Development of a Practical Synthesis of a Farnesyltransferase Inhibitor

Article abstract of DOI:10.1021/acs.oprd.8b00307

The development of a new and practical synthesis for a farnesyltransferase inhibitor 1 is described. The new route started from 2-nitro-5-cyanotoluene (9) and afforded desired 1 in eight chemical transformations. The key step involved formation of sulfonamide 13 from a hindered β-hydroxyamine 12 through an in situ protection of the hydroxyl group by forming TMS ether. Ultimately, this new route was successfully demonstrated to generate >10 kg of API in 29% overall yield.

Full text of DOI:10.1021/acs.oprd.8b00307

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Full Paper
Development of a Practical Synthesis of a Farnesyltransferase Inhibitor
Zhongping Shi, Junying Fan, David kronenthal, and Boguslaw M. Mudryk
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00307 • Publication Date (Web): 29 Oct 2018
Downloaded from http://pubs.acs.org on October 29, 2018
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Development of a Practical Synthesis of a Farnesyltransferase Inhibitor
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Zhongping Shi,* Junying Fan,* David R. Kronenthal, and Boguslaw M. Mudryk
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Chemical & Synthesis Development, Bristol-Myers Squibb Co., One Squibb Drive, P.O. Box 191,
New Brunswick, New Jersey, 08903-0191, United States
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* Email: zhongping.shi@bms.com
* Email: junying.fan@bms.com
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Table of Content Graphic
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CN
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CN
CN
CN
3 steps
57%
SO2Th
4 steps
62%
H
N
N
N
Bn
Bn
N SO2Th
Bn
N
83%
N
H
NO2
NO2
NO2
HO
13
Th = 2-thienyl
HO
9
12
1
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Abstract:
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The development of a new and practical synthesis for a farnesyltransferase inhibitor
1 is described. The new route started from 2-nitro-5-cyanotoluene (9) and afforded the
desired 1 in eight chemical transformations. The key step involved formation of sulfonamide
13 from a hindered -hydroxyamine 12 through an in situ protection of the hydroxyl group
by forming TMS ether. Ultimately, this new route was successfully demonstrated to generate
>10 kg of API in 29% overall yield.
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Keywards: benzodiazepine, sulfonylation, reductive amination, -hydroxyamine, aziridine
Introduction
Benzodiazepine compound 1 was identified as a lead candidate for efficient farnesyl
protein transferase inhibition and was chosen for development as a potential therapy for cancer
diseases.1-2 The initial Discovery Chemistry synthesis (Scheme 1) very efficiently generated 1
using four main commercially available fragments: D-phenylalanine (2), bromoisatoic anhydride
(4), 2-thienylsulfonyl chloride, and 4-formylimidazole. In the first step, D-phenylalanine (2) was
converted to its methyl ester 3, and subsequent reaction with bromoisatoic anhydride (4) provided
benzodiazepine 5. Reduction of 5 using excess borane/THF produced diamine 6 which was then
converted to 7 via a cyanation with either CuCN or Zn(CN)2/Pd. Reaction of 7 with 2-
thienylsulfonyl chloride generated sulfonamide 8 which was then converted to the desired product
1 by reductive amination with 4-formylimidazole and triethylsilane.
Scheme 1. Discovery chemistry synthesis of 1
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O
Br
Br
Br
O
SO2Cl2
MeOH
O
BH3 (5 eq)
COOH
NH2
COOMe
NH2
N
O
4
H
NH
HN
NH
HN
THF
78%
85%
pyridine
reflux, 3 d
70%
2
3
O
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CN
CN
N
CN
Zn(CN)2
CHO
N
SO2Cl
S
N SO2
S
S
H
N
(Ph3P)4Pd
70%
N SO2
N
NH
HN
TFA, Et3SiH
85%
HN
N
H
DIPEA
78%
1
7
8
The Discovery synthesis was successful in producing the initial quantities of 1 in good overall yield
(22 %). However, the conversion of 5 to 6 was performed with borane which is an undesirable reducing
reagent with respect to scalability. To address this, various reduction conditions with aluminum hydrides
or NaBH4/additives were evaluated. Unfortunately, the alternative reagents were not able to produce 6 in
as high quality or yield as the original borane conditions. Another scale-up concern with the Discovery
synthesis was the use of excess cyanide in conversion of 6 to 7. The special considerations around the safe
handling of cyanide on large scales in addition to the safe storage and disposal of the reaction waste stream
had to be considered. Furthermore, there was a practical challenge with this reaction. During the aqueous
workup, a dark black color was obtained for both the aqueous and organic layer, which led to a difficult
phase separation using visible observation and also limited the type of equipment that could detect the phase
separation when processing on-scale.
