The document describes improvements made to the process for manufacturing the potential therapeutic compound ELN 296571. It summarizes the original multi-step synthesis route and key intermediate compound ELN 361973. The route was optimized to require fewer steps and produce ELN 361973 in higher yields and purity. Later, production of the important intermediate ELN 361973 was outsourced to improve the overall process.

1. Process Improvements Resulting in the Successful
Manufacture of ELN 296571
David A. Quincy
Scientist Process Chemistry

2. ELN 296571 as a Potential Therapeutic
• Inhibits α4β1 (VLA-4) and α4β7 Integrin,
thereby inhibiting cell adhesion and cell
trafficking.
• Has potential use for the treatment of
Multiple Sclerosis, Inflammatory Bowel
Disease, Rheumatoid Arthritis, Tumor
Metastasis, Alzheimer’s Disease, Asthma,
and other medical conditions.
1. Stappenbeck, Frank; Konradi, Andrei; Jagodzinski, Jacek; Semko, Christopher M.; Xu, Ying-Zi; Smith,
Jenifer L.; Rossiter, Kassandra; PCT Int. Appl. (2006), WO 2006127584 A1 20061130.
2. Semko, Christopher Michael; Xu, Ying-Zi; Stappenbeck, Frank; Smith, Jenifer Lea; Rossiter, Kassandra
Inez; Fukuda, Juri Y.; Konradi, Andrei W.; PCT Int. Appl. (2007), WO 2007041270 A1 20070412.
3. Semko, Christopher Michael; Xu, Ying-Zi; Stappenbeck, Frank; Smith, Jenifer Lea; Rossiter, Kassandra
Inez; Fukuda, Juri Y.; Konradi, Andrei W.; PCT Int. Appl. (2007), WO 2007041324 A1 20070412.

3. The Original Med. Chem. Route
O N
O Cl 1. Tyr-OtBu, DIEA OH N
POCl 3 N
PhNMe2 2. Et2NH pyrrolidine carbamyl O
HN NH N N chloride N N
N N
One pot Et 3N, DMAP, O
O Reflux, then Cl O N
Distill THF, -10 deg N CH2Cl 2, reflux H
NO 2 NO 2 H NO 2 O
NO2 O
ELN 118853 ELN 361973
10% Pd/C (5% w/w)
5% H2O in THF
H2, 60 psi, 24 hrs
O N O N
N N O N
N
O MeSO2Cl, O PtO2, H2,
N N N N O
pyridine EtOH, 3 eq. Acetone, N N
O O 0.5 eq. AcOH
N 0oC-RT N O
H H N
N O HN O H
S NH2 O
O O
ELN 477943 ELN 441098
• Eight Steps in 7 “pots”
o
1. HCO2 H, 70 C
2. 1N HCl
• Utilizes a Pd catalyzed reduction followed
immediately by a PtO2 catalyzed reduction
O N
N
O
N N
N CO2H
• ELN 441098 only 70-87% pure (>3 impurities)
S
N
H
HCl • ELN 477943 purified by Chromatography
O O ELN 296571

4. ELN 361973 – A Key Intermediate
POCl3 OH
O Cl 1. Tyr-OtBu, DIEA N
PhNMe2 2. Et 2NH
HN NH Reflux, 115oC N N N N
THF, -10 deg
2 hrs. (One pot) O
O Cl N
H
NO2 64% yield NO2 NO2 O
400 g 316 g ELN 118853
(219 g) 577 g crude
now commer cially
available f r om AK Scientif ic pyrrolidine carbamyl
chloride
Et3N, DMAP,
CH2Cl2, reflux
O N
N
O
N N
O
N
H
NO2 O
ELN 361973
Chromatography & Crystallization
351 g (pure)
118 g (mixed)

5. Preparation of ELN 361973
Later, production of ELN 361973 is outsourced.

6. Original Route – Later Steps
O N O N
N N
O O
N N 5% H2O/THF, N N
O 5% Pd/C, 60 psi H2, N
O
N 16 hrs H
H NH2 O
NO2 O
ELN 361973 Uses two catalysts Prone to Air Oxidation
EtOH, 3 eq. Acetone,
0.5 eq. AcOH
PtO2, H2, overnight
O N O N
N N
MeSO2Cl,
O O
N N pyridine N N
N
O 0oC-RT O
H N
Me N O H
S HN O
O O
ELN 477943 ELN 441097
Purified by Chromatography Somewhat Prone to Air Oxidation
Low purity, 13-30% impurities

