Synthesis of (R)-Boc-2-methylproline via a Memory of Chirality Cyclization. Application to the Synthesis of Veliparib, a Poly(ADP-ribose) Polymerase Inhibitor

Article abstract of DOI:10.1021/acs.joc.8b02866

(R)-Boc-2-methylproline (3a) was synthesized in good yield with excellent stereochemical control from alanine benzyl ester hydrochloride 11. The process, which is based on a modification of one described by Kawabata, proceeds in four steps and requires no

Full text of DOI:10.1021/acs.joc.8b02866

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Article
Synthesis of (R)-Boc-2-Methylproline Via a Memory of
Chirality Cyclization. Application to the Synthesis of
Veliparib, a Poly(ADP-Ribose) Polymerase Inhibitor
Lawrence Kolaczkowski, Jufang Barkalow, David M. Barnes,
Anthony R. Haight, Wayne Pritts, and Adam Schellinger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02866 • Publication Date (Web): 04 Feb 2019
Downloaded from http://pubs.acs.org on February 5, 2019
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The Journal of Organic Chemistry
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Synthesis of (R)-Boc-2-Methylproline Via a Memory of Chirality
Cyclization. Application to the Synthesis of Veliparib, a Poly(ADP-
Ribose) Polymerase Inhibitor
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Lawrence Kolaczkowski†*, Jufang Barkalow†, David M. Barnes†, Anthony Haight†, Wayne Pritts‡ and
Adam Schellinger‡
†
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Process Research & Development, AbbVie Inc., North Chicago, Illinois, USA
‡
Process Analytical Chemistry, AbbVie Inc., North Chicago, Illinois, USA, Illinois, USA
*Corresponding author email: larry.kolaczkowski@abbvie.com
CONH2
Me
Me
N
4 Steps
3 Steps
H
Me
HO2C
N
+
NH3 Cl-
64% yield
N
H
N
BnO2C
66% yield
Boc
H
11
3a
1
> 99% ee
veliparib
ABSTRACT: (R)-Boc-2-methylproline (3a) was synthesized in good yield with excellent stereochemical control from alanine
benzyl ester hydrochloride 11. The process, which is based on a modification of one described by Kawabata, proceeds
in four steps and requires no chromatography. The product (R)-Boc-2-methylproline (3a) was then carried forward in
three steps to produce veliparib 1, a poly(ADP-ribose) polymerase inhibitor.
INTRODUCTION
.
Poly(ADP ribose) polymerase (PARP) is one of two primary mediators of DNA damage repair along with
the breast cancer susceptibility (BRCA) system. In preclinical testing, PARP inhibitors demonstrated the
ability to potentiate the effect of various chemotherapeutic agents as well as radiation therapy.1 Veliparib (1)
is a PARP inhibitor which is being investigated for the treatment of a broad spectrum of oncology
indications2 including BRCA1/2-mutated breast cancer3 and other solid tumors.4
A simple retrosynthetic analysis of veliparib (1, Scheme 1) reveals two key starting materials,
diaminobenzamide 4 and an N-protected (R)-2-methylproline 3. An efficient preparation of
diaminobenzamide 4 has been demonstrated previously.5 However, an efficient asymmetric synthesis of a
suitably N-protected (R)-2-methylproline remained a prerequisite to a robust supply of veliparib.
Scheme 1. Veliparib Retrosynthesis.
CONH2
CONH2
NH2
2 HCl
NH2
Me
Me
N
N
HO2C
N
H
N
O
OR
R
R = H (veliparib, 1)
R = Boc (2a)
R = Cbz (2b)
4
3a: R = t-Bu
3b: R = Bn
The discovery synthesis6 of veliparib employed the resolution, by chromatography, of racemic Cbz-
protected veliparib (±)-2b. For early deliveries of the chiral Cbz-protected starting material 3b, the classical
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resolution of (±)-N-Cbz-2-methylproline reported by Overberger7 was investigated (Scheme 2). Utilization of
this approached had the added benefit of capitalizing on a synthetic route parallel to that employed in the
original discovery process.
1
2
3
4
5
Scheme 2. Classical Resolution of Racemic Cbz-2-Methylproline.7
6
7
8
9
H
HCl
QuinineH+-O2C
HO2C
N
Me
HO
N
HO2C
Me
Me
N
86% yield
H
MeO
Cbz
N
Cbz
Solid
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N
(S)-3b
Cbz
: 97% ee
33% Recovery
quinine
99% (S) Isomer
Me
1) HCl
2) EtOAc
crystal
HO2C
N
Me
Me
Cbz
QuinineH+-O2C
N
HO2C
N
67% yield
Cbz
Cbz
Liquors
60% Recovery
(R)-3b
: 92% ee
86% (R) Isomer
Quinine directly afforded a crystalline salt with the (S)-enantiomer of 3b; the desired (R)-enantiomer was
recovered from the liquors, and could be crystallized to 92% ee after breaking the salt. It was further found
that the enantiomeric impurity could be rejected at the penultimate 2b, as the racemate of 2b was
significantly less soluble than the enantiomer. Therefore, enantiomeric enrichment could be achieved by
dissolution of the product and removal of the racemate by filtration. However, discovery of a stable
polymorph of the quinine salt of 3b ultimately rendered the classical resolution untenable leading to
abandonment of this route. Attempts to generate a suitable salt of the (R)-isomer 3b with the
pseudoenantiomeric quinidine were unsuccessful. Therefore, the search for a de novo asymmetric synthesis
of a suitably N-protected (R)-2-methylproline was undertaken.
2-Methylproline and its derivatives are versatile building blocks and have been employed as
organocatalysts,8 as well as structure modifiers and enzyme inhibitors in protein research.9 Several
asymmetric syntheses of chiral 2-methylproline derivatives have been described in the literature.10 Many of
these require the use of exotic chiral auxiliaries or catalysts (Scheme 3).
For example, the use of the pivaldehyde N,O-acetal described by Seebach and coworkers was reported to
proceed with high selectivity;10a however, this required the use of the unnatural D-proline as a starting
material. Also, the reported procedure described the formation of the acetal as challenging, requiring
azeotropic distillation from pentane. While this methodology has been employed successfully in kilogram-
scale processes20, we did not seek to optimize this process.
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Scheme 3. Selected Syntheses of (R)-2-Methylproline.
1
2
3
4
5
6
2 eq. LDA
6 eq. HPMA
THF
Me
H
O
O
N
N
-100 °C
N
N
O
O
10 eq. MeOTf
69%
Carlier (ref 10g)
O
> 99.5% ee
Me
Br
Me
Br
n-BuLi
THF
N
N
7
8
9
LDA
MeI
THF
-78 °C
H
Me
N
Me
MeO
Me
MeO
H
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-78 °C
Me
HO2C
N
O
N
O
N
N
N
OMe
N
93%
99% ee
81%
O
H
O
O
94% ee
Seebach (ref 10a)
Schoellkopf (ref 10c)
BEMP
LiI
LDA
I
I
Cl
Cl
Me
Me
O
CO2Me
Me
O
NMP
25 °C
CO2Me
H
O
THF
-78 °C
N
N
N
N
Cl
O
OH
Ph
Ph
OH
55%
99% ee
Me
56%
>95% ee
Bajgrowicz (ref 10d)
Chinchilla (ref 10f)
In 2003, Kawabata and coworkers described a novel and elegant approach to the synthesis of 2-substituted
proline derivatives.11 This “memory of chirality” (MOC) approach took advantage of the inherent chirality of
an appropriately derivatized alanine, and was reported to proceed with very high stereoselectivity (Scheme
4). Given the potential for generating a protected (R)-2-methylproline sourced from a readily available chiral
pool starting material, an investigation into application of the MOC methodology into the synthesis of
veliparib 1 was undertaken.
