november 21 st 2006

November 21st 2006by Isabelle Bonnaventure

Literature Meeting Charette’s Laboratories

Special Issue: Chem. Rev. 2006, vol. 7

An Overview of Process Chemistryor

“Honey, I blew up the baby!”

Process Chemistry: Contents

I. General Considerations

III. Asymmetric Hydrogenation: behind the scenes

II. High Troughput

IV. Metal Removal

V. Survey

VI. Synthesis of CGS 19755

VII. Synthesis of SB 214857 A

Process Chemistry: General Considerations

Zhang, T. Y. Chem. Rev. 2006, 106, 2583-95.

General Definition: "Make a defined product available to a given specification, on a given scale, in a defined time-frame"

For the pharmaceutical industry, this means scaling up material for - clinical development - toxicity study - processing knowledge (safety and efficacy of the drugs)

Major criteria:

Safety

Quality

Cost

Time

EnvironmentalImpact

DurabilityRobustness


- Heat and mass transfer controls

- Avoid accumulation of unstable or energetic intermediates

- Explosion hazard of static and organic dust (filtration, drying)

- Containment of potent compounds: workers safety in the exposure and elimination of cross-contamination between different process streams and decision to isolate intermediates.

Safety

Process Chemistry: Safety Issues

Barker, A. C.; Boardman, K. A.; Broady, S. D.; Moss, W. O.; Patel, B.; Senior, M. W.; Warren, K. E. H. Org. Process Res. Dev. 1999, 3, 253-55.

First route:OH

CH2CONH2

BrCH2CH2Br

Base

BrO

CH2CONH2

Br

+

genotoxicproperties

PhCH2NH21 9% overall yield

Second route:

2

NH

OH SOCl2, NMP, NMM

71%N

OS

O

NaH, NMP, 2

64%1

O

HN

HO

drug candidateZeneca Pharmaceuticals

ZD 2079

O

HN

1

HO2CH2CH2NOCH2C


First Route:

Second Route:

HO

HN

NH

O

O

O CH2OMe

MMP3 inhibitorPfizer

UK 370,106

OH

O

O

tBuO

Ashcroft, C. P.; Challenger, S.; Derrick, A. M.; Storey, R.; Thomson, M. N. Org. Process Res. Dev. 2003, 7, 362-68.

N

O

O

O

Ph

N

O

O

O

Ph

O

tBuO

NaHMDStBuO2CCH2Br

THF, 78 °C65%

LiOH, H2O2,THF, H2O, 0 °C

85%

OH

O

O

tBuO

OR

O

O

tBuO

Enantioselectivehydrogenation

65%

- 1994: explosion of a 70 gallon drum of H2O2

Pfizer, Groton

- 2002: explosion of BH3·THF



- Heat and mass transfer controls

- Avoid accumulation of unstable or energetic intermediates

- Explosion hazard of static and organic dust (filtration, drying)

- Containment of potent compounds: workers safety in the exposure and elimination of cross-contamination between different process streams and decision to isolate intermediates.

Safety

- Perfecting analytical methods for their detection

Quality

- Establishing procedures for their removal

- Minimising the introduction and generation of impurities

EnvironmentalImpact

- Solvent usage (limit the use of chlorinated solvents)

- E factor: actual amount of waste produced in the process, defined as everything but the desired product

Sheldon, R. A. Green Chem. 2005, 7, 267-78.


Substrates, reagents, catalysts, solvents, filtering media, transportation = 20 45%

Other costs: - labor (operators, analysts, quality control, other supporting personnel) - capital (equipment, instruments, facility depreciation) - utilities (water, steam, electricity, nitrogen, compressed air) - maintenance, waste treatment, taxes, insurance + overhead charges

These cost categories are directly proportional to concentration (space), duration (time), efficiency (yield) of a process

Cost

DurabilityRobustness

- Constant quality of starting material (suppliers)

- Availability of starting materials, solvents and reagents (transportation restrictions, use restrictions (chemical weapon, narcotics), environmental regulations, natural resource depletion)