The aforementioned issues with the initial synthesis prompted us to seek a more practical route.
We initially proposed a new synthesis with commercially available 2-nitro-5-cyanotoluene (9) as an optimal
starting material in which the cyanide moiety was built-in and obviated the need for developing and
conducting cyanation chemistry on-scale (Scheme 2). We expected amino alcohol 12 could be accessed
via bromination3 of 9 to 10 followed by alkylation using amine 11. Reaction of 12 with 2-thienylsulfonyl
chloride (ThSO2Cl) would give sulfonamide 13, which could be converted to sulfonate 14 by treatment
with benzenesulfonyl chloride (PhSO2Cl). Reduction4 of the nitro group in 14 affords aniline 15.
Cyclization under basic conditions would generate the key benzodiazepine intermediate 8 present in
Discovery route. As in Discovery synthesis, a reductive amination of 8 with 4-formylimidazole will
complete the synthesis of 1. Alternatively, the imidazole moiety of 1 could also be introduced before the
formation of the benzodiazepine ring. Reductive amination of aniline 15 with 4-formylimidazole would
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give intermediate 16 which would be cyclized under basic conditions to provide the desired 1. In this report,
we describe a successful development of a new and practical synthesis of 1, which enabled us to generate
clinical material on kilogram scale.
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Scheme 2. Alternative synthesis of 1
H2N
11
Bn
CN
CN
CN
CN
SO2Th
ThSO2Cl
HO
H
N
N
Bn
Br
Bn
NO2
NO2
NO2
NO2
HO
HO
9
10
12
13
CN
CN
CN
Pd(OH)2
hydrogen
SO2Th
N
PhSO2Cl
Et3N
SO2Th
N
base
Bn
Bn
N SO2Th
Bn
NO2
PhO2SO
14
NH2
HN
PhO2SO
15
8
CHO
CHO
HN
HN
N
N
CN
CN
Th =
SO2Th
N
S
base
N
Bn
N
N SO2Th
Bn
N
NH
PhO2SO
N
H
N
H
1
16
Results and Discussions
I.
Preparation of Amino Alcohol 12. The new synthesis starts from commercially available 2-
nitro-5-cyanotoluene (9) which was converted to amino alcohol 12 in two steps. The first step, bromination
of 9 to provide 10, proved to be problematic. The reaction using N-bromosuccinimide (NBS)5 with a radical
initiator gave either a low conversion (<50%) or a mixture of 9, 10 and the corresponding dibromide.
Various reaction conditions5,6 with different brominating reagents (NBS, bromine, and KBrO3) and
initiators (dibenzoyl peroxide, AIBN, and 1,1’-azobis(cyclohexanecarbonitrile) in different solvents
(carbon tetrachloride, dichloromethane, dichloroethane, and trifluoromethylbenzene) were evaluated. The
best results were obtained by reaction of 9 with AIBN (0.15 eq, added in three portions) and NBS (2.0 eq,
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added in three portions) in dichloroethane which was irradiated with a sun lamp for 7 h to provide an
18:70:12 mixture of 9/10/dibromide. After purification by chromatography, benzyl bromide 10 was
dissolved in DMF and treated with D-phenylalaninol 11 and K2CO3 to afford the desired product 12 in good
yield (86%). While effective at producing small quantities of 12, the need for chromatography to purify 10
made this approach less practical for scale up. Therefore, we continued our search for an alternative
approach for the preparation of 12.