RESULTS AND DISCUSSION
.
Initial Evaluation of the MOC Approach to the Synthesis of Veliparib. Kawabata’s preparation of (R)-
Boc-2-methylproline ethyl ester is shown in Scheme 4.11a,c
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Scheme 4. Kawabata’s MOC Synthesis of (R)-Boc-2-methylproline Ethyl Ester.
1
2
OH
3
4
1-bromo-
3-propanol
H
H
Me
Me
(Boc)2O
EtO2C
NH2
5
6
7
8
EtO2C
N
H
5
K2CO3
L-alanine ethyl ester
OH
Br
9
H
CBr4, PPh3
H
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Me
Me
EtO2C
EtO2C
N
N
chromatography
Boc
Boc
6
7
Br
KHMDS
THF/DMF, -60 °C
Me
EtO2C
H
Me
EtO2C
91% yield
95% ee
N
N
Boc
Boc
7
8
A preliminary analysis of this process revealed several advantages. Primary among these were the high
chemical yield and stereospecificity for the key cyclization step. The process relies on the chirality inherent
in the starting material to control the stereochemical outcome of the key cyclization step; importantly, the
process would utilize a readily available natural amino acid (L-alanine) as the source of chirality. Another
advantage is that the synthetic route to the cyclization precursor is reasonably concise.
While attractive for its ease in introducing the critical quaternary chiral center Kawabata’s approach
presented some challenges to adoption for a large-scale synthesis of veliparib. First, the cyclization substrate
7 was purified by chromatography and all of the intermediates in the synthesis were oils. This provided
limited opportunities for purification during processing and placed a significant burden on extractions and
washes to control impurities throughout the course of the synthesis.
The MOC cyclization employed by Kawabata for the (R)-2-methylproline synthesis utilized substrate (7)
for the key cyclization step (bromide leaving group, Boc-nitrogen protection, and ethyl ester carboxyl
protection). In evaluating the MOC methodology it was critical to determine if this precursor was a requisite
intermediate for the synthesis. Structurally similar alternate targets (9a, 9b) could lead to a more flexible and
manufacturable process (see Figure 1). Switching the leaving group from bromide to chloride would provide
an opportunity to introduce the halopropyl sidechain in a single step. Changing the nitrogen protecting group
from Boc to Cbz would allow for intercepting the veliparib discovery synthesis at a key intermediate.
Finally, utilization of a benzyl ester would provide a UV active chromophore for tracking reaction progress
by HPLC11b.
Br
Cl
H
H
Me
Me
R'O2C
N
R'O2C
N
Boc
7, R' = Et
CO2R
, R' = Bn, R = t-Bu
9b
9a
, R', R = Bn
Figure 1. Comparison of Cyclization Precursors.
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Mechanism of the MOC Cyclization. The mechanism proposed by Kawabata for the memory of chirality
cyclization is shown in Scheme 5.11 Deprotonation can occur from either of two substrate conformers; the
resultant enolates are axially chiral due to hindered rotation about the C-N bond.
4
5
Scheme 5. Proposed Mechanism of the Memory of Chirality Cyclization.
6
7
8
9
Boc
Boc
O
OR
OK
Me
OR
KHMDS
Me
N
Me
N
RO2C
N
favored
H
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Boc
Br
Br
A
C
(R)-enantiomer
rotational barrier
~ 16 kcal/mol*
Br
Br
O
OR
OK
Me
KHMDS
Me
OR
Me
N
RO2C
N
N
disfavored
H
Boc
Boc
Boc
(S)-enantiomer
B
D
Deprotonation of conformer A in which the hydrogen is antiperiplanar to the Boc group leads to enolate C
which cyclizes to afford the observed major product with net retention of configuration. Deprotonation of
conformer B, which would generate the enantiomeric enolate D upon cyclization, suffers an unfavorable
steric interaction between the Boc protecting group and the incoming base. Because enolates C and D are
atropisomeric, racemization can occur by rotation around the C-N bond. This rotational barrier has been
estimated by Kawabata to be about 16 kcal/mol for a structurally similar system.12
Based on this mechanism changes to the cyclization substrate could potentially impact the selectivity of the
cyclization.
Nature of the Leaving Group. All of the previously published examples for the MOC cyclization utilized
bromide as the leaving group. Switching to chloride could potentially impact selectivity if displacement of
the chloride were slow relative to carbon-nitrogen bond rotation.
Nature of the Nitrogen Protection. Kawabata reported that selection of the nitrogen protecting group was
critical to preserving chirality in the enolate formation step. The choice of Boc protection was based on
results obtained previously for work carried out on intermolecular alkylations of 2-amino acid derivatives12.
The potential impact of switching from Boc to Cbz was unclear for this intramolecular cyclization; however
there are no obvious steric or electronic considerations that would preclude consideration of Cbz protection
for the substrate.
Nature of the Ester Protection. The ester group is distal to the site of enolization and cyclization.
Consequently, changing the nature of the ester protection was expected to have minimal impact on the
selectivity in the cyclization.
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Probing the Impact of Changes to Substrate Structure on Selectivity in the Cyclization-Identification
of the Target. To probe the impact of the proposed changes to the cyclization precursor, compounds 9a and
9b were synthesized. They were then subjected to cyclization under standard conditions (Scheme 6).11
1
2
3
4
5
Scheme 6. Cyclization of Test Substrates.
6
7
Cl
M-HMDS
8
9
H
DMF
Me
Me
BnO2C
N
10
11
12
13
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BnO2C
N
cooling
30 minutes
CO2R
CO2R
10a,
10b,
R = t-Bu
R = Bn
9a,
9b,
R = t-Bu
R = Bn
Table 1. Effect of Base, Temperature and Protecting Group on the Stereoselectivity of the Cyclization Reaction.
Temp
(°C)
Selectivity
(R:S)
Entry Substrate
Base
1
2
3
4
5
6
7
8
9a
9b
9a
9a
9a
9a
9a
9a
KHMDS in toluene
KHMDS in toluene
KHMDS in toluene
KHMDS in THF
LiHMDS in THF
NaHMDS in THF
LiHMDS in THF
LiHMDS in THF
−60
−60
−20
−20
−20
−20
−10
0
98:2
97:3
96:4
96:4
95.5:4.5
89:11
95:5
94:6
The selectivity of cyclization of the Boc substrate (98:2, 96% ee, Table 1, entry 1) was virtually identical to
that observed by Kawabata for the conversion of 7 to 8 (95% ee). This result confirmed that replacement of
the bromide leaving group with the chloride group does not significantly slow the cyclization rate and
reaffirmed the predicted lack of interference from the change in ester group on the reaction stereoselectivity.
Of equal importance was the fact that switching nitrogen protection from Boc to Cbz had no significant
impact on selectivity (97:3, 94% ee, entry 2).
While both the Cbz and Boc protected substrates (9a and 9b respectively) gave excellent yield and
selectivity in the cyclization reaction (Table 1), neither gave enantiomerically pure material. As an additional
control element in the synthesis, it was necessary to investigate the ability of downstream isolation
operations to reject the minor enantiomer. In the case of the Cbz-protected product, hydrolysis of the benzyl
ester followed by recrystallization of the acid 3b led to no improvement in ee (Scheme 7).
Scheme 7. Hydrolysis and Recrystallization of the Cbz-Protected Cyclization Product.
LiOH
Me
Me
HO2C
BnO2C
N
N
MeOH/H2O
crystallization
Cbz
Cbz
10b
91% ee
3b
91% ee
As previously described, when Cbz-protected 3b of lower optical purity was carried forward the optical
purity of the corresponding veliparib penultimate 2b could be improved by dissolution of the crude product
and removal by filtration of the less soluble racemate. However, this strategy carries a risk that a new less-
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soluble form of the desired enantiomer would render this mechanism for optical enrichment unusable.