- Impact on environment

- Adaptability of the process (advances in chemistry science on engineering technology)

- Flexibility of the process (stability and storage of intermediates, adaptable to different equipments and sites)

- Designed process remains the route of choice as long as the product is on the market

- Reproducibility of the process (different teams involved, quality throughout the batches)

Route Scouting / Process Screening(early phase)

Process screening

Optimization

Validation

0.1 g

1 g

10 g

100 g 1 4

4 16

8 48

48 96

Single 1 L reactors with full dosageautomation and online analysis

Multiple 50 100 ml reactor stations,independent temperature control

and dosage opportunities

Multiple reaction blocks (5 100 ml)with low to medium automation degree

Workstations with dispenser,racks, analysis automation

Accuracy / Scale Typical parallelreactions throughput

Process Chemistry: Different Phases

Eckert, M.; Notheis, U. in Handbook of Combinatorial Chemistry,vol.2 (Eds: K. C. Nicolaou, R. Hanko, W. Hartwig), Wiley-VCH, Weinheim, 2002, pp.831-63.

Process Chemistry: Different Phases


Route Scouting / Process Screening(early phase)

Process screening

Optimization

Validation

0.1 g

1 g

10 g

100 g 1 4

4 16

8 48

48 96

Single 1 L reactors with full dosageautomation and online analysis

Multiple 50 100 ml reactor stations,independent temperature control

and dosage opportunities

Multiple reaction blocks (5 100 ml)with low to medium automation degree

Workstations with dispenser,racks, analysis automation

Accuracy / Scale Typical parallelreactions throughput

Route Scouting: "Biocomputers" wanted

Eli Lilly venture Innocentive @ www.innocentive.com You could win a US $ 100 000 reward

Process Chemistry: High Throughput Equipment

Route scouting: - Set of 48 96 experiments at a time

- Study viable routes

1 5 ml vessel

Chemspeed Accelerator

- 1.5 ml - 2 temperatures - 6 pressures - variability of metal, ligand, solvent - robotic dosing system

BASF: hydroformylation of olefin

DSM: phosphoramidite ligands librariesPremex multireactor

Jäkel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912-42.


Process screening: - Target parameters: conversion and selectivity

- Variables screened: solvent, temperature, additive, catalyst, PG, stoichiometry, reaction time, etc.

20 50 ml vessel

50 °C < T < 200 °C

Biotage Endeavor multireator

DSM: phosphoramidite screening in hydrogenation

Dow: asymmetric hydroformylation


Symyx parallel polymerization reactor PPr 48 - 48 catalysts - 3 substrates


Helgroup: HP autoMATE


Process optimization: - Target parameters: kinetics of the reaction, effects of differing rates of addition, stirring speed, effect of heating and cooling ramps on the reaction rates, impurity spectrum

- Work up development

50-250 ml vessel

mechanical stirrer

independent accurate temperature control


BASF: Premex miniautoclave

Simple laboratory plant for continuous processing


Process validation: Thermodynamic characterization, test of the stability of the process, scale up

1 2 L vessel

With HTE, 96 experiments at least are set = at least 96 analysis

Need for High Throughput Analytical Instruments

1Infrared Spectroscopy: measure the temperature change in a given reaction usually used for heterogeneous catalysis

Optical Techniques:

2Colorimetric Assays: easiest technique

B A DYE+

B A DYE

+ unreacted material

Wash

Solution

phase

Solid

phase

A DYE

MLn

+ MLn, By products

B A DYE

B

Process Chemistry: High Throughput Analysis

1Reetz, M. T.; Becker, M. H.; Kühling, K. M.; Holzwarth, A. Angew. Chem. Int. Ed. 1998, 37, 2647-50.2Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123-32.

3Reetz, M. T.; Kühling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew. Chem. Int. Ed. 2000, 39, 3891-93.

Process Chemistry: High Throughput Analysis

HighVoltage

anode cathode

capillary

detector

Buffersolutions

3Chiral Capillary Electrophoresis: >7000 ee separation per day

Common Techniques: HPLC, GCMS and NMR

Process Chemistry: Ligand Synthesis

Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23-39.