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A reductive amination approach for preparation of 12 utilizing D-phenylalaninol 11 and aldehyde 18 was
then evaluated. Aldehyde 18 can be prepared from 9 by oxidation of the methyl group. Our initial efforts
with permanganate based reagents were not successful. On the other hand, the reaction of 9 with N,N-
dimethylformamide dimethyl-acetal (DMF-DMA) in DMF generated enamine 17 in 85% yield. Oxidation
of 17 with sodium periodate in THF-water provided the desired aldehyde 18 in 80% yield.7 Heating a
solution of the aldehyde 18 in DCM in the presence of R-phenylalaninol 11 to form an imine followed by
reduction with NaBH4 initially gave only 15% conversion.8 However, substitution of NaBH4 with
NaBH(OAc)3 (1.5 eq)9 and HOAc (1.5 eq) generated amino alcohol 12 in 78% yield. We found preforming
the imine ahead of introduction of the reducing agent was required to avoid competitive reduction of the
aldehyde.
Scheme 3. Alternate preparation of 12
H2N
Bn
CN
O
O
CN
CN
CN
11
N
NaIO4
HO
H
N
Bn
THF-water
N
CHO NaBH(OAc)3
HOAc, DCM
DMF
NO2
NO2
NO2
NO2
18
HO
12
9
17
II.
Preparation of Sulfonamide 13. Preparation of sulfonamide 13 from 12 proved to be less than
straightforward. Though sulfonylation on -amino ethanol systems to form related sulfonamides was
reported in literature,10 sulfonylation of 12 with 2-thienylsulfonyl chloride/triethylamine (w/o DMAP) in
various solvents (such as DCM, DCE, THF, and PhMe) did not provide the desired 13. Instead, aziridine
20 was obtained as the major product (90%), which presumably resulted from formation of sulfonate 19
followed by intramolecular SN2 reaction (Scheme 4).11 Formation of 19 was kinetically favored over
formation of sulfonamide 13 due to the higher reactivity of the primary hydroxyl group versus the hindered
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secondary amine. Using pyridine as solvent at room temperature with excess 2-thienylsulfonyl chloride
(3 eq) generated a complex mixture (3:5:8:2:2) of 13, 20, 23, 24, and 21, via the reaction sequences shown
in Scheme 4. We then explored conducting the reactions at a higher temperature (50 °C). Reactions after
15 hours provided a ~2:1 mixture of chloride 24 and pyridium chloride 22. Under these conditions, the
aziridine 20 was converted to 21 and then 22, while compound 13 was converted to 23 and then 24.
Since chloride 24 is also a potential intermediate to compound 8 via reduction of nitro group to 25
followed by cyclization, the reaction was optimized to increase the formation of 24 and minimize formation
of 20. The ratio of 24/22 was improved to 3:1 from 2:1 when the reaction was carried out with 2-
thienylsulfonyl chloride at -20 °C for 2 d and then heated to 50 °C for 1 d. Chloride 24 was prepared and
isolated in 50% yield. Reduction of chloride 24 (sodium dithionite, 76%) followed by cyclization
(DBU/LiI, 70%) did provide the desired 8. However, this protocol was less attractive due to the long
reaction time and relatively low yield, together with the less efficient cyclization of 25 comparing to its
sulfonate analogue 15.