Therefore, the Cbz-protection route to veliparib was ultimately abandoned.
1
2
3
4
5
6
In contrast, Boc-protected amino acid 3a material with 91% ee improved to > 99% ee after a single
crystallization of the unpurified deprotection product from heptanes (Scheme 8).
7
8
Scheme 8. Hydrogenolysis and Recrystallization of the Boc-Protected Cyclization Product.
9
1) Pd/C, H2
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MeOH
Me
Me
HO2C
BnO2C
N
N
2) heptanes
crystallization
87.5%
Boc
Boc
10a
91% ee
3a
> 99% ee
Because the Boc-protected 3a could reliably be recrystallized to give material with the desired ee and it
allowed for control of the final product stereochemical purity to be introduced at an earlier stage in the
synthesis, the Boc-protected series was selected for the veliparib synthesis. All subsequent optimization was
carried out on the Boc-substrate 9a.
Optimization of the MOC Cyclization Conditions-Additional Considerations. Additional
considerations for the process centered on reaction temperature and base selection. Reactions carried out by
Kawabata were performed at −60 °C. The ability to carry out the reaction at higher temperature would
improve synthetic flexibility and robustness. In evaluating the base for the cyclization reaction, KHMDS,
while commercially available, can be more challenging to source on large scale. Use of a cheaper, more
readily available base could make the synthesis easier and more economical.
Cyclization Temperature. Investigation of the impact of temperature on the selectivity of the cyclization of
the Boc-protected substrate 9a using KHMDS in toluene as the base revealed that 92% ee could be obtained
at temperatures of up to −20 °C (entry 3, Table 1). With the ability to perform the reaction at an acceptable
temperature, we next focused on the nature of the base.
Base Selection. With regard to the source of the base, we found that a solution of KHMDS in THF
perfromed identically to a toluene solution (entries 4 and 3, Table 1). Because other bases were more readily
available as solutions in THF, we continued our optimizations using these. The identity of the metal cation
plays an unexpected role in the selectivity of the cyclization of Boc-protected substrate 9a. Both KHMDS
(entry 4, Table 1) and LiHMDS (entry 5, Table 1) afforded product with > 90% ee when added as a THF
solution. Reaction using NaHMDS, however, afforded product with significantly lower ee (entry 6, Table 1).
Based on its widespread availability and the high selectivity in the cyclization reaction, LiHMDS was chosen
as base for the veliparib process.
The reaction using LiHMDS proved to be quite robust with regard to temperature. Even at −10 °C (entry 7,
Table 1) and 0 °C (entry 8, Table 1) the reaction provided very high selectivity.
Synthesis of the Boc-(R)-2-Methylproline Target. Kawabata’s preparation of cyclization substrate 7,
while short, required chromatography for purification. In adapting this process to the efficient synthesis of
9a, elimination of the chromatography step was an important consideration. Additionally, because all of the
intermediates in the synthesis are oils, the inability to purify through recrystallization imparted a significant
burden on the extractions and washes to control impurities (Scheme 9).
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3
4
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6
7
8
To optimize process efficiency, a study was undertaken to introduce the halopropyl group in a single step
using a 1,3-dihalopropane. Selective monoalkylation of primary amines has been a long standing and
fundamental challenge in organic synthesis.13 Several approaches to this problem are reported in the
literature including base promoted alkylation (with13,14 and without partial N-protection15), reductive
amination,16 and reductive alkylations.17 Most of these, by virtue of the reaction conditions would preclude
the direct introduction of a halopropyl moiety. A more direct approach for introduction of the halopropyl
functionality would employ reaction of the amino acid with a differentially substituted 1,3-dihaloalkane.
While base catalyzed alkylations are operationally simpler, they are also prone to over-alkylation. The
proposed monoalkylation of alanine benzyl ester with a 1,3-dihalopropane was further complicated by
possible intermolecular couplings and intramolecular cyclization. Fortunately, when alanine benzyl ester
hydrochloride (11) was reacted with 1-iodo-3-chloropropane in the presence of diisopropylethylamine in
acetonitrile, the desired monoalkylated product (12) was the major product (Scheme 10). In addition to
recovered unreacted starting material, small amounts of intramolecular cyclization (13) and dialkylation (14)
impurities were formed. Because 1-iodo-3-chloropropane was difficult to source in large quantities, use of
the cheaper and more readily available 1-bromo-3-chloropropane was evaluated. Except for a longer reaction
time and slightly different impurity profile, there were no noticeable effects in switching from iodide to
bromide.
9
10
11
12
13
14
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In practice once approximately 80% of the starting alanine benzyl ester had been consumed, the rate of
dialkylation and azetidine impurity formation surpassed that of product and the reaction was halted. The
alkylation reaction mixture was quenched and made mildly acidic by dilution with aqueous citric acid.
Residual 1-bromo-3-chloro propane was then removed by washing with heptanes, the protonated basic
species remaining in the aqueous acetonitrile phase. The pH was then adjusted to around 6 with aqueous
sodium hydroxide and the alkylation products were extracted into MTBE; unreacted alanine benzyl ester
remained in the aqueous phase. Attempts to isolate monoalkylation product 12 by crystallization were
unsuccessful so the downstream process was designed to remove the remaining impurities. The partially
purified monoalkylation product 12 (along with impurities 13 and 14) was treated with excess di-t-
butyldicarbonate to generate the Boc-protected cyclization substrate 9a. Excess di-t-butyldicarbonate was
decomposed by reacting with N,N-dimethylethylenediamine. The crude solution of 9a was then washed with
a dilute aqueous phosphoric acid solution. The Boc-protected cyclization precursor remained in the organic
phase and tertiary amine impurities (13, 14 and the Boc-protected N,N-dimethylethylenediamine) partitioned
into the aqueous phase and were discarded.
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Scheme 9. Non-chromatographic Process to the Cyclization Substrate 9a.
1
2
3
4
5
6
7
8
X
Cl
I
Cl
Cl
Organic
or
Br
pH to 5.8
MTBE
Me
NH2
Me
i-Pr2NEt
MeCN
Aqueous
Aqueous
BnO2C
BnO2C
NH3+Cl-
2N citric acid
heptane
11
Organic
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
Me
BnO2C
Cl
NH
+
BnO2C
N
BnO2C
N
+
Cl
Cl
13
14
12
X = I 12:13:14
X = Br 12:13:14
= 82:6:9
= 83:8:6
1) (Boc)2O
NH2
2)
N
1N H3PO4
MTBE
Me
Me
BnO2C
N
BnO2C
Cl
N
+
+
Cl
Me
13
14
Boc
BnO2C
Cl
N
O
O
N
N
H
9a
93% Purity by HPLC
72% Yield for 2 steps
Aqueous
Organic
This sequence afforded cyclization substrate 9a in 93% purity and a yield of 72% for the two step process
without requiring chromatographic purification. The memory of chirality cyclization was performed at -30
°C on large scale to afford the benzyl ester 10a with 91.2% ee in quantitative yield. Deprotection by
hydrogenolysis and crystallization of the acid from heptanes produced the desired (R)-Boc-2-methylproline
2a in 88% yield with an ee of 99.6%.
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Scheme 10. Synthetic Route to (R)-Boc-2-Methylproline 3a.
1
2
3
4
5
6
7
Br
Cl
Me
NH3 Cl-
Me
NH
DIPEA
MeCN
+
BnO2C
BnO2C
Cl
11
12
74%
8
9
Me
LiHMDS
THF/DMF
1) (Boc)2O
MTBE
Me
BnO2C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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59
60
Boc
BnO2C
Cl
N
N
-30 oC
Boc
2)
H2N
98%
NMe2
9a
10a
100%
91.2% ee
H2,
5% Pd/C
EtOH
Me
HO2C
N
crystallization
from heptanes
Boc
3a
88%
99.6% ee
Thus, a process was developed capable of producing multikilogram quantities18 of (R)-Boc-2-
methylproline 3a in a 64% overall yield for the four-step process from alanine benzyl ester hydrochloride 11.