Me

PCy2

Me2N

PCy2iPr

PCy2

iPr

iPr

Ligands for C N coupling reactions:

1 2 3

Me

MgBr

Br

Cl

MgBr

Me

+Cy2PH

CuCl (cat.), 60 °C

Me

PCy2

Mg turnings were used instead of powder

Mg was added in 2 batches

Slow addition of the reagentsRq: the addition of aryl bromide to Mg could, theoretically, produced the heat to evaporate 93% of the initial THF

50%

10 kg / batch(Rhodia)

For 1 and 2:

1

Mg


Process Chemistry: Ligand SynthesisFor ligand 3:

Cl

NH2

Cl

NMe2

Methylation

Methylation attempts:

CH2O, HCO2H, NaBH3CN: good on small scale but polymeric by products observed on large scale

Me2SO4 in alkaline soln: - good on both small and large scale

- but tedious aqueous work up: addition of an excess of SM to the RM solved that problem

- but monomethylated and product were not separable by distillation (1 °C difference) which was solved by addition of Ac2O to transform the monomethylated product into acetanilide

MgCl

NMe2

Grignardformation

Grignard formation: - aryl halide was added slowly (analytical checks)

- took 8 12 h to go to completion

MgCl

Me2N

Biphenylformation

Biphenyl formation: Wurtz type coupling products observed for long reaction times and if excess of reagent is used

Me2N

PCy2

C P coupling

C P coupling: CuI / LiBr was preferred to CuCl (more homogeneous, easier work up)

63%

3

Process Chemistry: Ligand Synthesis


250 L vessel for pilotscale production of ligand 1 and 2

150 L vessel for pilotscale production of ligand 3

Process Chemistry: Ligand Library

de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799-811.

Homogeneous Catalysis

Key success factors: - the rate of the reaction expressed as the TOF (TurnOver Frequency) TOF = moles of product / moles of catalyst x hour

- the stability of the catalyst expressed as the TON (TurnOver Number) TON = moles of product /moles of catalyst

Economics = decisive factor in the choice of production methods

But ... some metals may be quite expensive as well as ligands

screening of a reaction usually involves screening of a broad spectrum of ligand types

Necessity to define ligand libraries

For example, chiral bis(phosphane) ligands will cost 45 000 150 000 / kg


Gao, X.; Kagan, H. B. Chirality 1998, 10, 120-24.

Supported catalysts under heterogeneous or homogeneous conditions

Ligand Metal

Anchoringagent

1heterogeneous

2homogeneous

Solid Support

CatalystSolid Support

Drawbacks: - Few viable processes, very substrate specific, metal leaching, less active,

- Optimization necessary, loss of their activity and selectivity on separation, re use difficult

1Gilbertson, S. R.; Wang, X. Tetrahedron 1999, 55, 11609-618.2Augustine, R. L.; Goel, P.; Mahata, N.; Reyes, C.; Tanielyan, S. K. J. Mol. Catal. A: Chem. 2004, 216, 189-97.

Multi-substrate screening procedure

Substrates (up to 7)

Catalyst

Reagent

Requirements: - SM, products peaks should not overlap with each other

- Substrates and products should not interfere during the reaction (e.g. autocatalysis)


O

OMe

NHAc

Ph

LRh(COD)2BF4

H2, DCM

O

OMe

NHAc

Ph

96 ligands tested within 1 day

hits

Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Org. Lett. 2004, 6, 1733.

Easily tunable ligands:

P N

O

O R2

R1

P

O

O

Cl HN

R2

R1

+

Phosphoramidite type ligands: - Highly tunable

- SM commercially or easily available

Process Chemistry: Ligand LibraryBuy them from suppliers: Solvias, JM catalysts, Chiral Quest

BINAP analogs DuPHOSanalogs

Ferrocenyl-basedLigands

P-chiralLigands

Monodentate Ligands

Process Chemistry: Legendary Example

Blaser, H-U. Adv. Synth. Catal. 2002, 344, 17-31. Blaser, H-U.et al in Asymmetric Catalysis on Industrial Scale,(Eds: H. U. Blaser, E. Scmidt), Wiley-VCH, Weinheim, 2004, pp.55-70.

