Development of a Recycling Process for an Industrial-Scale Production of Tipifarnib

Article abstract of DOI:10.1021/acs.oprd.1c00132

Current production of tipifarnib involves a late-stage chiral resolution where the mother liquor containing ～2/3 of the product is disposed of as waste. As part of an effort to develop an efficient recycling process, a NaNO2-mediated racemization was initially devised and successfully implemented at kilogram scale. However, formation of a new hard-to-purge impurity and concerns about potential N-nitrosamine contamination prompted exploration of a NaNO2-free process. Additional experimentation with acidic conditions at elevated temperatures afforded a highly efficient, robust recycling process that was seamlessly incorporated into the original process. The resulting production output of tipifarnib increased over 60%, and waste disposal was dramatically decreased.

Full text of DOI:10.1021/acs.oprd.1c00132

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Article
Development of a Recycling Process for an Industrial-Scale
Production of Tipifarnib
Xiaohu Deng,* Pingda Ren, Wanping Mai, Thomas Fu, Hang Zhang, Xianfeng Cai, and Lu Wang
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ABSTRACT: Current production of tipifarnib involves a late-stage chiral resolution where the mother liquor containing ∼2/3 of
the product is disposed of as waste. As part of an effort to develop an efficient recycling process, a NaNO2-mediated racemization
was initially devised and successfully implemented at kilogram scale. However, formation of a new hard-to-purge impurity and
concerns about potential N-nitrosamine contamination prompted exploration of a NaNO2-free process. Additional experimentation
with acidic conditions at elevated temperatures afforded a highly efficient, robust recycling process that was seamlessly incorporated
into the original process. The resulting production output of tipifarnib increased over 60%, and waste disposal was dramatically
decreased.
KEYWORDS: green chemistry, recycle, racemization, N-nitrosamine, sodium nitrite, tipifarnib
the use of NaNO2 created concerns about potential N-
nitrosamine contamination.5 In addition, a new impurity
associated with NaNO2 was generated and hard to purge that
would complicate the regulatory path forward for commerci-
alization. A second-generation, NaNO2-free process was then
devised and optimized to ensure regulatory compliance
through stringent impurity control. In the end, the robust
and economical recycling process was successfully incorpo-
rated into the original process and scaled up for the current
Good Manufacturing Practice (cGMP) production of final
active pharmaceutical ingredient (API) qualified for human
use. We believe a similar recycling through racemization
process could be applied to other analogous compounds.
INTRODUCTION
■
Green chemistry is defined as the design of chemical products
and processes that reduce or eliminate the generation of
hazardous substances and utilize renewable sources of raw
materials. The overarching goals of green chemistry, namely,
more resource-efficient and inherently safer design of
molecules, materials, products, and processes, can be pursued
in a wide range of contexts.1 Since its conception in the 1990s,
the concepts and practices of green chemistry have been
increasingly adopted in the chemical industries.2 The
pharmaceutical and biotechnology industry also recognizes
the importance of sustainability and embraces the general
concepts,3 with notable examples of the International
Consortium for Innovation and Quality in Pharmaceutical
Development (IQ) and ACS Green Chemistry Institute
Pharmaceutical Roundtable that represent >40 major pharma-
ceutical and biotechnology company members. Still, practical
applications performed at the industrial scale are relatively
scarce,4 probably due to a number of factors unique to the
pharmaceutical and biotechnology industry, such as technical
feasibility, cost benefit, quality control, scalability, regulatory
compliance, and time line. For instance, pharmaceutical
products tend to be high value, low volume, and highly
regulated, and their production requires stringent quality
control for human use. Therefore, the significant efforts
necessary for development of “greener” processes are often
deemed economically unjustifiable. How to balance the
sustainability and social responsibility with the economic
reality is a perpetual question that process chemistry
professionals must address.