With a reliable source of the (R)-Boc-2-methylproline in hand its application to the synthesis of veliparib
was investigated (Scheme 11).
Synthesis of Veliparib
The synthesis of veliparib began by reaction of (R)-Boc-2-methylproline 3a with CDI to afford the
corresponding acylimidazolide. Without isolation of the activated species, 2,3-diaminobenzamide
dihydrochloride 45 was added and the mixture was stirred until formation of the 3-coupled intermediate 15
was complete. Again, without isolation, a mixture of sodium acetate and glacial acetic acid was added. With
heating, 15 underwent cyclodehydration yielding the Boc-protected benzimidazole intermediate 2a. Dilution
of the crude reaction mixture with water, followed by an extractive work up with ethyl acetate, yielded, after
crystallization, pure Boc-benzimidazole 2a in 74% yield for the activation/coupling/cyclization sequence.
The Boc-group was cleaved by treatment with HCl in isopropanol yielding veliparib dihydrochloride 16 in
93% yield. The dihydrochloride penultimate was converted to veliparib free base 1 with aqueous sodium
hydroxide and sodium carbonate in water (96% yield). The overall yield for the three-step process from 3a
was 66%.
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Scheme 11. The Synthesis of Veliparib.
1
CONH2
NH3+Cl-
2
3
4
5
6
NH3+Cl-
4
7
8
9
CDI
NMP
imidazole
RT
CONH2
NaOAc 2 eq.
HOAc 2 eq.
120 °C
NH2
Me
N
Me
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
NH
Me
N
N
HO2C
90 °C
74%
O
Boc
3a
Boc
O
N
Boc
15
NaOH,
Na2CO3
H2O
HCl
IPA
CONH2
N
CONH2
CONH2
Me
Me
Me
N
N
80 °C
N
H
N
N
H
N
N
H
N
93%
96%
H
H
Boc
2a
2HCl
16
1
veliparib
CONCLUSION
.
26
27
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43
44
45
46
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53
54
55
56
57
58
59
60
In conclusion, a rapid, scalable synthesis of (R)-Boc-2-methylproline utilizing a modification of
Kawabata’s memory of chirality process has been demonstrated. The process requires no chromatography
and has been executed on multikilogram scale with excellent yield (64%) and optical purity (99.6% ee) for
the resultant (R)-Boc-2-methylproline 3a product (Scheme 10). This material was carried on to produce
veliparib, a PARP enzyme inhibitor, in 66% overall yield and high optical purity for the multistep process
(Scheme 11).
EXPERIMENTAL SECTION
.
General Information. All reagents and solvents were purchased from commercial vendors and used
without further purification. 1H NMR spectra were recorded on a either a 400 or 700 MHz spectrometer and
chemical shifts (δ) are reported in parts per million (ppm) downfield from TMS. Data are represented as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b =
13
broad), coupling constant (J, Hz), and integration. C NMR spectra were obtained at 100 or 176 MHz and
referenced to the internal solvent signals (central peak is 77.0 ppm in CDCl3).
Analytical HPLC was conducted on an Agilent Technologies Model 1200 system equipped with a DAD –
UV detector. The reaction progress was tracked using reverse phase HPLC. Samples were analyzed using a
YMC ODS-AQ 120 Å column, 150 x 4.6 mm, 3 µm (AQ12S03-1546WT). A column temperature of 20 °C
was utilized with a flow rate of 1.5 ml/min, a 16 minute run time, 20 µL injection volume and detection at
210 nm. The mobile phases consisted of 0.05% H3PO4 in water (mobile phase A) and 0.05% H3PO4 in
acetonitrile (mobile phase B) and the following elution gradient was utilized: Gradient from 90:10 (A:B) to
10:90 (A:B) over 12.0 minutes, hold at 10:90 (A:B) for 1.3 minutes, then return to 90:10 (A:B) over 0.01
minutes followed by equilibration at 90:10 (A:B) for 2.69 minutes.
The chiral purity of 3a was determined by chiral HPLC. Samples were analyzed using a Chiralpak AD-H
column, 250 x 4.6 mm (Diacel Chemical Industries, LTD). Column temperature of 40 °C with a flow rate of
1.2 ml/min, a 12 minute run time, 10 µL injection volume and detection at 210 nm. The mobile phase was
prepared by mixing 97% hexane and 3% EtOH with 0.1% TFA and the method was isocratic.
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(S)-Benzyl-2-(3-chloropropylamino)propanoate (12). L-Alanine benzyl ester hydrochloride 11 (24.00 g,
111.28 mmol, 1.00 equiv), acetonitrile (96 mL), 1-bromo-3-chloropropane (70.63 g, 448.62 mmol, 4.03
equiv) and N,N-diisopropylethylamine (43.20 g, 334.24 mmol, 3.00 equiv) were charged to a reactor and
mixed at room temperature for 74 hours. The reaction mixture was cooled to 20 °C and quenched with 112 g
of 2 N aqueous citric acid. The excess 1-bromo-3-chloropropane was removed from the aqueous phase by
washing twice with heptanes (2 × 105 mL). The pH of the aqueous phase was adjusted to pH 5.8-6.0 with 4
N aqueous NaOH solution. The product was extracted from the aqueous phase with MTBE (2 × 120 mL and
1 × 100 mL). The combined organic phases were washed with 76 mL of saturated aqueous sodium
bicarbonate solution and 48 mL of brine. The organic phase was dried by passing it through a bed of sodium
sulfate and distilled to approximately half of the original volume. Assay yield 74%, HPLC purity = 91.8
area%. 1H NMR (400 MHz, Chloroform-d) δ 7.44 – 7.21 (m, 5H), 5.16 (d, J = 1.9 Hz, 2H), 3.70 – 3.50 (m,
2H), 3.37 (q, J = 7.0 Hz, 1H), 2.69 (ddt, J = 57.5, 11.5, 6.8 Hz, 2H), 1.89 (pd, J = 6.5, 1.5 Hz, 2H), 1.46 (d, J
1
2
3
4
5
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7
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9
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11
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46
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53
54
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56
57
58
59
60
13
= 7.0 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). C{1H} NMR (101 MHz, Chloroform-d) δ 175.1, 135.6, 128.4,
128.2, 128.1, 66.7, 57.0, 45.2, 43.2, 33.3, 19.5.
In order to prepare a solid HCl salt derivative of 12 for characterization, the corresponding Boc-protected
derivative 9a was treated with 4 N HCl in dioxane.
To a 40-mL vial equipped with magnetic stirring was charged 1.07 g (3.01 mmol) of 9a, 4 mL of dioxane
and 2 mL (2.66 equiv) of 4 M HCl in dioxane. The reaction mixture was stirred at ambient temperature
overnight. The following morning the resultant solid was isolated by filtration, washed with fresh dioxane
and dried to a constant weight. The HCl salt was submitted for combustion analysis. Anal. Calcd for
C13H19Cl2NO2: C, 53.44; H, 6.55; N, 4.79. Found: C, 53.23; H, 6.66; N, 4.71
(S)-Benzyl-2-((tert-butoxycarbonyl)(3-chloropropyl)amino)propanoate
(9a).