Behind the scenes ....

Milestones in the history of metolachlor:

NO

O

Cl

(S) metolachlor (Dual®)

Syngenta most important herbicide>10 000 tons / year

16 years study


Blaser, H-U. Adv. Synth. Catal. 2002, 344, 17-31. Blaser, H-U.et al in Asymmetric Catalysis on Industrial Scale,(Eds: H. U. Blaser, E. Scmidt), Wiley-VCH, Weinheim, 2004, pp.55-70.

Behind the scenes ....

Milestones in the history of metolachlor:

NO

O

Cl

(S) metolachlor (Dual®)

Syngenta most important herbicide>10 000 tons / year

16 years study

4 stereoisomers: - 1 atropisomerism - 1 stereogenic center

Process Chemistry: Legendary Example4 routes were defined

- Enamide hydrogenation

"Selective synthesis for one particular enamide isomers was judged to be difficult"

NO

O

Cl

- Nucleophilic substitutionO

OMe

OTs

OMe

NH R

+1. Enantioselective H2

2. TsX(S) metolachlor

- Pt cinchona catalyzed hydrogenation on methoxyacetone ??

- Nucleophilic substitution: weak nucleophile, no activation of the leaving group

- Imine hydrogenationN

O

MEA imine

H2(S) metolachlor

H2(S) NAA

Only 1 example of imine hydrogenation (22% ee)

Catalyst

Nucleophilic

substitution

Catalyst

- Direct catalytic alkylation

OH

OMe

NH2

+Chiral

Catalyst(S) NAA

Based on N alkylation of aliphatic amines with alcohols using Ru phosphine catalyst

Process Chemistry: Legendary Example- Enamide hydrogenation

- Nucleophilic substitution

- Imine hydrogenation

- Direct catalytic alkylation

3 isomers prepared with >95% purity

No conversion with 7 different Rh-diphosphine catalysts (50 °C, 1 bar)

O

OMe *OH

OMe

cinchonidine modified Pt / CH2

12% ee

NO

MEA imine

(S) NAA

cinchonidine modified Pt / CH2

0% ee

Not tested

J. P. Kutney from UBC: 69% ee ( 25 °C), TOF = 15h 1, TON = 1000 (65 bar, rt) on DMA with Rh cycphos

cycphos:PPh2

PPh2


First Major breakthrough (1985): Ir catalyzed imine hydrogenations

- 84% ee reached (original goal) with Ir bdpp but TOF < 150h 1

- TON = 10 000 (goal was 40 000) with Ir diop but 63% ee

But catalyst deactivation during the reaction

1987: End of project, results were patented and published

Philosophy: "Try the impossible and succeed or fail with grandeur"

Second Major breakthrough (1992): Xyliphos

Fe PPh2

P

Me

2

s/c = 800, 73% ee, 6h

no catalyst deactivation"S DUAL Breakthrough Party"

Third Major breakthrough (1993): AcOH and I2

TON > 600 000, 76% ee, 50h

Xyliphos

Process Chemistry: Legendary ExampleFrom laboratory procedure to the first production batch

- MEA imine: multi step continuous distillation process (recovery of solvent and non reacted SM)

80 bar, 50 °C, 4h s/c > 1 000 000, TOF = 1 800 000h 1, 79% ee

- Xyliphos was synthesized on a 100 kg scale in 2500 L reactors

- Catalyst formulation: liquid, highly active catalyst formulation stable over several months

addition of the catalyst was safer and easier

- Reactor technology: loop reactor

The reaction mixture is pumped via a heat exchanger through a nozzle where H2 is fed into the reaction solution (good mixing and exchange surface)

- Optimization of reaction medium and conditions:


- Scale up of the process:

1. Laboratory procedure developped in a 300 ml reactor2. Production of 100 kg of enriched metolachlor in a stirred tank 50 L autoclave3. (2.) was reproduced on a loop reactor of the same size4. First tons were produced in a dedicated 1000 L loop reactor

- Work up:

1. Continuous aqueous extraction (neutralization and elimination of acid from the crude)2. Flash distillation (residual water removal)3. Catalyst separation from the (S) NAA by distillation on a thin film evaporator

- Ir is recovered- Xyliphos is lost

In the end

November, 16th 1996: 10 tons of (S) NAA (79% ee) are produced with 34 g of Ir, 70 g of Xilyphos in 2 h, 99.6% conversion

No major changes needed for the plant

Sandmeyer Prize 1999 of the New Swiss Chemical Society

Process Chemistry: Metal Removal

1Note for Guidance on Specification Limits for Residues of Metal Catalysts, The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use; London, 17 December 2002; http://www.emea.eu.int

Absorption of palladium is highly dependent on its chemical form:

PdCl2 (i.v. administration): 3 mg / kg body weight

PdO (oral administration): >4900 mg / kg body weight

Element Oral PDE (g/kg/day) Parenteral PDE (g/kg/day)

Pt, Pd, Ir, Rh, Ru, Os

Mo

V

Cu

Ni

Cr

Mn

Zn

Fe

2.6

5

10

50

20

25

100

300

250

0.25

2.5

0.5

10

2

2.5

5

30

25

PDE = Permitted Daily Exposure

1Specification limits for residues of metal catalysts:

LD50 (rats, mice, rabbits):

Concentration (ppm) =(y / 100) x PDE x Body weight

Dose

y = % of PDE apportioned to drug substancePDE = permitted daily exposure (g / kg / day)Dose = daily intake of the drug substance in g / dayBody weight expressed in kg (standard is 60 kg)

Element Oral concentration Limit (ppm) Parenteral Concentration Limit (ppm)

Pt, Pd, Ir, Rh, Ru, Os

Mo, V, Ni, Cr

Cu, Mn

Zn, Fe

5

10

15

20

0.5

1

1.5

2

Procedure for determining limits


MS

Garrett, C. E.; Prasad, K. Adv. Synth. Cat. 2004, 346, 889-900.

How to detect such low level of metal in a given sample?

- USP metal test (visual) MH2S

buffer solnMS

coloured precipitateppm level

- Atomic Absorption Spectroscopy

Measure the concentration of gas-phase atoms using their absorption of light

ppb level

- ICP-MS

Samples are decomposed to neutral elements in a high temperature argon plasma and analyzed by MS

ppt level

Usually used to analyse several metal in one analysis

Usually used to analyse one metal at a time


Garrett, C. E.; Prasad, K. Adv. Synth. Cat. 2004, 346, 889-900.

Heterogeneous catalysis: simple filtration except when metal leaching into the medium

Homogeneous catalysis:

- Adsorbents

- Distillation

- Extraction

- Crystallization

Optimization needs to be done on the solvent wash

Requires at least 24h

N N

NHS

SH

SH

TMT(and supported TMT)

NH

N

NH2

NH2

PS

PS bound EDA

Activated carbon(carbon cartridges available)

Glass Bead sponges

SmopexTM (polyethylene or cellulose based fibers with FG)

Silica bound scavengers

SHSi

Usually to remove the last traces of metal

N acetylcysteineHO

O

NHAc

SH

N acetylcysteine / L cysteine

PBu3 / lactic acid

PBu3

Process Chemistry: Survey

General data:

Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2004, 4, 2337-47.



Summary of reaction categories:

C-C bond forming reactions: Pd catalysis (Suzuki, Heck)

Ester condensation

Organometallic (Aryl-Met,Directed lithiation, Grignard)Friedel-Crafts

Other



Protections

Amino (Boc, Bn, Cbz)

Hydroxyl (Bn, SiR3, Ac)

Carboxylic acid

other

Deprotections

Amino (Boc, Bn, Cbz)

Carboxylic acid

Bn, SiR3, phenol

Thiol

Other



Relative induction Asymmetric

synthesis

ResolutionPurchased

Where does chirality come from?