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Scheme 4. Preparation of 8
CN
CN
CN
CN
Bn
pyridine
ThSO2Cl
H
SO2Th
H
N
N
Bn
Bn
N
N
Bn
NO2
NO2
NO2
NO2
N+
ThSO3
Cl-
N+
Cl-
20
19
21
22
ThSO2Cl
Et3N/DMAP
CN
CN
CN
CN
SO2Th
Bn
Cl-
SO2Th
Bn
SO2Th
RSO2Cl
H
N
N
N
N
Bn
+
Bn
pyridine
NO2
NO2
NO2
NO2
Cl
24
HO
HO
ThSO3
23
12
13
reduction
CN
CN
SO2Th
cyclization
N
Bn
N SO2Th
Bn
NH2
HN
Cl
25
8
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Since our efforts to prepare sulfonamide 13 by direct sulfonylation of 12 were unsuccessful, a
protocol with in situ protection of the hydroxyl group with trimethylsilyl chloride (TMSCl) was explored
6
7
i
(Scheme 5). Initially, amino alcohol 12 was treated with two equivalents of TMSCl (EtNPr ) in 1,2-
2
8
9
dichloroethane to form the TMS ether 26, which was then reacted with benzenesulfonyl chloride (2 eq.,
DMAP, 60 °C, 24 h). The TMS amine group of 26 was less stable under the reaction conditions and reacted
with benzenesulfonyl chloride to give intermediate 27a, which was converted to the desired 13a (75%
reaction yield ) after workup with HCl to remove the TMS group. It was found that when pyridine was
used as solvent, the reaction was faster and gave a 90% in-process yield. Reaction of 2-thienylsulfonyl
chloride with 26 was significantly slower and generated the desired 2-thiophenesulfonamide 13 in lower
yield (70% in-process) after treatment with HCl. A major side product 28 was observed, which could be
resulted from a nucleophilic attack at the benzylic position of the TMS ether 27 by chloride which is
generated in the reaction. Reaction at 45-50 °C gave the best results while higher temperature (>55 °C) led
to higher levels of 28, together with formation of some 23 and 24. Also, a minimum of 2 eq of TMSCl was
required to avoid increased levels of 23 and 24.
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Scheme 5. Preparation of 13
CN
CN
CN
CN
TMSCl
or BSA
work up
with HCl
SO2Th
TMS
N
RSO2Cl
SO2R
N
SO2R
H
N
HN Bn
Bn
Bn
N
Bn
Bn
pyridine
NO2
TMSO
26
NO2
HO
NO2
NO2
HO
HO
TMSO
27a
28
12
Cl-
13a
R= Ph
R = Th
R= Ph
13
27
R = Th
As the major side product 28 in the above reaction was generated from a SN2 reaction of 27 and
chloride, we hypothesized that minimizing the amount of the chloride would decrease levels of 28 and
therefore increase the yield of the desired 13. Indeed, when TMSCl was substituted with O,N-
bis(trimethylsilyl)acetamide (BSA, 0.75 eq), the reaction generated significantly less 28 (~5% versus 25%).
The best results were obtained by reaction with 0.75 eq BSA and 2 eq of ThSO2Cl in THF containing N-
methyl morpholine to give an 83% yield of sulfonamide 13 after work up and crystallization from methanol.
III.
Preparation of Aniline 15. Aniline 15, the precursor for cyclization to the current final
intermediate 8, can be prepared from 13 by sulfonylation to 29 followed by reduction of the nitro group.
Sulfonylation of 13 with benzenesulfonyl chloride (TEA/DMAP, DCM) was quite straightforward and
generated the desired sulfonate 29 in 95% yield. For preparation of 15 from 29, our initial efforts using
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hydrogenation over Pd/C or Pearlman’s catalyst were not successful.12 Hydrogenations were very slow and
generated a mixture of 15 and hydroxylamine analogue 30, even with up to 50 w% catalyst loading and
addition of methanesulfonic acid. As an alternative, reduction of 29 with sodium hydrosulfite13 in THF-
water was evaluated. The reaction at room temperature provided 15 in 85% yield. Residual sulfamic acid
°
31 was observed in 10-12% yields. It was found that reaction at higher temperatures (40-50 C) led to
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lower levels of 31 (<5%). Further raising the reaction temperature led to formation of trace amounts of
°
cyclized product 8 (3% at 70 C). We also found that sulfamic acid 31 can be converted to the desired
°
aniline 15 by treating with HCl in THF-water. With the optimized conditions (6 eq. Na2S2O4, 45 C) or
running reaction at rt followed by treatment with HCl, aniline 15 was prepared in 91% yield after
purification by silica gel column chromatography. Since our efforts to crystallize 15 were not successful,
crude 15 was used directly for cyclization to 8 in next step.