RESULTS AND DISCUSSION
■
Tipifarnib is a farnesyltransferase inhibitor that blocks the
activity of the farnesyltransferase enzyme by inhibiting
prenylation of the CAAX tail motif, which ultimately prevents
Ras from binding to the membrane and rendering it inactive.6
Originally developed by Johnson & Johnson for various
indications including AML,7 tipifarnib was more recently
developed using a precision medicine approach and has
demonstrated promising clinical activity8 for the treatment of a
variety of solid tumors and blood cancers.9
The original synthetic route for the production of tipifarnib
drug substance is shown in Scheme 1.10 Whereas this robust
process is capable of producing tipifarnib at kilogram scale, the
main drawback is a low-yielding chiral resolution step 2, where
Received: April 16, 2021
Published: June 25, 2021
Herein, we share the development of an industrial-scale
recycling process through racemization that returns the waste
stream containing ∼2/3 of the potential product back to the
final product at kilogram scale. The first-generation NaNO2-
mediated process demonstrated the technical feasibility, but
https://doi.org/10.1021/acs.oprd.1c00132
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© 2021 American Chemical Society
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Scheme 1. Original Synthesis of R-(+)-Tipifarnib
Scheme 2. Racemization of Tipifarnib through NaNO2-Mediated Diazotization
Scheme 3. NaNO2-Mediated Conversion of 4 to 2
∼2/3 of advanced intermediate 3 was disposed as waste.
Evidently, recycling the undesired enantiomer through
racemization would be economically attractive and environ-
mentally appealing.11
useful. NaNO2-mediated diazotization of aromatic amine
(Sandmeyer reaction)13 is well documented in the literature.
In comparison, diazonium salts of aliphatic amines such as
compound 5 tend to lose N2 too rapidly, making the method
much less synthetically useful and thus rarely reported in the
literature.14 However, in our case, we envisioned that a high
reactivity of intermediates 5 and 6 might be employed toward
our advantage to achieve the racemization to afford 2 through
a facile hydrolysis.
Indeed, when enantiopure dibenzoyltartrate salt 4 was
subjected to 1.5 equiv of NaNO2 with 2 equiv of H2SO4 in
the presence of water, a facile conversion to 2 and complete
racemization were achieved in high yield at room temperature,
as shown in Scheme 3.
The chiral center of tipifarnib is a triaryl-substituted
quaternary carbon bearing a primary amine with no other
adjacent functional groups, which renders direct racemization
back to racemic 3 rather difficult.12 Our cue came from the
stability study on enantiomerically pure 1, where a trace
amount of 2 was observed as a degradant over the long-term
storage (Scheme 2). Chiral high-performance liquid chroma-
tography (HPLC) analysis showed complete racemization of
the quaternary carbon center, presumably via hydrolysis of the
achiral, planar carbocation intermediate 6. However, this
degradation in the solid state was rather slow, with <0.5%
conversion observed over 6 months of storage at 40 °C/75%
RH (relative humidity). Facile formation of active intermediate
6 would be a requisite for the racemization to be synthetically
Encouraged by the above result, the mother liquor 4-ML
was then utilized as the input material for the racemization. It
was found that an additional H2SO4 was not required,
presumably because benzoyltartaric acid present in the mother
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Scheme 4. NaNO2-Mediated Racemization Process of 4-ML
liquor was sufficient to promote the reaction. A racemization
process (Scheme 4) was therefore developed consisting of (1)
concentrating the acetone mother liquor solution at 50 °C
under vacuum to ∼6v; (2) charging water (1.5v) and NaNO2
(1.8 equiv) and stirring at room temperature for 16 h. N2 off-
gassing was observed; (3) after workup, concentrated HCl was
added to afford 2-recycle as the HCl salt. Safety evaluation,
mostly differential scanning calorimetry (DSC) evaluation, was
also performed to demonstrate the scalability of this robust
process, and kilogram-scale production was successfully
conducted. However, during the scale-up campaign, a new
impurity 7 was observed in small amounts. Impurity 7 did not
exist in the original synthesis, and the nitro group presented a
structural alert for potential mutagenicity per in silico
assessment. Albeit the negative Ames test result, a good
control strategy of impurity 7 was evidently necessary to
incorporate the recycling step into the original one. Extensive
optimization of the racemization step was conducted, but
impurity 7 was inevitably present in the range of 0.1−1.1%. We
then turned our attention to hopefully controlling it in the
subsequent steps (2 → 3 → 4). Unfortunately, it was found
that impurity 7 was not effectively purged, rather enriched
through the steps. Lack of control of impurity 7 presented two
significant hurdles for incorporating this recycling process: (1)
in vivo toxicology qualification of impurity 7 and (2) separate
specifications for the recycled material, which would render the
recycling process economically unviable. While we were
working on the NaNO2-mediated racemization process, the
news on N-nitrosamine contamination of Valsartan in 2018
and later Zantac in 201915 broke out that resulted in multiple
high-profile recalls and later a new FDA guideline for tighter
regulation of N-nitrosamine in 2020.5 Use of a stoichiometric
amount of NaNO2 would no doubt raise questions on the
potential formation of N-nitrosamine like impurities 8.