(N)-3-Chloropropyl
alanine benzyl ester 12 (18 wt% solution in MTBE, 10.18 g in 56.56 g of solution) was charged to a reactor
containing di-tert-butyldicarbonate (10.00 g 1.15 equiv). This mixture was stirred at 25 °C overnight. N,N-
dimethylethylenediamine (1.15 g, 0.33 equiv) was then charged to react with the excess di-tert-
butyldicarbonate. After mixing at 25 °C for 1 h, the reaction mixture was washed twice with 26 mL of 1 N
aqueous H3PO4 solution to remove basic impurities (Boc-protected N,N-dimethylethylenediamine, residual
N,N-dimethylethylenediamine, azetidine 13, and dialkyl 14). The product phase was then washed with 5%
aqueous NaHCO3, water, and brine. The product solution was passed through a bed of Na2SO4, and then
concentrated by vacuum distillation to dryness. Following a chase distillation with toluene the product was
diluted with toluene (9 mL). The product solution was transferred to a tared, labeled bottle and assayed (98%
1
step yield, HPLC purity = 97.5 area%). H NMR (400 MHz, Chloroform-d) δ 7.33 (s, 5H), 5.14 (d, J = 7.6
13
Hz, 2H), 4.50 – 3.98 (m, 1H), 3.72 – 3.08 (m, 4H), 2.18 – 1.84 (m, 2H), 1.61 – 1.23 (m, 12H). C{1H}
NMR (101 MHz, Chloroform-d) δ 171.4, 154.5, 128.4, 128.2, 128.1, 80.7, 80.6, 80.6, 77.2, 67.1, 56.7, 55.5,
45.3, 44.1, 43.0, 42.8, 32.9, 32.3, 28.7, 16.3, 15.7. Anal. Calcd for C18H26ClNO4: C, 60.75; H, 7.36; N, 3.94.
Found: C, 60.59; H, 7.44; N, 3.95.
(R)-2-Benzyl-1-tert-butyl-2-methylpyrrolidine-1,2-dicarboxylate (10a). To a reactor was charged 50.00
g of a 60 w/w% solution of N-Boc-N-chloropropyl alanine benzyl ester (9a) in toluene. DMF (240 mL) was
added and the solution was cooled to <−30 °C. LiHMDS (70.00 g of 24.7 wt% in THF, 1.25 equiv) was
added continuously over ~3 hours, such that the internal temperature was maintained. After 30 min., (post
base addition) the reaction was sampled. HPLC revealed no starting material present. The reaction was
quenched into 250 g of 10% aqueous NH4Cl solution and the resulting mixture was extracted twice with
heptane (2 × 225 mL). The combined heptane layers were washed with 10% aqueous NaCl solution (206 g)
then 20% aqueous NaCl solution (200 g). The heptane layer was distilled; i-PrOAc was added (175 mL) and
distilled once again. More i-PrOAc (175 mL) was added, the solution was filtered to remove inorganic salts,
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then more i-PrOAc (30 mL) was charged as a rinse. Finally, the i-PrOAc was distilled to about 40 g,
followed by an i-PrOAc rinse. Assay yield = 100%, ee of product = 91.2%. H NMR (400 MHz,
1
2
3
4
5
6
7
8
1
Chloroform-d) δ 7.22–7.10 (m, 5H), 5.10 – 4.85 (m, 2H), 3.49 – 3.26 (m, 2H), 2.08 – 1.88 (m, 1H), 1.81 –
1.59 (m, 3H), 1.42 (d, J = 24.1 Hz, 3H), 1.23 (d, J = 22.8 Hz, 9H). 13C{1H} NMR (101 MHz, Chloroform-d)
δ 232.8, 174.0, 153.1, 135.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 116.5, 79.9, 79.4, 77.3, 77.2, 77.0,
1
76.7, 66.7, 65.3, 64.9, 48.1, 48.0, 40.5, 39.4, 28.7, 28.5, 23.6, 23.5, 23.0, 22.6, 1.7. H NMR (400 MHz,
Methanol-d4) δ 7.34 – 7.11 (m, 5H), 5.18 – 4.91 (m, 2H), 3.54 – 3.28 (m, 2H), 2.14 – 1.96 (m, 1H), 1.94 –
1.72 (m, 3H), 1.45 (d, J = 3.6 Hz, 3H), 1.27 (d, J = 27.6 Hz, 9H). 13C{1H} NMR (101 MHz, Methanol-d4) δ
175.1, 154.9, 136.9, 136.8, 129.2, 129.0, 128.9, 128.9, 128.7, 128.7, 127.5, 81.5, 80.8, 67.9, 67.8, 66.5, 66.3,
41.3, 40.3, 32.7, 28.9, 28.8, 28.7, 24.4, 23.7, 23.6, 22.6. Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N,
4.39. Found: C, 67.32; H, 7.88; N, 4.45.
9
10
11
12
13
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(R)-1-(tert-Butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (3a)19. A pressure reactor was
charged with 5% Pd/C (2.56 g of 5% Pd/C, 3 wt%) and purged with nitrogen. The (R)-Boc-2-methylproline
benzyl ester (10a, 146.32 g of 59.4 wt%, 87.13 g = 272.79 mmol) was added, along with 426 mL of
denatured EtOH. The mixture was hydrogenated (40 psig) at room temperature. After completion of the
reaction, the catalyst was filtered off (99.3% assay yield, 91.4% ee product), the product solution was
concentrated and then chase distilled with 275 mL of isopropyl acetate. Heptanes were charged (290 mL) to
the reactor and distilled off under vacuum, and then heptanes were charged one final time (730 mL). The
mixture was heated to reflux to dissolve the solids, and then cooled to 20 °C to crystallize the product. The
solids were isolated by filtration and washed with 120 mL of heptanes and dried under vacuum at 50 °C to
yield 54.57 g (88% yield, HPLC purity = 100 area% of the title compound. The benzyl ester starting solution
1
assayed at 91.2% ee; the acid product assayed at 99.6% ee. H NMR (400 MHz, Chloroform-d) δ 11.11 (s,
1H), 3.66 – 3.39 (m, 2H), 2.53 – 2.20 (m, 1H), 2.02 – 1.75 (m, 3H), 1.56 (d, J = 34.1 Hz, 3H), 1.44 (d, J =
17.5 Hz, 9H). 13C{1H} NMR (101 MHz, Chloroform-d) δ 180.4, 177.3, 155.1, 153.1, 116.5, 80.9, 80.4, 77.3,
77.2, 77.0, 76.7, 66.1, 64.8, 48.6, 47.9, 40.5, 39.0, 28.7, 28.6, 23.2, 23.1, 23.1, 22.6. Anal. Calcd for
C11H19NO4: C, 57.62; H, 8.35; N, 6.11. Found: C, 57.66; H, 8.07; N, 6.10
(R)-tert-Butyl-2-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidine-1-carboxylate (2a).
Activation: To a 1-L three neck flask was charged 1H-imidazole (11.85 g, 174 mmol) and di(1H-imidazol-
1-yl)methanone (CDI, 35.10 g, 183 mmol). To a second 250 mL flask equipped with magnetic stirring was
charged 128 mL of NMP and (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (40.00 g,
174 mmol). The mixture was stirred to dissolve the solid acid at room temperature. The Boc-acid solution
was charged to the CDI/imidazole with stirring, followed by a 40 mL NMP rinse.
At t = 2.0 hours a sample was pulled, quenched with benzylamine, then assayed for the benzylamide. The
amide was measured at 99.4% vs theory, and the reaction was called complete.
Coupling: 3-carbamoylbenzene-1,2-diaminium chloride5 (39.00 g, 174 mmol) was charged to the
acylimidazolide solution, and heated to 90 °C overnight. The following morning a sample was pulled,
quenched with benzylamine, and then assayed for the benzylamide. HPLC revealed the acylimidazolide was
consumed.
Cyclization: To the reaction flask was charged 28.70 g of anhydrous sodium acetate, and 21.00 g of
glacial acetic acid. The flask was sealed and the reaction contents were heated to an internal temperature of
120 °C. After heating for 8 hours HPLC revealed the uncyclized starting material had been consumed. Assay
yield = 81.9%. The reaction mixture was then cooled to room temperature.