Scheme 6. Preparation of 15
CN
CN
CN
CN
CN
SO2Th
Bn
SO2Th
Bn
SO2Th
N Bn
Na2S2O4
SO2Th
Bn
PhSO2Cl
SO2Th
N
N
N
N
Bn
TEA/DMAP
DCM
NO2
THF-water
91%
NH2
NHOH
NHSO3H
PhO2SO
31
NO2
HO
PhO2SO
PhO2SO
PhO2SO
13
29
95%
15
30
IV.
Cyclization of 15 to Benzodiazepine 8. Cyclization of 15 to benzodiazepine 8 was carried out
under basic conditions (Scheme 7). Various bases were evaluated as summarized in Table I. The best
results were obtained with 1 equivalent of potassium t-butoxide or potassium t-amylate in THF to give an
84-85% yield of 8 after crystallization from methanol. The major side product observed in the reaction
mixture was alkene 32 (3-6 %), which resulted from a -elimination of 15 under basic conditions. This
impurity was readily purged during the crystallization of 8 from methanol. Alternative reaction conditions
typically gave lower yields of 8 due to formation of higher levels of 32, while reactions with DBU or K2CO3
also required long reaction times at high temperatures.
Scheme 7. Preparation of 8
CN
CN
CN
SO2Th
SO2Th
Bn
base
N
Bn
+
N
N SO2Th
Bn
HN
NH2
PhO2SO
NH2
32
8
15
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Table 1. Results for cyclization of 15 to benzodiazepine 8.
7
8
9
Entry
Reagent
Reaction
Reaction
Yield
temperature (°C)
time (h) (crystallization)
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1
2
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4
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6
DBU/toluene
K2CO3/DMF
LHMDS/THF
NaH/THF
100-110
100
22
15
1
65%
79%
65%
79%
84%
85%
-20
25
10
1
KOBut/THF
-10 to 0
0
Potassium
t-amylate/THF
1
V.
Preparation of 1. As shown in Scheme 2, there are two approaches to convert intermediate 15 to
compound 1. The first involves a reductive amination of 15 with 4-formylimidazole to produce 16 followed
by a cyclization under basic conditions to afford the desired product 1. Indeed, reaction of 15 with 4-
formylimidazole and triethylsilane/TFA in DCM affords a 94% yield of 16, which was then cyclized by
treating with potassium t-amylate in THF to give 1 in 80% yield. Although this sequence did generate 1
in high yield, isolation of 16 was challenging. Our attempts to isolate 16 repeatedly afforded the compound
as an amorphous solid making this a less practical approach for scale-up. The second approach inverts the
sequence with cyclization to afford benzodiazepine 8, followed by reductive amination. The advantage to
this approach was that benzodiazepine 8 is a highly crystalline intermediate and was easily isolated by
crystallization from methanol. With 8 as the final intermediate, the desired 1 was prepared by reductive
amination with 4-formylimidazole (triethylsilane, TFA in toluene) in 85% yield after crystallization.1, 14
Scheme 8. Multikilogram-scale synthesis of 1.
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H2N
HO
Bn
O
O
CN
CN
CN
CN
N
(1)
(2)
11
KIO4
H
N
Bn
THF-water
80%
N
CHO
DMF
91%
NaBH(OAc)3
HOAc, DCM
78%
NO2
NO2
NO2
9
NO2
18
HO
12
17
10
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CN
CN
CN
SO2Th
PhSO2Cl
Na2S2O4
SO2Th
(1) BSA, pyridine
SO2Th
N
N
Bn
Bn
N
Bn
(2) ThSO2Cl
83%
Et3N, DMAP
95%
THF-water
91%
NO2
NH2
NO2
HO
PhO2SO
PhO2SO
13
14
15
CN
CN
CHO
potassium
t-amylate
HN
N
N
N SO2Th
Bn
Th =
HN
N SO2Th
Bn
THF
84%
Et3SiH, TFA
85%
N
S
N
H
8
1
Summary
A practical and scalable synthesis of 1 has been developed (Scheme 8). The new synthesis
addressed the scalability issues that existed in the original route, namely the borane reduction and
cyanide introduction steps. The desired 1 was prepared in a total of eight steps starting with
commercially available 2-nitro-5-cyanotoluene 9. An in situ protection protocol was developed
for conversion of amino alcohol 12 to sulfonamide 13 in order to eliminate the formation of
aziridine 20. Although the new route required 2 more steps than the original synthesis, the
improvements to safety, scale-ability and cost-effectiveness were of significant advantage. The
optimized processes were executed at multi-kilogram scale to prepare >10 kg of 1 in 29% overall
yield.