Coupled with the lack of an effective control strategy of
impurity 7, the NaNO2-mediated process was abandoned.
Upon closer examination of the racemization mechanism
shown in Scheme 2, we reasoned that it might be feasible to
form intermediate 6 through direct acid-catalyzed cationiza-
tion, instead of NaNO2-mediated diazotization, owing to the
three cation-stabilizing aromatic rings adjacent to the
quaternary carbon. To our pleasant surprise, when enantiopure
dibenzoyltartrate salt 4 was heated in pure water (Table 1,
entry 1) for 18 h, an 86% conversion to 2 with complete
racemization was observed. Addition of 2 equiv of HCl (entry
2) had no impact on the reaction rate and conversion,
consistent with the previous observation in the NaNO2-
mediated conditions. For entries 1 and 2, both reactions stalled
after 18 h, which we attributed to the heterogeneity of the
reaction mixture due to the poor solubility of compounds 4
and 2 in pure water even at an elevated temperature. A number
Table 1. Investigation of NaNO2-Free Racemization
reaction
a
entry
solvent/acid
6v H2O
6v H2O/2 equiv HCl
6v:1v MeCN/H2O
temp/°C
time/h
conversion /%
1
2
3
50
50
80
18
18
3
86
86
79
89
93
94
46
67
97
33
46
83
93
41
55
83
92
6
24
48
3
6
24
3
4
5
6v:1v MEK/H2O
80
60
6v:1v acetone/H2O
6
24
48
3
6
6v:1v DMF/H2O
80
6
24
48
a
Complete racemization was observed based on the chiral HPLC
analysis of the final sampling point.
of organic solvents were then explored to generate
homogeneous reaction solutions, and the results were
summarized in entries 3−6. Among the four solvents
investigated, MeCN and MEK afforded more rapid reaction
and fewer impurities.
Impacts of water volume for both MeCN and MEK systems
were further investigated. Data summarized in Table 2 showed
that increasing the water volume from 1v to 3v had a limited
impact on the conversion for both solvent systems. MeCN
demonstrated faster reaction rate, whereas MEK afforded an
improved impurity profile.16
We then investigated both solvent systems on the mother
liquor (4-ML) recovered from the real-world production. The
recovered mother liquor was an acetone solution (typically
∼15v) containing ∼1:3 mixture of R/S enantiomers. In
addition, the remaining (∼2.0 equiv) resolution reagent (i.e.,
benzoyltartrate) and degradants such as benzoic acid were
present. The large volume of acetone in the mother liquor was
first reduced down to ∼3v, and precipitation of some solids (a
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chosen as the preferred solvent due to (1) slightly improved
reaction impurity profile; (2) MEK being a class 3 solvent vs
MeCN a class 2 solvent according to the ICH Q3C guideline;
(3) MEK belongs to the same chemical class of solvents as
acetone that was the solvent in the mother liquor as well as in
the subsequent HCl salt formation of compound 2 (Scheme
5); and (4) MEK has lower water miscibility than MeCN,
which was advantageous to effect cleaner phase separation in
the workup.