After diluting the reaction mixture with 322 g of 7% aqueous NaCl solution the quenched reaction mixture
was extracted with three times with EtOAc. The pooled organic phases were then washed 3 × 480 g with
15% aqueous NaCl solution. Loss of product to pooled 15% NaCl washes was 1.6%
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The organic phase was concentrated to a final volume of approximately 150 mL. Methanol (about 700 g)
was charged while maintaining a volume of 150-mL in a constant volume distillation. Finally enough
methanol was added to raise the total volume to approximately 860 mL. The mixture was heated under reflux
to dissolve all solids and then cooled slowly to room temperature overnight.
1
2
3
4
5
6
7
8
Under vacuum, the contents of the reaction flask were slowly distilled to a final volume of approximately
120 mL. The resultant slurry was cooled to 0 °C, and then filtered. The wet cake was washed twice with
fresh, cold methanol, and then dried in an oven at 45 °C for >2 h under house vacuum with a stream of dry
nitrogen. The liquors and washes were pooled and analyzed for product loss. Loss to liquors and wash =
4.9%. Dry weight = 48.33 g, 74%, HPLC purity = 100 area%. Note: product 2a crystallizes as the methanol
solvate. 1H NMR (700 MHz, DMSO-d6) δ 12.62 (d, J = 73.9 Hz, 1H), 9.32 (dd, J = 19.3, 3.6 Hz, 1H), 7.81
(dd, J = 7.6, 1.0 Hz, 1H), 7.72–7.52 (m, 2H), 7.28 (td, J = 7.7, 4.2 Hz, 1H), 3.78–3.62 (m, 1H), 3.53 (dt, J =
10.4, 6.2 Hz, 1H), 2.24–2.06 (m, 2H), 2.00 – 1.89 (m, 2H), 1.84 (d, J = 21.4 Hz, 3H), 1.15 (d, J = 301.7 Hz,
9
10
11
12
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48
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60
13
9H). C{1H} NMR (176 MHz, DMSO-d6) δ 166.8, 166.8, 161.1, 160.5, 153.3, 153.2, 141.0, 140.9, 135.4,
135.3, 122.5, 122.5, 122.1, 121.9, 115.3, 115.0, 79.1, 78.7, 62.0, 61.8, 49.1, 48.4, 48.0, 42.9, 42.2, 40.4, 40.2,
40.1, 40.0, 39.9, 39.8, 39.7, 28.6, 28.0, 24.1, 23.3, 22.9, 22.6.
To prepare a sample of solvent free material a portion of the product was carried through the following
procedure. Charge to a 500 mL 3-neck RB flask equipped with mechanical stirring, J-Kem temperature
controller, heating mantle, and dry nitrogen line, 30.00 g of the Stage 1 material (previously recrystallized
twice from MeOH) along with 21.90 g of DMSO and 159.90 g of purified water. The mixture was warmed
to 60 °C with stirring overnight. Cool the reaction slurry to ambient temperature. Filter product slurry,
recirculating liquors to aid in product transfer. Wash cake with 190 mL of fresh water. Dry in vacuum oven
at 55 °C over the weekend. Remove sample from drying oven. Final dry weight = 27.04 g (90% recovery).
1
1H NMR reveals MeOH has been removed. Package 25.00 g of the dried material in an amber bottle. H
NMR (700 MHz, DMSO-d6) δ 12.62 (d, J = 73.8 Hz, 1H), 9.32 (dd, J = 19.1, 3.7 Hz, 1H), 7.81 (d, J = 7.5
Hz, 1H), 7.70–7.61 (m, 2H), 7.27 (td, J = 7.8, 4.3 Hz, 1H), 3.77–3.62 (m, 1H), 3.53 (dt, J = 10.5, 6.3 Hz,
1H), 2.25–2.05 (m, 2H), 2.00–1.89 (m, 2H), 1.84 (d, J = 21.3 Hz, 3H), 1.15 (d, J = 301.7 Hz, 9H). 13C{1H}
NMR (176 MHz, DMSO-d6) δ 166.8, 166.8, 161.1, 160.5, 153.3, 153.2, 141.0, 140.9, 135.4, 135.3, 122.5,
122.5, 122.1, 121.9, 115.3, 115.0, 79.1, 78.7, 62.0, 61.8, 48.4, 48.0, 42.9, 42.2, 40.4, 40.3, 40.1, 40.0, 39.9,
39.8, 39.7, 28.7, 28.0, 24.1, 23.3, 22.9, 22.6. Anal. Calcd for C18H24N4O3: C, 62.77; H, 7.02; N, 16.27.
Found: C, 62.77; H, 6.98; N, 16.22.
(R)-2-(2-Methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide, Dihydrochloride, (16).
Deprotection: To a 1000-mL flask was charged 53.91 g of the cyclization product 2a (as the methanol
solvate) and 459 mL isopropyl alcohol. The mixture was stirred and heated to 65 °C until the solids had
dissolved. To this solution was added 38 mL conc. hydrochloric acid. The reaction temperature was raised to
80 °C, and then held at temperature for 4 hours. The reaction mixture was cooled to room temperature,
filtered and washed with fresh i-PrOH. The wet cake was dried in a vacuum oven at 50 °C with a nitrogen
purge until dry. Dry weight = 42.04 g, 93%. HPLC purity = 99.5 area%, 5.1% loss to liquors and washes. 1H
NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.61 (s, 1H), 9.55 (s, 1H), 8.92 (s, 1H), 7.86 (dd, J = 7.6, 1.1
Hz, 1H), 7.72 (dd, J = 8.0, 1.1 Hz, 2H), 7.51–7.22 (m, 1H), 2.55 (ddd, J = 13.1, 8.1, 5.2 Hz, 1H), 2.24 (dt, J
= 13.1, 7.9 Hz, 1H), 2.10 (dddd, J = 13.5, 11.0, 8.2, 5.6 Hz, 1H), 1.89 (s, 3H), 1.83 (ddd, J = 15.4, 10.4, 6.3
13
Hz, 1H). C{1H} NMR (101 MHz, DMSO-d6) δ 165.3, 153.7, 137.8, 135.5, 122.5, 122.1, 121.8, 115.8,
64.9, 44.1, 40.1, 39.9, 39.8, 39.7, 39.5, 39.3, 39.1, 38.9, 36.9, 23.3, 22.4. Anal. Calcd for C13H18Cl2N4O: C,
49.22; H, 5.72; N, 17.66. Found: C, 49.37; H, 5.74; N, 17.49
(R)-2-(2-Methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide
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Free Basing: A 6.34 g (20 mmols) sample of the dihydrochloride starting material 16 was charged to a
reactor and dissolved in 17.6 mL of water. The dihydrochloride was converted to the monohydrochloride by
adding 3.28 mL of 20% aqueous sodium hydroxide solution followed by precipitation with an excess of 20%
aqueous sodium carbonate solution. The resultant slurry was filtered then washed with water. The product
was dried to a constant weight in a vacuum oven with a slight nitrogen purge at 50 °C. Dry weight = 4.68 g,
96%, HPLC purity = 100.0 area%. 1H NMR (700 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.79 (d, J = 7.4 Hz, 1H),
7.74–7.56 (m, 2H), 7.24 (t, J = 7.7 Hz, 1H), 3.11–3.07 (m, 1H), 2.85 (ddd, J = 10.4, 8.0, 5.2 Hz, 1H), 2.45–
1
2
3
4
5
6
7
8
13
2.33 (m, 1H), 1.93–1.72 (m, 2H), 1.72–1.62 (m, 1H), 1.56 (s, 3H). C{1H} NMR (176 MHz, DMSO-d6) δ
9
163.6, 122.3, 121.6, 62.4, 46.6, 40.4, 40.3, 40.1, 40.0, 39.9, 39.8, 39.7, 39.7, 27.9. Anal. Calcd for
10
11
12
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15
16
17
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C13H16N4O: C, 63.91; H, 6.60; N, 22.93. Found: C, 63.98; H, 6.57; N, 22.93.
