Mark J. Cooney has over 20 years of experience in academia and industry conducting research and process development. He has a PhD in organic chemistry from the University of Nevada, Reno and has worked at various academic and industrial laboratories. At Ricerca Biosciences, his responsibilities included benchmarking client chemistry, improving processes, demonstrating processes at lab or pilot scale, and providing technical support. He summarized improvements made to several processes, including reducing reaction times, improving purifications, and developing crystallization procedures.

1. Mark J. Cooney, PhD

2. PhD: University of Nevada, Reno 1993
Post Doc: Victoria University of Wellington 1993-1995
Oak Ridge National Laboratory 1995-1996
Research Triangle Institute 1997
Industry: Starks Associates 1997-2000
Centaur Pharmaceuticals 2000-2001
ISP 2001-2012
Ricerca Biosciences 2012-2015
Mark J. Cooney, PhD

3. Alkylidene Cycloproparenes
VUW

4. Synthesis of an Alkylidene Cycloproparene
VUW

5. Planar Ketones for Alkylidene Synthesis
VUW

6. Ketone Synthesis
VUW

7. Alkylidene Synthesis
VUW

8. UV Spectral Data
VUW

9. X-Ray Structures
VUW

10. X-Ray Structures
VUW

11. X-Ray Structures
VUW

12. Responsibilities at Starks Associates
• Synthesis of Complex Molecules
• Purification
• Identification
• Characterization
• Process Development
• Technical Reports

13. Aminoflavone
Currently looking at a prodrug form
of aminoflavone in combination with
a variety of anticancer drugs for the
treatment of breast cancer.

14. Synthesis of Fragment A

15. Synthesis of Fragment A

16. Synthesis of Fragment A

17. Synthesis of Fragment B

18. Coupling Reaction

19. CDDO

20. Synthesis and Process Development of CDDO

21. Synthesis of CDDO

22. Synthesis of CDDO

23. Synthesis of CDDO

24. Flecainide Acetate
(Anti-arrhythmia drug)

25. Synthetic Route

26. Process Problems for Step A
1. Reaction time limited to 2 h at 110-115 O
C
2. Solid addition of reagents
3. Dilute reaction mixture
4. Workup procedure:
a. Too much ice/HCl used for reaction quench.
b. Crude product dissolved with an excessive amount of
water/KOH prior to extraction with methylene chloride.
c. Use of too much base resulted in having to add more
HCl than was really necessary to acidify the mixture.

27. Process Development
Step A FineTech ISP
CF3CH2OH NaH 7.5 eq 5.1 eq 5.0 eq 4.0 eq
Concentration of Benzoic Acid 0.44 M (11%) 0.62 M (16%)
CuI Added as solid Added as suspension
Benzoic Acid Added as solid Added as a solution
Reaction 2 h/110-115 O
C Up to 17 h at 100 O
C
Quench 3000 g ice/780 mL of
HCl
1000 mL H2O/70 mL HCl
Extraction CH2Cl2 Heptane
Yield 64% 78%

28. Step B Process
The Fine Tech process was adequate for scale up. Only minor
modifications were attempted.
1. Reagent amounts were decreased by 17%.
2. Solvent volume was decreased by 21%.
3. The reaction was run at 75 O
C (below reflux).
4. An intermediate drying step was removed from
the purification procedure.
5. The crude material was crystallized with heptane
instead of hexanes.
These modifications resulted in a 7% yield
improvement without decreasing the purity

29. Step C Process
Two procedures for the preparation of Flecainide Acetate were provided
by Fine Tech:
Procedure A used dried purified material from Step B in the reaction
with 2-(aminomethyl)piperidine in EtOAc.
Procedure B used the EtOAc solution of cyanomethyl ester from Step B
for formation of Flecainide
The use of purified material from Step B is
preferred as this will prevent carry over of
excess reagents and by-products to the
next step.

30. Step C Process Continued
A number of differences relating to workup, acetate formation and
purification were noted in the two procedures that were supplied.
1.Concentrate
2.Dissolve in CH2Cl2 and dry (Na2SO4)
3.Concentrate
4.Dissolve in hot EtOAc
5.Add HOAc
6.Crystallize from EtOAc
Procedure 1 Procedure 2
1.Dilute with EtOAc
2.Stir with Na2CO3
3.Azeotropic distillation until H2O  0.3%
4.Add EtOAc to return to original
volume
5.Add HOAc
6.Crystallize from EtOAc
Procedure 2 is better suited for scale up and also deals
with the reaction by-product (cyanomethanol) prior to
acetate formation.