Table 2. Investigation of Water Volume
With the above results, we selected the reflux condition in 6v
MEK and 3v H2O with no acid additive for further scale-up to
produce racemized 2 in excellent yield and purity. Compared
with 2 from the original process, the only difference was one
single impurity generated in step 1 that was carried over from
4-ML. Importantly, when racemized 2 was subjected to step 1,
essentially identical 3 as the normal process was produced and
no new impurities were observed. Therefore, for intermediates
3 and 4, no distinction between normal and recycled materials
was necessary and the identical specifications were used for
release. To the end, the recycling process was seamlessly
incorporated into the original production process, as outlined
in Scheme 5. In addition, every recycling cycle would generate
a new batch of mother liquor, which in turn could be subjected
to recycling. Indeed, we repeated this recycling cycle three
times and 4 was still well within the predetermined
specifications, which further demonstrated the robustness of
the recycling process. Ultimately, the regular and recycled 4
was carried over to produce tipifarnib API qualified for human
use, with the overall output increased by >60% and waste
disposal significantly reduced.
entry
1
solvent
reaction time/h
conversion/%
6v:1v MeCN/H2O
3
6
24
48
3
79
89
93
94
89
94
96
96
46
67
97
49
68
93
98
2
6v:3v MeCN/H2O
6
24
48
3
6
24
3
6
24
48
3
4
6v:1v MEK/H2O
6v:3v MEK/H2O
mixture of product and resolution reagents) was observed.
MeCN (6v) or MEK (6v) along with 3v of water was added to
dissolve all solids to form a biphasic solution that were heated
to the reflux temperature. Additional acid additive (H2SO4)
was also investigated, and the results are listed in Table 3.
Consistent with the previous data, extra acid (H2SO4) had no
apparent impact (entries 2 and 4) and MeCN as solvent
afforded faster reaction rate. However, in the end, MEK was
CONCLUSIONS
■
A recycling process for a greener and industrial-scale
production of tipifarnib was successfully developed. Initially,
Table 3. Racemization of Mother Liquor 4-ML
entry
1
solvent/additive
MeCN
reaction time/h
conversion/%
2
4
94
99
6
8
2
100
100
96
2
3
MeCN/0.5 equiv H2SO4
4
6
8
2
99
100
100
63
MEK
4
85
6
95
8
96
16
2
100
68
4
MEK/0.5 equiv H2SO4
4
84
6
97
8
97
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Scheme 5. Integrated Production Process of Tipifarnib
a NaNO2-mediated process was devised, but introduction of
impurity 7 and concerns about potential N-nitrosamine
contamination necessitated an alternative approach. Careful
understanding of the racemization mechanism led to a
streamlined recycling process that was seamlessly incorporated
into the original process, and the resulting process was both
environmentally friendly and economically advantageous. We
expect this recycling through the racemization process
applicable to analogous compounds that have a chiral
quaternary carbon center bearing a primary amine.
Hz, 2H), 6.57 (s, 1H), 6.20 (s, 1H), 3.66 (s, 3H), 3.35 (s, 3H).
13C NMR (100 MHz, DMSO) δ: 160.4, 152.2, 148.5, 146.6,
140.6, 139.4, 138.3, 138.2, 135.0, 133.3, 130.5, 130.0, 128.9,
128.7, 128.4, 128.0, 127.5, 124.7, 123.3, 121.2, 118.3, 115.4,
75.3, 33.2, 29.3. IR (cm−1): 1640, 1578, 1520, 1348, 1264,
1068, 812, 731, 701. HRMS: C27H21ClN4O4 [M + H]+: calcd:
501.1325; found: 501.1321.