Process Chemistry: Synthesis of CGS 19755

Giannousis, P.; Carlson, J.; Leimer, M. in Process Chemistry in the Pharmaceutical Industry,(Ed: K. G. Gadamasetti), Marcel Dekker Inc., New York, 1999, pp.173-88.

NH

CO2H

P(O)(OH)2

CGS 19755

Antiischemic agent in the treatment of stroke and head trauma

Discovered in 1985

Challenges: - Not a thermally recrystallizable solid

- Polyionic nature and low solubility in organic solvents

- Hydrochloride salt generated esterification by products from crystallization from alcohols


N

OH

N

Cl

N

P(O)(OEt)2

N

P(O)(OEt)2

CN

N

P(O)(OEt)2

CONH2NH

P(O)(OEt)2

CONH2 NH

P(O)(OH)2

COOH

SOCl2

DCM

93%

1. NaOH / toluene

2. NaH, HP(O)(OEt)2

1. m CPBA, DCM

2. TMSCN, Et3N

91%

1. H2SO4

2. H2O

71%

H2 / PtO2, AcOH

100%

1. 6N HCl

2. EtOH, H2OO

74%( ) CGS 19755

Medicinal Route:

- cis:trans = 95:5 ratio

- Use of m CPBA, TMSCN, propylene oxide, 2 is highly irritating

·HCl

100g, 200$ (Aldrich)

1 2 3 4

5 6cis:trans = 95:5

Drawbacks:

88%


N

P(O)(OEt)2

N

P(O)(OEt)2

CN N

P(O)(OEt)2

CONH2

NH

P(O)(OEt)2

CONH2 NH

P(O)(OH)2

COOH

1. m CPBA, DCM 77%2. TMSCN, Et3N 88%

1. H2SO42. H2O 71%

H2 / PtO2, AcOH100%

1. 6N HCl2. EtOH, H2O

O

74%

2. i. (CH3O)2SO2 MeCN ii. NaCN / H2O 84%

1. NaOEt / EtOH2. HCl / H2O 65%

COOEt

COOEt

65% 0. i. NaOH / EtOH ii. HCl / MeCN 65%1. 50%, >99.5% purity2. NaHCO3 / H2O 84%

First scale up:

Objective: avoid the presence of the trans isomer

too exothermic

300 g, 6.3% yield

intermediates purification difficult due to not recrystallizable solids

3 4

6

5

cis:trans = 95:5

( ) CGS 19755

Drawback:


N

OH

N

P(O)(OEt)2

N

P(O)(OEt)2

CONH2 N

P(O)(OH)2

COOH

NH

P(O)(OH)2

COOH NH

P(O)(OH)2

COOH NH

P(O)(OH)2

COOH

1. SOCl2, DCM then1. NaOH / toluene2. NaH, HP(O)(OEt)2 85%

1. SOCl2, DCM2. NaOH / toluene3. HP(O)(OEt)24. t AmOK / toluene 11% of by product5. Distillation 57%

Cyanation followedby hydrolysis

1. HCONH2, H2SO4, (BzO)22. DCM3. n BuOAc 44%

6N HCl,reflux

1. H2 / 5% Rh / C NaOH / H2O2. HCl / H2O Acetone 90%

H2 / PtO2, AcOH65%

PiperidineH2O / EtOH

77%

6N HCl50%

1. HCl / H2O / IPA2. NaOH / H2O3. HCl / H2O 89%

crude <1% trans isomerdifficult to monitor by analytical techniques

Advantages: - 5 and 7 are stable and recrystallizable solids

- recrystallization of adduct 9

- one pot conversion (3 to 5)

7

13.8%, 51 kg

Second scale up:

Objective: rapidity and cost

3 51

( ) CGS 197558 9

·Pip

cis:trans = 90:10

Drawbacks: - isolation of 3 lengthy

- low yield in the one pot conversion

- cis:trans ratio

89%


N

P(O)(OEt)2

N

O

1. HP(O)(OEt)2 LiNH2, toluene2. EtOAc3. H3PO4, EtOH 64%

from corresponding alcohol: 57%

N

P(O)(OEt)2

CONH2

1. HCONH2, H2SO4, (BzO)22. DCM3. n BuOAc 44%

1. HCONH2, H2O (NH4)2S2O82. DCM, extraction

Solvent exchange /6N HCl, reflux

56%

N

P(O)(OH)2

COOH

1. Piperidine H2 / 4.5% Pd 0.5% Rh / C, MeOH

2. i PrOH3. EtOH 79% N

H

P(O)(OH)2

COOH NH

P(O)(OH)2

COOH

1. HCl / H2O / IPA2. NaOH / H2O3. HCl / H2O 89%

Advantages: - cheaper SM (100 g, 96$ (Aldrich))

- 3 isolated as a solid

23% overall yield

Optimal scale up:

3 5

( ) CGS 197557

·Pip

·H3PO4

9

cis:trans = 97:3

- one pot conversion 3 to 7

- only 4 isolations

Process Chemistry: Synthesis of SB214857A

NH

NMe

O

MeO2C

N

O

HN ·HCl

Lotrafiban SB 214857 AGSK

Potent non peptidic glycoprotein IIb/IIIa receptor antagonist to prevent platelet aggregation and thrombus formation


NH

NMe

O

MeO2C

NH

NMe

O

MeO2C

N

O

HN ·HCl

NO2

Lotrafiban SB 214857 AGSK

Potent non peptidic glycoprotein IIb/IIIa receptor antagonist to prevent platelet aggregation and thrombus formation

NH

NMe

O

MeO2C

N

O

HN ·HCl

OH

Miller, W. H.; Ku, T. W. et al Tetrahedron Lett. 1995, 36, 9433-36.


BrMg Me

F

t-BuO2C Me

F

t-BuO2C

F

NHMe

t-BuO2C

F

NMe

O

CO2Me

NH2

NH

NMe

O

CO2Me

t-BuO2C

t-BuO2C

F

NMe

O

CO2Me

+

NH

NMe

O

CO2Me

HO2C

NH

MeN O

CO2MeN

O

BocN

1. CO2, THF 77%

2. isobutylene TfOH (5 mol%)

Et2O, 78 °C to rt sealed pressure bottle

94%

1. NBS, (PhCO)2O2, CCl4, reflux

2. MeNH2 (40% H2O) THF 70%

1. Cbz-L-Asp--Me-ester DCC, HOBt·H2O, DMF

86%

2. H2, 10% Pd / C, MeOH 98%

DMSO (0.1M)125 °C

6:4 ratio

47%

anisoleDCM / TFA (1:1)

95%

1-Boc-4,4'-piperidineEDC, DIPEA, DMF

94%

1. 2N NaOH (2 equiv) MeOH / THF (1:1) then AcOH, 81%2. 4M HCl, CHCl3 then 1N KOH / EtOH 75%

3. precipitation from aqueous soln (pH 6.8) 83%

> 99:1 ratio (S:R)

Discovery route:

50 ml, 67$ (Aldrich)

SB 214857 A


Morgan, D. O.; Wells, A. S. Org. Process Res. Dev. 2003, 7, 655-62.

NO2 NO2

Br

NH

CO2Me

NMeBoc

MeO2C

NH

NMe

O

MeO2C

OH

NO2

NHMe

NH2

NMeBoc

NH

CO2Me

NMeBoc

MeO2C

NH

CO2Me

NHMe

MeO2C

Bromination Amination 1. Protection

2. Hydrogenation

Michael reaction Reduction Deprotection

Cyclization

- lengthy route

- oily intermediates

- lachrymatory material

- by products

Drawbacks:

+ by products

First scaleup route:


NO2 NO2

OMs

NH

NMe

O

MeO2C

OH

NO2

NHMe

NO2

NMe

MsCl, Et3NTHF

MeNH2 aq.12 equiv

92%

EtOAc

100%

Pd / C, NaBH4,MeOH, H2O

93%

- lengthy route

- too much extraction steps

- by products

Drawbacks:

+ by products

CO2Me

CO2Me

NH2

NMe

CO2Me

CO2Me

Pd / Ccyclohexene

5 equiv

92%NH

NMe

O

MeO2C

NH

NMeCO2Me

CO2Me

AcOHMeOH

94%

NaOMeMeOH

95%

MeOCO OCOMe

Scaleup route:


Never subjected to scaleup (clinical programme was halted at phase III)

Alternative scaleup route:

CHO

NO2 NH2

NHMe

NH

NMe

O

MeO2C

NH

NMe

O

MeO2C

1. MeNH2, NaBH4 MeOH, H2O

2. H2, Pd / C, MeOH 97%

1. MeOH,2. AcOH, MeOH

3. NaOMe, MeOH 68%

MeOCO OCOMe NH4CO2HPd / C, MeOH

93%

Process Chemistry: Synthesis of SB-214857-A

Carey, J. S.; Wells, A. S. Org. Process Res. Dev. 2003, 7, 663-75.

NH

NMe

O

MeO2C

NH

NMe

O

MeO2C

NH

NMe

O

HO2C

NH

NMe

O

HO2C

I

NH

NMe

O

HO2C

N

O

N

NH

NMe

O

HO2C

N

O

HN

Novozym 435,t BuOH, H2O,

NH3, pH 7

NaOMe, MeOH(MeO)2CO, 38%

Py ICl, H2ONaOH, pH 7

38%

PdCl2(PPh3)2, COanisole,86%

N

NH

1. H2, Pd / C, i PrOH2. Py·HCl, IMS DCM, H2O 78%

·HCl

+

25% overall yield

End of the synthesis:

Process Chemistry: Conclusion

Process Chemistry:

- The link between medicinal chemistry and drug manufacturing (pharmaceutical industry)

- Major factors: Safety, Quality, Environmental impact, Cost, Durability / Robustness

TIME

Process Chemistry: Conclusion

Process Chemistry:

- The link between medicinal chemistry and drug manufacturing (pharmaceutical industry)

- Major factors: Safety, Quality, Environmental impact, Cost, Durability / Robustness

TIME

Chemical Transformations:

- Think simple and practicle

- Chiral Compounds: - Buy chirality

- Asymmetric Hydrogenations

- Resolution (diastereomeric crystallization or enzymatic) - Enzymatic processes

Process Chemistry: Bulk Chemistry vs Fine Chemistry

Variable/Constraint Basic Chemicals Fine Chemicals

Scale of the process

Plant

Time line

Ratio material costs per total costs

Budget for process screening

1000 100 000 tons 0.01 1000 tons

Continuous

Dedicated

Batch

Multipurpose

1 10 years 10 days to 2 years

High Low

LowHigh


Bulk chemicals: priority = cost of the product radical new approaches are often pursued to effect the large reduction in cost (an improvement in the reaction selectivity of less than 1% saves several million $)

Fine chemicals: priority = time to market much smaller quantities and shorter lifetime (generics) strict quality requirements

Process Chemistry: High Throughput Experimentation

de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799-811.

High throughput experimentation = Screen all parameters to their full extent in a reasonable amount of time

1999: the cost and time to develop a new drug averaged $500 million and 15 years

Parameters for HTE in homogeneous catalysis:

Requirements for HTE in homogeneous catalysis:

Hardware (robots), Software and data handling,

Libraries of ligands and catalysts, Fast analysis

Metal, Counterion, Ligand, Metal/Ligand ratio, Method of catalyst preparation, Substrate/catalyst ratio, Reactant,

Solvent, Temperature, Pressure, Substrate/reactants ratio, Concentrations of catalyst, substrate and reactants,

Order of mixing catalyst and reactants, Rate of addition of one or more reactants, pH, Additives (acids, bases, R4N+X )

november 21 st 2006

Documents

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