar Gadamasetti

"Thus, early on in a project, 'Make stuff!' wins out over 'Learn to make itbetter!'" – Richard Mueller


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 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 (2- MeTHF 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.

– 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."

Anderson, Neal G. Practical Process Research & Development.


Group Meeting

Vitamin D Analogs:

Me

OH

Me

OHMe

MeH

H

HO

calcitriol

Me

Me

H

HO

Me

Me OH

R

Me

Me

Me

MeH

H

HO

Me

vitamin D2

Gadamasetti, Process Chemistry in the Pharmaceutical Industry. Pages 73 – 89. JOC, 1995, 60, 6574.

1. SO2

2. TBSCl 97%

Me

Me

Me

MeH

H

TBSO

Me

SO2

1. O3, DCM/ MeOH, – 10 ºC; NaBH4, 87%2. I2/PPh3, imid, DCM, 71%

Me

Me

IH

H

TBSO

SO2

NiCl2/ZnPyridine

CO2Et

Me

Me

H

H

TBSO

SO2

CO2Et

1. NaHCO3, EtOH, 73%2. SeO2, NMO, DCM, MeOH; TBSCl, imid., DCM, 41%

83%

Me

Me

H

H

CO2Et

OTBSTBSO

Me

OH

Me

OHMe

MeH

H

HO

1. MeMgBr, THF, 82%

2. TBAF, THF, 81%3. h!, MeOH, 93%

calcitriolseveral batches100g each10 steps9% overall

expensive

safety, toxicity

chromatography

chromatography

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

Common Process Reactor:

Mixer Drive

Manway

Carbon Steel(Low Temp)

Jacket

Top HeadNozzles

Fin Baffle

Impeller

safety


Group Meeting

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

MeO

O

Me

O

O

3 stepsMe

7 steps

Me

OAcH

CHO

Me OTBSMe

Me

Me

OAcH

OH

Me

Me OTBS

4 stepsMe

Me

H

Me

Me OTBS

O

Ro 24-2090 / Ro 23-7553

Preparation of starting material for Ro 23-7553.

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

OMe

H

H

H

MeHO

HO

OMe

H

H

H

Me

HO

Penicillium

ATCC 12556

Synthesis of Ro 24-2090

OMe

H

H

H

Me

HO

1. Ac2O, DCM, BF3•OEt22. cyclohexane,

OMe

H

H

H

Me

AcO Br

N

NO

Br

Br

OMe

Me1. TBAF, THF2. NaOMe, MeOH3. TDSCl, imid., DCM, 44%

OMe

HH

Me

TDSO

1. EtPPh3Br, Tol., t-BuOK, 94%2. Me2AlCl, hex., – 55 ºC,

Me

HH

Me

TDSO

Me

Me

Me

OTBS

OH

OHC

Me

OTBS

Me

1. NaH, THF, PhNCS2. Bu3SnH, hex., AIBN, 50 ºC3. TBAF, THF, 48%4. Ac2O, TEA, DMAP, DCM, 90%

Me

HH

Me

AcO

Me

Me

Me

OAc

toxicity

effective lowerlimit of cooling

toxicity

Acetate required for subsequent crystallization.

JOC 1995, 60, 767.

*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.*

cost

safety


Group Meeting

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

Me

HH

Me

AcO

MeR'

Me

HH

Me

AcO

MeR'

Me

H

Me

RO

MeR'

MeR'

Me

H

AcO

MeR'

Me

H

AcO

h!

h!

h!

provitamin lumi-isomer

previtamin

tachy-isomer vitamin D

"

<270 nm

>305 nm >305 nm

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 lumi- isomers.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 lamp2. 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 Chromatography5. 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.*

photosensitizedisomerization

Me

Me

H

AcO

Me

Me OAc

NaOH,EtOH

91%

Me

Me

H

HO

Me

Me OH

Ro 24-2090Must be stored in solution for stability13 steps6% overall1 Chromatography

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

JOC 1995, 60, 767.


Group Meeting

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.

Med. Chem. Route:

NN

O

PhHO OH

PhHO OH

NN

O

PhHO OH

PhH2N NH2

DMP 323 DMP 450

Ph

NH2

OH

1. CbzCl, 95%

2. Swern, 84%Ph

NHCbz

O

Zn/Cu, VCl3

55%

NHCbzCbzHN

PhHO OH

Ph

1. MEMCl, 81%2. H2, Pd/C3. CDI, DCM, 76%

4. NaH,

5. HCl, 80%

Cl

OTHP

NN

O

PhHO OH

PhHO OH

DMP 3238 steps23% Overallfinal de of 99.5+%Used for 5 kg in the kilo lab

chromatography

need crystallinaty - protecting groups

contains carcinogenic impurity

unstable, allowed monoalkylation

cost (unnatural)

waste stream

epimerize &polymerize

–78 ºC, stench

Initial Process Route to DMP 323:

JOC 1996, 61, 444.Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 201-219.