Experimental Section
All reagents purchased from vendors were used as received unless otherwise indicated. Reported
yields have not been corrected for impurity levels or moisture content. Proton and Carbon NMR
were run on a Bruker AVANCE 400 at 400 MHz for proton and 100 MHz for carbon.
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3-formyl-4-nitrobenzonitrile 18. N,N-Dimethylformamide dimethyl acetal (94%, 6.40 L, 5.71
kg, 45.1 mol) was added to a solution of 3-methyl-4-nitrobenzonitrile 9 (3.90 kg, 24 mol) in DMF
(9.7 L) at 25 °C. The mixture was heated to 90 °C for 18 h and then cooled to 25 °C. Water (33.0
L) was slowly added to the reaction mixture with vigorous stirring over 45 min (observed
temperature rise from 25 °C to 43 °C). The resulting suspension was stirred for 1 h while cooling
to 25 °C. The solid was collected by filtration. The cake was washed with water (45.0 L) and then
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°
with 9:1 hexane-EtOAc (22.5 L). Drying under vacuum at 40 C afforded (E)-3-(2-
(dimethylamino)vinyl)-4-nitrobenzonitrile 17 (4.44 kg, 20.4 mol). The dry enamine 17 was
dissolved in THF (42.1 L) containing triethylamine (1.92 kg, 40.8 mol). To the solution was added
water (37.2 L), followed by sodium periodate (13.23 kg, 61.2 mol) in three portions over 80 min
°
(observed exotherm to 46 C). The reaction mixture was stirred vigorously for 19 h. The
suspended salt was filtered and the cake was rinsed with ethyl acetate (17.2 L). The two-phase
filtrate was separated and the aqueous layer was extracted twice with 23.5 L ethyl acetate. The
first organic layer was concentrated to 7.2 L and then combined with the two EtOAc layers. The
resulting organic solution was washed twice with 12.3 L of 1.4 N HCl followed by 15 L of a 7%
aqueous sodium bicarbonate solution and then 15% brine (15 L). The organic solution was treated
with activated carbon to remove color and then filtered. The filtrate was concentrated to 15.0 L to
afford a slurry. Hexane (22.5 L) was slowly added over 1 h to the slurry, which was then aged at
25 °C for 2 h. The solid was collected by filtration, washed with 2:1 hexane-EtOAc (2.25 L), and
°
dried under vacuum at 40 C to give 2.88 kg of 18 as a beige powder (73% yield from 9). m.p.
1
115.0-116.0 °C. H NMR (CDCl3, 400 MHz)  10.41 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.25 (d, J
= 8.6 Hz, 1H), 8.06 (dd, J = 8.6, 1.8 Hz, 1H). 13C NMR (CDCl3, 101 MHz) 185.6, 151.1, 136.9,
133.8, 131.8, 125.5, 118.3, 115.8. Elemental Analysis: Calcd for C8H2N2O3: C, 54.55; H, 2.29;
N, 15.91. Found: C, 54.73; H, 2.21; N, 15.82.
(R)-3-[N-(1-Hydroxymethyl-2-phenylethyl)amino]methyl]-4-nitrobenzenecarbonitrile 12.