31. Step C Process Continued
 GC analysis, prior to washing with Na2CO3, indicated that a number of by-products
were present in the reaction mixture.
 Stirring with Na2CO3 did wash out a yellow impurity.
 Azeotropic distillation reduced the water content to 0.16%.
 Addition of HOAc resulted in acetate formation. The crude crystalline product was
an unacceptable chocolate color.
 A number of attempts to recrystallize with EtOAc failed to remove the brown color.
 Recrystallization with IPA/heptane removed the brown color resulting in a white
crystalline product.

32. Indolylboronic Acid

33. Indolylboronic Acid

34. 1,9-Decadiene

35. 1,9-Decadiene
Mg 317 kg
1,4-Dichlorobutane 735 kg
Lithium Chloride 9.82 kg
Copper (II) Chloride 15.6 kg
Allyl Bromide 1611 kg
Decadiene 480 kg

36. Responsibilities at Ricerca
• Benchmark client chemistry usually on a small scale
o SciFinder
• Improve process as necessary to provide material that meets specifications
o Chemistry
o Reaction parameters
o Purification
• Small scale up of process in the laboratory
o Impurity profile and identification of impurities if possible
• Provide markers for intermediates and final product to the Analytical Group for
method development
• Run demonstration batch in the laboratory or in the Kilo-Lab depending on the
scale
o Process Safety and Operations Review (PSOR)
• Transfer process to Production (TIP)
• Do use tests as needed for Process Engineering
• Provide plant support and analytical support as necessary
• Technical report

37. Process Development of a Ricerca Project
 Details of Original Process
o THF used as the solvent. 20 h reaction
time
o The THF layer was separated followed by
pH adjustment to 3
o Water was stripped
o Cmp 2 was extracted from the residue
o Purified with chromatography.
o 90% yield
 Process Improvements
o Reduced reaction time to 6 h
o Use of a mixed solvent system
improved layer break
o Adjusted pH to 3. No water strip
o Collected Cmp 2 by filtration
o Cmp 2 was close to 100% pure by
HPLC
o No purification required
o 95% yield

38. Process Development Continued
 No process improvements needed
 Solvent was evaporated yielding solid Cmp 3
that was used as is

39. Process Development Continued
 Details of Original Process
o Due to extremely tight specifications for
two known impurities purification was
done by the client using column
chromatography (3 x)
o 61% yield
 Process Improvements
o Crude Cmp 5 was passed through a
silica gel pad to remove dark colored
material. Eliminated column
chromatography
o A crystallization procedure was
developed that removed the
impurities to below the required
specification
o 74% yield

40. Process Development Continued
 Details of Original Process
o Salt formation was done using HCl in
dioxane
o Filtration of the salt was not problematic
o No information was provided by the client
for residual dioxane or for MTBE
o 99% yield
 Process Improvements
o HCl in ether was used for salt
formation
o Filtration of the salt was more
difficult
o Residual MTBE (above the allowed
limit) was replaced with water in a
humidity chamber.
o The hydrated salt was easily dried to
constant weight.
o 98.5% yield
o The material easily passed the
specifications

41. Production Project
Target Molecule

42. Step S-1
 Reaction was highly exothermic and was best
run at about -20 OC. MeTHF was used to
facilitate a layer break during the workup
 The reaction was very sensitive to the water
content. A few 100 ppm was tolerable.
 The starting material contained 4.5% water and
was dried with azeotropic distillation using
MeTHF
 The solvent was stripped after the workup and
exchanged with NMP for the next reaction

43. Step S-2
 All solids were charged up front and then the
NMP solution of C-1 was added.
 The reaction ran as advertised and was
complete in 4 h. By HPLC the phenol had been
consumed and there was a trace of C-1.
 An aqueous workup was done to remove NMP.
Extraction was done with isopropyl acetate
which was the solvent for the next reaction.

44. Step S-3
 Tosic acid was charged to the reactor followed
by the C-2 solution.
 The reaction was complete in 8 h by HPLC.
 The salt was isolated and dried and used as is
for the next step. Purity was very close to
100%.

45. Step S-4
 The salt was not free based
before the reaction
 All solids were charged up
front followed by solvent and
TEA.
 The reaction was run at RT and
was usually complete after
about 2 h.
 The solvent was exchanged for
MeOH and the crude material
went into the next step
 The quality of the phenoxy acetic acid was critical
and there were differences between vendors that
lead to impurity formation.
 Residual C-3 needed to be removed during the
workup using an acid wash.
 However, excess contact time with the aqueous
acid had to be avoided due to hydrolysis the
solvent.

46. Step S-5
 NaBH4 was charged in 5
portions at about 0 oC
otherwise impurity formation
became an issue.
 The reaction was very rapid
and was usually complete soon
after the NaBH4 had been
added.
 If C-3 was present as an impurity then reductive
amination took place to form a new impurity.
 The crude API purity was in the high 90% range but
still needed crystallization to remove an impurity
that was formed during Step S-4.
 The percent yield for Steps S-4 and Step S-5
combined was about 75%.