ASSOCIATED CONTENT
.
Supporting Information: The supporting information is available free of charge on the ACS Publications
website at DOI:
1H and 13C spectra for adducts 1, 2a, 3a, 9a, 10a, 12 and 16.
ACKNOWLEDGEMENTS
.
Lawrence Kolaczkowski, David Barnes, Anthony Haight, Wayne Pritts and Adam Schellinger are
employees of AbbVie Inc. and Jufang Barkalow is a former employee of AbbVie. The design, study
conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the
interpretation of data, review, and approval of the publication.
REFERENCES
(1) Donawho, C. K.; Luo, Y.; Luo, Y-p.; Penning, T.D.; Bauch, J. L.; Bouska, J. J.; Bontcheva-Diaz, V. D.; Cox, B. F.; DeWeese, T. L.;
Dillehay, L. E.; Ferguson, D.C.; Ghoreishi-Haack, N. S.; Grimm, D. R.; Guan, R.; Han, E. K.; Holley-Shanks, R. R.; Hristov, B.; Idler, K. B.;
Jarvis, K.; Johnson, E. F.; Kleinberg, L. R.; Klinghofer, V.; Lasko, L. M.; Liu, X.; Marsh, K. C.; McGonigal, T. P.; Meulbroek, J. A.; Olson, A.
M.; Palma, J. P.; Rodriguez, L. E.; Shi, Y.; Stavropoulos, J. A.; Tsurutani, A. C.; Zhu, G-D.; Rosenberg, S. H.; Giranda, V. L.; and Frost, D. J.
ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models,
Clin. Cancer Res. 2007, 13, 2728-2737, http://dx.doi.org/10.1158/1078-0432.CCR-06-3039.
(2) See for example Palma, J. P.; Wang, Y.-C.; Rodriguez, L. E.; Montgomery, D.; Ellis, P. A.; Bukofzer, G.; Niquette, A.; Liu, X.; Shi, Y.;
Lasko, L.; Zhu, G.-D.; Penning, T. D.; Giranda, V. L.; Rosenberg, S. H.; Frost, D. J. Donawho, C. K. ABT-888 Confers Broad In vivo Activity in
Combination with Temozolomide in Diverse Tumors, Clin. Cancer. Res. 2009, 15, 7277-7290, http://dx.doi.org/10.1158/1078-0432.CCR-09-
1245
(3) Han, H. S.; Dieras, V.; Robson, M.; Palacova, M.; Marcom, P. K.; Jager, A.; Bondarenko, I.; Citrin, D.; Campone, M.; Telli, M. L.;
Domchek, S. M.; Friedlander, M.; Kaufman, B.; Garber, J. E.; Shparyk, Y.; Chmielowska, E.; Jakobsen, E. H.; Kaklamani, V.; Gradishar, W.;
Ratajczak, C. K.; Nickner, C.; Qin, Q.; Qian, J.; Shepherd, S. P.; Isakoff, S. J.; Puhalla S. Veliparib with temozolomide or
carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer:
randomized phase II study, Ann. Oncol. 2018, 29, 154-161, http://dx.doi.org/10.1093/annonc/mdx505.
(4) Ramalingam, S. S.; Blais, N.; Mazieres, J.; Reck, M.; Jones, C. M.; Juhasz, E.; Urgan, L.; Orlov, S.; Barlesi, F.; Kio, E.; Keiholz, U.; Qin,
Q.; Qian, J.; Nickner, C.; Dziubinski, J.; Xiong, H.; Ansell, P.; McKee, M.; Giranda, V.; Gorbunova, V. Randomized, Placebo-Controlled,
Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non–Small Cell Lung Cancer, Clin.
Cancer Res. 2017, 23, 1937–1944, http://dx.doi.org/10.1158/1078-0432.CCR-15-3069.
(5) Barkalow, J. H.; Breting, J.; Gaede, B. J.; Haight, A. R.; Henry, R.; Kotecki, B.; Mei, J.; Pearl, K. H.; Tedrow, J. S.; Viswanath, S. K.
Process Development for ABT-472, a Benzimidazole PARP Inhibitor, Org. Proc. Res. Dev. 2007, 11, 693-698, http://dx.doi.org/10.1021/
op7000194.
(6) Penning, T. D.; Zhu, G.-Z.; Gandhi, V. B.; Gong, J.; Liu, X.; Shi, Y.; Klinghofer, V.; Johnson, E. F.; Donawho, C. K.; Frost, D. J.;
Bontcheva-Diaz, V.; Bouska, J. J.; Osterling, D. J.; Olson, A. M.; Marsh, K. C.; Luo, Y.; Giranda, V. L. Discovery of the Poly(ADP-ribose)
Polymerase (PARP) Inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the Treatment of Cancer, J.
Med. Chem. 2009, 52, 514-523, http://dx.doi.org/10.1021/jm801171j
(7) Overberger, C. G.; Jon, Y. S. Synthesis and solution properties of poly(2‐methylproline), J. Polym. Sci. A Polym. Chem. 1977, 15, 1413–
1421, http://dx.doi.org/10.1002/pol.1977.170150612.
Page 15 of 17
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Page 16 of 17
(8) a) Vignola, V.; List, B. Catalytic Asymmetric Intramolecular α-Alkylation of Aldehydes, J. Am. Chem. Soc. 2004, 126, 450-451, http://dx.
doi.org/10.1021/ja0392566, b) Córdova, A.; Sundén, H.; Engqvist, M.; Ibrahem, I.; Casus, J. The Direct Amino Acid-Catalyzed Asymmetric
Incorporation of Molecular Oxygen to Organic Compounds, J. Am. Chem. Soc. 2004, 126, 8914-8915, http://dx.doi.org/10.1021/ja047930t.
(9) Torbeev, V.; Ebert, M.; Dolenc, J.; Hilvert, D. Substitution of Proline32 by α-Methylproline Preorganizes β2-Microglobulin for
Oligomerization but Not for Aggregation into Amyloids, J. Am. Chem. Soc. 2015, 137, 2524-2535, http://dx.doi.org/10.1021/ja510109p, Bisang,
C.; Weber, C.; Inglis, J.; Schiffer, C. A.; van Gunsteren, W. F.; Jelesarov, I.; Bosshard, H.. R.; Robinson, J. A. Stabilization of Type-I .beta.-Turn
Conformations in Peptides Containing the NPNA-Repeat Motif of the Plasmodium falciparum Circumsporozoite Protein by Substituting
Proline for (S)-.alpha.-Methylproline, J. Am. Chem. Soc. 1995, 117, 7904-7915, http://dx.doi.org/10.1021/ja00135a008.
(10) a) Beck, A.K.; Blank, S.; Job, K.; Seebach, D.; Sommerfeld, Th. Synthesis of (S)-2-methylproline: A General Method for the
Preparation of α-Branched Amino Acids (L-Proline, 2-methyl-), Org. Synth. 1995, 72, 62–73, http://orgsyn.org/demo.aspx?prep=cv9p0626.
b) Ferey, V.; Vedrenne, P.; Toupet, L.; Le Gall, T.; Mioskowski, C.J. Asymmetric Synthesis of α-Alkylproline Derivatives from a Chiral
Borane−Amine Adduct:ꢀ Inversion of Enantioselectivity in the Presence of a Crown Ether, J. Org. Chem. 1996, 61, 7244–7245, http://dx.doi.
org/10.1021/jo961432o.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c) Schöllkopf, U.; Hinrichs, R.; Lonsky, R. Asymmetric Synthesis of Cyclic α‐Amino Acids by the Bislactim Ether Method, Angew. Chem.