Under a nitrogen atmosphere, a solution of 5-cyano-2-nitrobenzaldehyde 18 (2.70 kg, 15.33 mol)
and D-phenylalaninol (2.41 kg, 15.95 mol) in dichloromethane (42.0 L) was heated at reflux for 2
°
hours. After cooling the reaction mixture to 5 C, acetic acid (1.48 kg, 24.58 mol) was added,
followed by the portion wise addition of sodium triacetoxy borohydride (4.56 kg, 85% real, 18.31
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mol). The reaction mixture was warmed to room temperature and stirred at room temperature
°
overnight, cooled to 15 C and diluted with 1N sodium hydroxide solution (18.2 L) while
°
maintaining the reaction mixture temperature below 25 C. The phases were separated. The
7
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organic phase was distilled to remove dichloromethane. The pot was chased twice with tert-butyl
°
°
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methyl ether (2 x 36.4 L). The resultant slurry was stirred overnight at 25 C, cooled to 0-5 C,
held at 5 °C for 1 hour and filtered to obtain a solid. The solid was washed twice with 10 L portions
of 5 °C tert-butyl methyl ether and dried in a 30 °C vacuum oven to give the title product as a solid
(3.70 kg, 77% yield). m.p. 111.0-112.0 °C. H NMR (400 MHz, DMSO-d6)  8.07 (d, J=1.8 Hz,
1
1H), 8.05 (d, J=8.5 Hz, 1H), 7.96 (dd, J=8.5, 1.8 Hz, 1H), 7.20-7.29 (m, 2H), 7.11-7.20 (m, 3H),
4.56 (t, J=5.1 Hz, 1H), 3.99 (br s, 2H), 3.18-3.43 (m, 3H), 2.53-2.73 (m, 3H). 13C NMR (101
MHz, DMSO-d6)  151.7, 140.2, 138.2, 135.1, 132.5, 129.7 (2C), 128.6 (2C), 126.4, 125.6, 118.0,
115.7, 63.1, 61.0, 46.9, 38.3. Elemental Analysis: Calcd for C17H17N3O3: C, 65.58; H, 5.50; N,
13.50. Found: C, 65.69; H, 5.61; N, 13.43.
(R)-N-(5-cyano-2-nitrobenzyl)-N-(1-hydroxy-3-phenylpropan-2-yl)thiophene-2-sulfonamide
13. Under a nitrogen atmosphere, N,O-Bis-(trimethylsilyl)acetamide (BSA, 1.72 kg, 8.48 mol) was
added to a mixture of amino alcohol 12 (3.50 kg, 11.2 mol) and N-methyl morpholine (NMM, 2.49
L, 22.4 mol) in THF (2.80 L) at 22-33 °C (exotherm observed). The resulting reaction mixture was
°
stirred at 22-30 C for 1 h. A solution of 2-thienylsulfonyl chloride (3.22 kg, 16.8 mol) in THF
°
(700 mL) was prepared and then added at 20-30 C (exotherm observed) to the above reaction
mixture, which was then stirred at 25-30 °C for 12 h. THF (21.0 L), MTBE (21.0 L), and then 0.5
N aq. HCl (11.2 L) were added to quench the reaction. The organic layer was separated, washed
with water (11.2 L), and then concentrated to 7.5 L. A solvent swap to methanol (17.5 L) was
performed by adding methanol (35.0 L) and then distillation to 17.5 L twice respectively. The
resulting slurry was cooled to 22 °C for 3 h. The solid was collected by filtration, wash with cold
methanol (5.6 L), and dried under vacuum at 45 ºC to give 4.26 kg (83.0%) 13 as a slightly yellow
crystalline solid. m.p. 146.0-147.0 °C. H NMR (400 MHz, DMSO-d6)  8.15-8.24 (m, 2H), 7.98-
1
8.08 (m, 2H), 7.79 (dd, J=3.9, 1.5 Hz, 1H), 7.16-7.33 (m, 4H), 7.10 (d, J=7.4 Hz, 2H), 4.94 (d,
J=18.6 Hz, 1H), 4.81 (d, J=18.6 Hz, 1H), 4.10-4.25 (m, 1H), 3.18-3.45 (m, 2H), 2.81 (dd, J=13.7,
9.8 Hz, 1H), 2.39 (dd, J=13.7, 5.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6)  150.4, 140.0, 138.3,
136.1, 134.62, 134.56, 133.7, 132.6, 129.5 (2C), 129.0 (2C), 128.8, 127.1, 126.0, 117.9, 116.0,
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62.7, 60.3, 44.7, 34.9. Elemental Analysis: Calcd for C21H19N3O5S2: C, 55.13; H, 4.19; N, 9.18,
S, 14.01. Found: C, 54.99; H, 3.94; N, 9.10; S, 13.88.