NaNO2-Free Racemization. The mother liquor solution
in acetone recovered from the chiral resolution step (typically
∼15v, containing ∼1.64 kg of R/S mixture of 3 based on the
assay) was concentrated to ∼3v, and then MEK (7.3 kg, 6v)
and process water (4.5 kg, 3v) were sequentially charged. The
biphasic reaction mixture was heated to reflux until complete
reaction was monitored by HPLC analysis and then cooled to
room temperature. Process water (3.8 kg, 2.5v) was added
followed by a 30 w/w% NaOH aqueous solution to adjust pH
EXPERIMENTAL SECTION
■
NaNO2-Mediated Racemization. In a 30 L reactor, the
mother liquor solution in acetone from the regular production
campaign (∼15v, containing ∼1.445 kg of R/S mixture of 3
based on the assay) was concentrated to ∼6v, and water (2.16
L, 1.5v) was added. NaNO2 (175 g, 1.8 equiv) was charged,
and the reaction solution was stirred at room temperature until
i
∼ 8. The aqueous layer was back-extracted with PrOAc (6.0
kg, 4.5v) one more time. The organic layers were combined,
i
washed with water (4.5 kg, 3v), and concentrated below 50 °C
complete reaction was monitored by HPLC analysis. PrOAc
i
under reduced pressure to ∼5.5v. PrOAc (3.3 kg, 2.5v) was
(7.2 L, 5v) was added followed by a 10% NaOH aqueous
solution to adjust the pH to ∼10. The aqueous layer was
extracted with iPrOAc (7.2 L, 5v) one more time. The organic
layers were combined, and then concentrated hydrochloric
acid (37 wt %, 1.5 equiv) was slowly charged. The precipitated
solid was collected by filtration, washed with iPrOAc, and dried
slowly charged, and the suspension was stirred at room
temperature for 16 h. The precipitated solid (compound 2, free
base) was collected by filtration and washed with acetone (1.3
kg, 1.0v). The wet cake was collected, resuspended in acetone
(6.0v), and then a concentrated HCl aqueous solution (37 wt
%, 1.3 equiv) was charged slowly at room temperature. The
precipitated solid was collected by filtration, rinsed with
acetone (3.3 kg, 2.5v), and dried at 80 °C to afford 2 (HCl
salt) as a white solid.
1
to afford compound 2 (HCl salt) in an ∼90% yield. H NMR
(400 MHz, DMSO) δ: 9.17 (s, 1H), 7.63−7.70 (m, 2H),
7.46−7.55 (m, 3H), 7.39−7.42 (m, 3H), 7.29−7.31 (m, 1H),
7.22−7.24 (m, 2H), 7.17 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 1.5
Hz, 1H), 6.60 (s, 1H), 3.68 (s, 3H), 3.53 (s, 3H). 13C NMR
(100 MHz, DMSO) δ: 160.6, 148.7, 139.8, 138.2, 137.6, 137.5,
133.5, 130.7, 128.9, 128.7, 128.7, 128.5, 127.7, 121.4, 118.6,
115.8, 75.0, 35.6, 29.5. MS: C27H21Cl2N3O2 [M + H]+: calcd:
490.1; found: 490.2.
The same protocol was also performed on >1000 L mother
liquor batches and repeated 3 times, and the product quality
was still well within predetermined specifications. The typical
yield was consistently at 80−90%.
Impurity 7 was isolated from 30 gm of crude 2 free base
(containing ∼1% based on HPLC analysis) via preparatory
HPLC as a yellow solid. 1H NMR (400 MHz, DMSO) δ: 8.19
(d, J = 8.8 Hz, 2H), 7.83 (s, 1H), 7.66 (m, 2H), 7.45−7.52 (m,
4H), 7.37 (s, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 6.8
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
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(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Xiaohu Deng − Kura Oncology Inc., San Diego, California
92130, United States; orcid.org/0000-0003-1393-4446;
Email: xdeng1000@yahoo.com
Authors
Pingda Ren − Kura Oncology Inc., San Diego, California
92130, United States
Wanping Mai − Kura Oncology Inc., San Diego, California
92130, United States
Thomas Fu − Kura Oncology Inc., San Diego, California
92130, United States
Hang Zhang − STA Pharmaceutical Co., Ltd., (“WuXi STA”),
a WuXi AppTec Company, Shanghai 200131, China
Xianfeng Cai − STA Pharmaceutical Co., Ltd., (“WuXi
STA”), a WuXi AppTec Company, Shanghai 200131, China
Lu Wang − STA Pharmaceutical Co., Ltd., (“WuXi STA”), a
WuXi AppTec Company, Shanghai 200131, China
̀
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S.; Burrows, F. Tipifarnib as a precision therapy for HRAS-mutant
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank Dr. Troy Wilson, Dr. Roger Bakale,
Dr. Brad Sun, and Dr. Tiffany Montellano for reviewing the
manuscript.
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