2-propanol (425 mL, 8.5 vol) was added followed by (rac)-
camphorsulfonic acid (49.2 g, 0.8 equiv). The mixture was
stirred for 2 h, and then 180 mL of 2-propanol were added.
The solid was collected by filtration and washed with 2-propanol
(2 × 85 mL), cyclohexane/2-propanol 1/1 (170 mL) and
cyclohexane/2-propanol 3/1 (255 mL). The solid was dried
under high vacuum at room temperature, obtaining of the
racemic camphorsulfonate salt of 6 (52.47 g, 46.8% th).
1H NMR (400 MHz, DMSO-d6): δ ppm 9.42 (br.s, 2H),
7.66 (dd, 1H), 7.31-7.37 (m, 2H), 7.28 (dt, 1H), 4.99 (dd, 1H),
3.54-3.68 (m, 2H), 2.90-2.99 (m, 2H), 2.90 (d, 1H), 2.59-2.69
(m, 1H), 2.50-2.59 (m, 2H), 2.41 (d, 1H), 2.36 (s, 3H),
2.20-2.28 (m, 1H), 1.94 (t, 1H), 1.80-1.91 (m, 1H), 1.80 (d,
1H), 1.23-1.34 (m, 2H), 1.03 (s, 3H), 0.74 (s, 3H). HRMS
(ES+) Calcd for C12H15NO [M + H]+: 190.1232; found
190.1235.
high risk to the process falling outside the design space or
proven acceptable ranges in the unit operation or stage inputs,
stage outputs, device etc.
Quality Attribute in the Unit Operation or Stage Inputs,
Stage Outputs, Device etc measurable property of inputs and
outputs that (as determined by Risk Assessment) present a low
risk to the process falling outside the design space or proven
acceptable range.
Critical Process Parameter (CPP) process parameter
whose variability has an impact on a critical quality attribute
and therefore should be monitored or controlled to ensure the
process produces the desired quality [ICH Q8].
Design Space multidimensional combination and interaction
of input variables (e.g., material attributes) and process param-
eters that have been demonstrated to provide assurance of
quality; working within the design space is not considered as a
change, and movement out of the design space is considered
to be a change and would normally initiate a regulatory post
approval change process. Design Space is proposed by the
applicant and is subject to regulatory assessment and approval
[ICH Q8].
Quality Critical Process Parameter process parameter that
influences a critical quality attribute and (as determined by risk
assessment) presents a high risk to the process falling outside
the design space or proven acceptable ranges.
Quality Process Parameter process parameter that influ-
ences a critical quality attribute but (following a risk assessment)
presents a low risk of the process falling outside the design
space or proven acceptable ranges.
Control Strategy (planned) set of controls, derived from
(current) product and process understanding that assures process
performance and product quality; the controls can include
parameters and attributes related to drug substance and drug
product materials and components, facility and equipment
operating conditions, in-process controls, finished product
specifications, and the associated methods and frequency of
monitoring and control. (ICH Q10 definition).
Proven Acceptable Range (PAR) upper and lower limits
for process parameter or attribute values between which the
parameter or attribute is known to produce a process output
(e.g., intermediate, API or DP) that meets the CQAs; the PAR
may or may not represent the point of failure, and the PAR for
a given process parameter or attribute may be dependent upon
the PAR values for one or more other process parameters or
attributes (e.g., multivariate).
Synthesis of the Defluorinated Impurity (2R,4S)-4-(4-
Acetyl-1-piperazinyl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phe-
nyl]ethyl}-N-methyl-2-(2-methylphenyl)-1-piperidinecarbox-
amide (7). Prepared as described in the published literature.10
Compound 7 can be precipitated as the methanesulfonate
salt as described in the published literature.10a
1H NMR (600 MHz, DMSO-d6): δ ppm 9.65 (br.s., 1H),
8.01 (s, 1H), 7.70-7.76 (m, 2H), 7.20 (d, 1H), 7.10 (d, 1H),
7.07 (t, 1H), 7.03 (t, 1H), 5.36 (q, 1H), 4.40-4.49 (m, 1H),
4.24 (dd, 1H), 3.94-4.04 (m, 1H), 3.53-3.62 (m, 1H),
3.43-3.52 (m, 3H), 3.39 (t, 1H), 3.10-3.22 (m, 1H), 2.93-3.03
(m, 1H), 2.84-2.94 (m, 1H), 2.80 (t, 1H), 2.75 (s, 3H), 2.36
(s, 3H), 2.33 (s, 3H), 2.13-2.19 (m, 1H), 2.07-2.13 (m, 1H),
2.02 (s, 3H), 1.85-1.96 (m, 1H), 1.64-1.74 (m, 1H), 1.46 (d,
3H). HRMS (ES+) Calcd for C30H36N4O2F6 [M + H]+:
599.2821; found 599.2805.
Acknowledgment
We are grateful to Orsola Vecchi, Simon Bryant, Riet Dams,
Giulio Camurri, Stefano Provera, Lucilla Turco, Ornella Cur-
curuto, Jill Trewartha, Paola Russo, Anna Nicoletti, Luca
Martini, Matteo Gonzi, Vern De Biasi, Vance Novack, Damiano
Papini, and Luca Mantilli for helpful discussions and to Matt
Kersey for critical reading of the manuscript.
Appendix 1: Glossary
Drug Product Critical Quality Attributes or Drug
Substance Critical Quality Attributes measurable properties
of drug product or API that are critical to ensuring patient safety
and efficacy. The property must be within a predetermined range
to ensure product quality. A property which is measured outside
the range indicates a batch failure.
Supporting Information Available
Critical Quality Attributes measurable properties of inputs
and outputs that (as determined by risk assessment) present a
Detailed description of the root cause analysis mentioned
in paragraph 2 by using the Ishikawa diagram and the ANOVA
analysis of the DOE reported in paragraph 2.2. This material is
(10) (a) Alvaro, G.; Di Fabio, R.; Maragni, P.; Tampieri, M.; Tranquillini,
M. E. PCT Int. Appl. WO 2002/032867, 2002; Chem. Abstr. 2002,
136, 325568. (b) Bientinesi, I.; Cimarosti, Z.; Guercio, G.; Leroi, C.;
Perboni, A. PCT Int. Appl. WO 2007/048642, 2007; Chem. Abstr.
2007, 146, 461973. (c) Guercio, G.; Bacchi, S.; Perboni, A.; Leroi,
C.; Tinazzi, F.; Bientinesi, I.; Hourdin, M.; Goodyear, M.; Curti, S.;
Provera, S.; Cimarosti, Z. Org. Process Res. DeV. 2009, 13, 1100–
1110.
Received for review March 26, 2010.
OP1000836
Vol. 14, No. 4, 2010 / Organic Process Research & Development
•
839