7. Improvements to the Process
O N O N
N N
O O
N N 1) 5% H2O in THF, N N
O PtO2, 60 psi H2, 4 hrs O
N N
H 2) 1.5 eq. Acetone, HN
H
O
NO2 O
0.25 eq. AcOH, EtOH
ELN 361973 H2 (60 psi), overnight ELN 441097
High purity, 90-95%
• Telescoped the two reductions into one pot. MeSO2Cl,
pyridine
• Adjusted reagent load to achieve high purity 0oC-RT
• Discovered penultimate cmpd could be
crystallized, though still required chromat. N
O N
O
N N
O
Purif ied by Chromatography, N
H
then crystallization from EtOAc + MT BE / Me N O
S
cyclohexane O O
ELN 477943

8. Process Improvements – Generation 2
O N
N
O
N N
O
N
H
HN O
ELN 441097
High purity, 90-95%
THF,
L-Tartaric Acid
CH2Cl2
O N
N
O O N
N N 1) free base N
O 2) 3 eq. MeSO2Cl, O
N N N
Me N
H
O
pyridine O
N
S 0oC-RT H
O O OH HN O
ELN 477943 HO2C
CO2H
Still required chromatographic HO
pre-purification in order to crystallize Precipitated white solid
95-98% pure

9. Generation 3 – Refinements
(as implemented by CMO)
O N
N
O
N N
O
N
H
HN O
ELN 441097
High purity, 90-95%
L-Tartaric Acid,
Toluene,
concentrate,
i-PrOH
O N
N
O O N
N N 1) free base N
O 2) 1.3 eq. MeSO2Cl, O
N N N
Me N
H
O
Toluene, 1.3 eq. Et3N O
N
S 0oC-RT H
O O HN O
OH
ELN 477943 HO2C
CO2H
Could be crystallized from HO
MTBE - Methylcyclohexane Precipitated white solid
without pre-purification, but 97-99% pure
unnecessary due to the 76% isolated yield (up from ~60%)
high purity of precursor

10. ELN 296571 - Final Step
O N O N
N N
N N
O 1) HCO2H, 70oC, 2-4 hrs. N N
O
O 2) neutralize OH
N N
H H
Me N O Me N O
S S
O O O O
ELN 477943 ELN 296571
Discovered API crystallized from
Acetonitrile

11. Major Contributions
• Telescoped the reduction/reductive amination into
a single pot with a single catalyst.
• Adjusted reagent stoichiometry to achieve high
purity for ELN 441098
• Discovered that ELN 441098 formed a reasonably
insoluble salt with L-Tartaric acid that provided an
isolable high purity intermediate following
trituration.
• Discovered ELN 477943 could be crystallized /
precipitated under certain conditions.
• Discovered ELN 296571 could be crystallized from
Acetonitrile.

12. Result
• ELN 296571 has been successfully
manufactured on > 100 kg scale

13. Acknowledgements:
• Elan Pharmaceuticals
• Michael Dappen, Lee Latimer, Chris
Semko, Jenifer Smith, and Andrei
Konradi

14. From: Anna Marie M.
Sent: Wednesday, January 26, 2011 10:23 AM
To: Hing S.; John S.; Mark H.
Cc: Quincy, David; Ted Y.; Chris F.
Subject: Presentation Approval: Process Improvements Resulting in the
Successful Manufacturing of ELN 296571
Following internal review, David Quincy's seminar presentation, entitled:
Process Improvements Resulting in the Successful Manufacturing of ELN 296571
Authors: David Quincy, Michael Dappen, Chris Semko, Andrei Konradi, Lee Latimer
was approved on January 25, 2011 for presenting at an interview seminar, taking
place at XXXXXXX Pharmaceuticals and other companies yet to be determined.
A copy can be found on xxxxx at the attached link: …………..
Thank you.
Anna Marie M.
Elan Pharmaceuticals, Inc.
800 Gateway Blvd,
South San Francisco, CA 94080