Ph

NH2

OH

1. CbzCl, 95%

2. NaOCl, NaBr TEMPO, 90%

Ph

NHCbz

O

Zn/Cu, VCl3

50%

NHCbzCbzHN

PhHO OH

Ph

1. TESCl, imid.2. H2, Pd/C

3. CDI4. HCl, MeCN, H2O, 78%

NHHN

O

PhHO OH

Ph

C(CH3)2(OMe)2,pTsOH, DMF95%

NHHN

O

PhO O

Ph

MeMe

1. KOtBu, THF, 91%

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

Cl

OTr

DMP 3238 steps 27% overallNo chromatography required

Avoid protecting group switch

cost (unnatural)

waste stream

Rational for necessity of acetonide to favor bis-alkylation:

NN

OR

OR

Bn

BnR

O NN

O

Bn

BnR

ROR

ORVS

safety

safety

atom economy


Group Meeting

NN

O

PhHO OH

PhH2N NH2

DMP 450

Process Route to DMP 450:

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

NHCbzCbzHN

PhHO OH

Ph

NH2NH2

PhO O

Ph

MeMe

1. C(CH3)2(OMe)2

2. H2, Pd/C, 90%

CDI,MeCN

15%

NH2NH2

PhO O

Ph

MeMe

1. CDI, DCM

2. TCE, 147 ºC 67%

NHHN

O

PhO O

Ph

MeMe

required high dilution of high-boiling chlorinated solvents

NH2NH2

PhO O

Ph

O

CDI, TEA, MeCN

92%

NHHN

O

PhO O

Ph

O

trioxepane is thermally unstable and releases 2 equivalents of formaldehyde

HIV Protease Inhibitors (Continued):

Studies to solve the cyclization problem:

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.

1. MeOH, H+

2. C(CH3)2(OMe)2 CSA, Tol., 85 ºC, 85%

3. DIBAL-H, Tol., –40 ºC;

i-PrOH, –10 ºC;

H2NNMe2, –5 ºC, 85%

NN

O O

MeMe

NMe2Me2N

CO2MeMeO2C

HO OH

1. Tol., s-BuLi, THF; H2O, 90%2. Ra Ni, MeOH, 100 ºC, 250 psi H2, 85%

NH2NH2

PhO O

Ph

MeMe

1. TEA, Tol., 80 ºC

2. NaBH(OAc)3, AcOH, 35 ºC, 96%

O2N CHO

HNNH

PhO O

Ph

MeMe

O2N NO2

1. COCl2, PhCl, TEA, 125 ºC; MeOH, PhCl, H2SO4, 88%2. Pd/C, MeSO3H, i-PrOH, H2O, H2, 90%

DMP 45012 steps (5 isolated intermediates)36% OverallUsed for 20 kg in the pilot plant

pyrophoric

flammable

toxic


Group Meeting

Initial Process Route to LY300164:

Gadamasetti, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 263–282.

Epilepsy Therapy:

Slightly Modified Med. Chem. Route:

O

O N

NAc

H2N

Me

LY300164

O

O

Me

O

1. NaBH4

2. p-NO2PhCHO, HCl

O

O

Me

O

NO2

1. CrO3, H2SO4

2. HBF4OMe2

O

O

Me

O+BF4-

NO2

1. H2NNH2

2. BH3•DMS,

O

O N

NH

O2N

Me

Me

Me

OH

Ph Ph

NH2

1. Ac2O2. H2, Pd/C

LY3001648 steps14% overall73% ee (raised to 96% w/ recrystallization)

56% yieldstoichiometric auxiliary (expensive)

47% yield, Cr waste

"The most significant issues [with this synthesis] were symptoms of an overall strategic problem which centered on excessive manipulation of oxidation state"

O

O

Me

O

NO2

KMnO4,

0 ºC, 70%

O

O

Me

O

NO2

OH 1. H2NNHAc

2. DIAD, PPh3

Pracemic

waste

purification

O

O

Me

O

Process Route to LY300164:

1. Z. rouxii, XAD-7

2. p-NO2PhCHO, HCl, 87%

O

O

Me

O

NO2

1. air, NaOH, DMSO2. H2NNHAc3. MsCl, TEA, 75%

O

O

Me

OMs

NO2

NNHAc

1. NaOH, EtOH

2. KO2CH, Pd/C 91%

O

O N

NAc

H2N

Me

LY3001647 steps3 isolated intermediates55% overall99.9% ee

rocket fuel

strong acid


Group Meeting

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

Cholesterol Lowering Drug:

Med. Chem. Route:

N

MeMe OH

OH

CO2Na

F

Lescol

F

Br EtOAcAc

FCO2Et

Me

O

PhN2+

NH

CO2Et

F

1. NaH, DMA, MeI

2. DIBAL-H3. MnO2, Et2O

NMe

CHO

F

1. BuLi,Bu3SnCH=CHOEt

2. MeOAcAc

NMe

OH

O

MeO2C

F

1. t-BuNH2•BH3

2. NaOH

3. H+

4. heatNMe

F

O

O

OHSDZ 61-98311 stepsVery low yeilding

expensive

dangerous

dangerous

pyrophoric,waste, expensive

poor de

First Process Route:

AlCl3

COClCl

FF

O

Cl PhNHiPr, EtOH;

ZnCl2, EtOH, 99%

N

MeMe

F

POCl3

Me2NCHO

N

MeMe

CHO

F

1. NaH, BuLi, THF, MeOAcAc2. Et3B, NaBH4

–90 ºC3. NaOH, H2O, MeOH

Lescol

cost - 67% of total for route

spontaneously flammabletoxic, removing B to 10 ppmtoo low temperaturepoor selectivity (8:2)

freeze drying

N

MeMe

F

POCl3, MeCN, 75%

N

MeMe

CHO

F

PhMeNCHO

1. t-BuOAcAc, THF BuLi, hex., NaH2. NaBH4, THF Et2BOMe, MeOH; H2O2, 73%3. NaOH, EtOH, H2O

Lescol6 steps54% overall

New Reaction

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

JOC, 1992, 57, 3250.

toxicity

TiCl4, TEA, TMEDA, –20 ºC;

p-anisaldehyde78%


Group Meeting

Gadamasettie, Kumar G. Process Chemistry in the Pharmaceutical Industry. Pages 221 – 242.

Cholesterol Lowering Drug:

Process Route to Sch 48461:

NO

OMe

OMe

N

O

FHO

OH

Cl

Sch 48461 Sch 58053

ONH

O

Bn

BuLi, THF;

Ph(CH2)4COClXc

O

(CH2)3Ph

Bu2BOTf, DIPEA, –78 ºC;

p-anisaldehyde85%

Xc

O

(CH2)3Ph

OH

Ar

1. LiOH, H2O2

2. p-anisidine, HOBT, DCC 80%

ArHN

O

(CH2)3Ph

OH

Ar

Bu3P, DEAD,

80%

Sch 484615 steps54% overall>99.9% ee

pyrophoric, expensive,

safety issues

toxic

required 2 chromatographies(on one step)

ONH

O

Bn

TEA, DMAP;

Ph(CH2)4COClXc

O

(CH2)3Ph

Xc

O

(CH2)3Ph

OH

Ar

1. LiOH, H2O2

THF, H2O

2. p-anisidine, HOBT, DCC DCM, 80%

ArHN

O

(CH2)3Ph

OH

Ar

(EtO)2POCl,50% NaOH

PTC,85%

Sch 484615 steps53% overall

still required 1 chromatography

expensive (unnatural)

TiCl4, DIPEA, –20 ºC; 65%,

ONH

O

Ph

TEA, DMAP;

Ph(CH2)4COClXc

O

(CH2)3Ph

Xc

O

(CH2)3Ph

NHAr

Ar

N

MeO

OMe

BSA; TBAF (cat.);

MeOH85%


OEt

O

Process Route to Sch 58053:

1. LDA, TMSCl, 95%

2. 4-BnOC6H4CHO, A; TBAF, 90%

ArO2SNBH

O

i-Pr O

OEt

O

HO Ar

O

O

O

O

A

1. 4-FC6H4NH2, Me3Al2. (EtO)2POCl, 50% NaOH, PTC, 59%

N

O

Ar'Ar

O

1. 4-ClC6H4MgBr, 80 ºC, 90%

2. 10% Pd/C, ZnBr2, 70%


richter masterpieces in process chemistry ii group … masterpieces in process chemistry ii1/11/06...

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