Int. Ed. 1987, 26, 143–145, http://dx.doi.org/10.1002/anie.198701431.
d) Bajgrowicz, J.; El Achquar, A.; Roumestant, M-L.; Pigière, C.; Viallefont, P. Asymmetric Synthesis of Cyclic Imino Acids via Chiral
Shiff Bases, Heterocycles 1986, 24, 2165-2167, http://dx.doi.org/10.3987/R-1986-08-2165.
e) El Achquar, A.; Boumzebra, M.; Roumestant, M-L.; Viallefont, P. 2-Hydroxy-3-pinamone as chiral auxiliary in the asymmetric
synthesis of α-amino acids, Tetrahedron 1988, 44, 5319-5332, http://dx.doi.org/10.1016/S0040-4020(01)86039-7. f) Chinchilla, R.; Galindo, N.;
and Nájera, C. Asymmetric synthesis of (S)-α-methyl α-amino acids by alkylation of chiral 3,6-dihydro-2H-1,4-oxazin-2-ones using
unactivated alkyl halides and organic bases, Tetrahedron Asymmetry 1998, 9, 2769-2772, http://dx.doi.org/10.1016/S0957-4166(98)00288-2. g)
MacQuarrie-Hunter, S.; and Carlier, P. Highly Enantioselective Synthesis of Rigid, Quaternary 1,4-Benzodiazepine-2,5-diones Derived from
Proline, Org. Lett. 2005, 7, 5305-5308, http://dx.doi.org/10.1021/ol052182d. h) For a recent review on the synthesis of quaternary proline
analogues see Calaza, M. I.; Cativiela, C. Stereoselective Synthesis of Quaternary Proline Analogues, Eur. J. Org. Chem. 2008, 3427–3448,
http://dx.doi.org/10.1002/ejoc.200800225.
(11) a) Kawabata, T.; Kawakami, S.; and Majumdar, S. Asymmetric Cyclization via Memory of Chirality:ꢀ A Concise Access to Cyclic
Amino Acids with a Quaternary Stereocenter, J. Am. Chem. Soc. 2003, 125, 13012-13013, http://dx.doi.org/10.1021/ja0378299.
b) During the review of this manuscript one of our reviewers pointed out that Kawabata has now demonstrated a Memory of
Chirality alkylation on a benzyl ester protected substrate as well as α-deuteration of an aminoacid benzyl ester (see Kasamatsu, K;
Yoshimura, T; Mandi, A; Taniguchi, T; Monde, K; Furuta, T; and Kawabata, K. α-Arylation of α-Amino Acid Derivatives with Arynes via
Memory of Chirality: Asymmetric Synthesis of Benzocyclobutenones with Tetrasubstituted Carbon, Org. Lett. 2017, 19, 352-355,
http://dx.doi.org/10.1021/acs.orglett.6b03533, and Ohtsuki, H; Takashima, M.; Furuta, T; and Kawabata, T. Direct Asymmetric Synthesis of
α-Deuterated α-Amino Acid Derivatives from the Parent α-Amino Acid via Memory of Chirality, Tetrahedron Letters, 2018, 59, 1188-1191,
http://dx.doi.org/10.1016/j.tetlet.2018.02.012, respectively). The authors thank the reviewer for making us aware of these works.
c) Kawabata has reported a highly selective asymmetric cyclization utilizing KOH in DMSO and DMF (Kawabata, T.; Moriyama, K.;
Kawakami, S.; and Tsubaki, K. Powdered KOH in DMSO: An Efficient Base for Asymmetric Cyclization via Memory of Chrality at Ambient
Temperature, J. Am. Chem. Soc. 2008, 130, 4153-4157, http://dx.dio.org/10.1021/ja077684w). We have tried Kawabata’s KOH/DMF procedure
on substrate 9a. In our hands the selectivity was poor (ee = 70.3%).
(12) Kawabata, t.; Suzuki, H.; Nagae, Y.; Fuji, K. A Chiral Nonracemic Enolate with Dynamic Axial Chirality: Direct Asymmetric
α‐Methylation of α‐Amino Acid Derivatives, Angew. Chem. Int. Ed. 2000, 39, 2155–2157, http://dx.doi.org/10.1002/1521-3773(20000616)
39:12%3C2155::AID-ANIE2155%3E3.0.CO;2-N.
(13) Dalla Croce, P.; La Rosa, C.; Ritieni, A. Selective Monoalkylation of Amines, Journal of Chemical Research, Synopses 1988, (10), 346-347.
(14) Garcia Ruano Jose Luis; Parra Alejandro; Aleman Jose; Yuste Francisco; Mastranzo Virginia M, Monoalkylation of primary amines
and N-sulfinylamides, Chemical Communications (Cambridge, England) 2009, (4), 404-406, http://dx.doi.org/10.1039/B816846F.
(15) Bhattacharyya, Shubhankar; Pathak, Uma; Mathur, Sweta; Vishnoi, Subodh; Jain, Rajeev, Selective N-alkylation of primary amines
with R–NH2·HBr and alkyl bromides using a competitive deprotonation/protonation strategy, RSC Advances, 2014, 4, 18229-18233, http://dx.
doi.org/10.1039/C4RA01915F.; R. N. Salvatore, A. S. Nagle and K. W. Jung, Cesium Effect:ꢀ High Chemoselectivity in Direct N-Alkylation of
Amines, J. Org. Chem. 2002, 67, 674-683, http://dx.doi.org/10.1021/jo010643c; (b) R. N. Salvatore, A. S. Nagle, S. E. Schmidt and K. W. Jung,
Cesium Hydroxide Promoted Chemoselective N-Alkylation for the Generally Efficient Synthesis of Secondary Amines, Org. Lett. 1999, 1,
1893-1896, http://dx.doi.org/10.1021/ol9910417; (c) C. B. Singh,V. Kavala, A. K. Samal and B. K. Patel, Aqueous‐Mediated N‐Alkylation of
Amines, Eur. J. Org. Chem. 2007, 1369-1377, http://dx.doi.org/10.1002/ejoc.200600937.
(16) Mataloni, M; Petrini, M; Profeta, R. Synthesis of Secondary Amines by Reduction of α-Amidoalkylphenyl Sulfones with Sodium
Acetoxyborohydride, Synlett 2003, (8), 1129-1132, http://dx.doi.org/10.1055/s-2003-39895.
(17) Sajiki, H.; Ikawa, T.; Hirota, K. Reductive and Catalytic Monoalkylation of Primary Amines Using Nitriles as an Alkylating Reagent,
Org. Lett. 2004, 6, 4977–4980, http://dx.doi.org/10.1021/ol047871o.
(18) The process has been successfully transferred to manufacturing scale, with batch sizes in excess of 170 kg of 3a being regularly
produced.
Page 16 of 17
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(19) Yu, J.; Liu, H.; Xia, G.; Liu, L.; Xu, Z.; Chen, Q.; Ma, C.; Sun, X.; Xu, J.; Li, P.; Shi, Y.; Xiong, B.; Liu, X.; Shen, J. Discovery of 2-Alkyl-1-
arylsulfonylprolinamides as 11ß-Hydroxysteriod Dehydrogenase Type 1 Inhibitors, ACS Med. Chem. Lett. 2012, 3, 793-798, http://dx.doi.
org/10.1021/ml300144n.
(20) Anson, M. S.; Clark, H. F.; Evan, P.; Fox, M. E.; Graham, J. P.; Griffiths, N. N.; Meek, G.; Ramsden, J. A.; Roberts, A. J.; Simmonds, S.;
Walker, M. D.; and Willets, M. Complemetary Syntheses of N,O-Protected-(S)-2-methylserine on a Multikilogram Scale, Org. Process Res.
Dev. 2011, 15, 389-397, http://dx.doi.org/10.1021/op100299d.
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