7
8
9
(R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-
carbonitrile 8. Benzenesulfonyl chloride (1.49 kg, 8.42 mol) was slowly added to a mixture of (R)-
N-[5-cyano-2-nitrophenyl)methyl]-N-[(1-hydroxymethyl)-2-phenylethyl]thiophene-2-sulfonamide
13 (3.50 kg, 7.66 mol), 4-dimethylaminopyridine (84.2 g, 0.69 mol), and triethylamine (1.09 kg,
10.72 mol) in dichloromethane (3.0 L). The resultant reaction mixture was stirred at room
temperature for 3 h, diluted with 15.0 L tetrahydrofuran and cooled to 10-15 °C. A sodium dithionite
solution (prepared from 6.27 kg of 85% sodium dithionite and 35.0 kg of water) was added to the
cooled reaction mixture at such a rate as to maintain the reaction mixture temperature below 15 °C.
After the addition was complete, the reaction mixture was warmed to and stirred at room temperature
overnight, then treated with concentrated hydrochloric acid to a pH of about 1.5-2.0. The organic
phase was separated, washed with brine, and then concentrated to 5 L. The resulting solution was
diluted with 20 L tetrahydrofuran. After cooling to 0-5 °C, the solution was treated with a potassium
t-amylate solution (5.0 L of a 25 wt% solution in toluene, 9.96 mol) at 0-5 °C for 30 minutes. The
reaction mixture was treated with a 5 wt% potassium monobasic phosphate solution (17.5 L) while
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°
maintaining the reaction mixture temperature at 5-10 C. The organic phase was separated and
concentrated to 5 L. The residue was diluted with methanol (31.5 L), decolorized with charcoal, and
concentrated under vacuum to a volume of about 9.4 L. The resulting solution was warmed to 50
°C, seeded, cooled to room temperature and held overnight. The solution was then cooled to 0 °C
and held for 2 h. The resulting slurry was filtered to obtain a solid. The solid was washed with a
9:1 methanol-water solution at 4 °C, and dried at 45 °C to give 2.20 kg (70%) 8 as a white solid. m.p.
1
149.5-151.0 °C. H NMR (400 MHz, DMSO-d6)  7.72 (dd, J=4.9, 1.5 Hz, 1H), 7.29-7.41 (m, 3H),
7.20-7.29 (m, 3H), 7.07-7.20 (m, 2H), 6.88 (dd, J=4.9, 3.9 Hz, 1H), 6.41 (d, J=4.9 Hz, 1H), 6.20 (d,
J=8.3 Hz, 1H), 4.87 (d, J=17.1 Hz, 1H), 4.48 (d, J=17.6 Hz, 1H), 4.32-4.10 (m, 1H), 3.74-3.52 (m,
1H), 3.03-2.74 (m, 3H). 13C NMR (101 MHz, DMSO-d6)  152.6, 140.4, 138.0, 134.6, 133.1, 132.4,
132.2, 129.8 (2C), 129.1 (2C), 127.6, 127.1, 120.7, 120.4, 116.2, 97.5, 62.7, 46.1, 45.7, 39.9.
Elemental Analysis: Calcd for C21H19N3O2S2: C, 61.59; H, 4.68; N, 10.26; S, 15.66. Found: C,
61.57; H, 4.48; N, 10.21; S, 15.62.
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(R)-1-((1H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepine-7-carbonitrile 1 MSA salt. (R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-
(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile 8 (1.30 kg, 3.17 mol) and imidazole-4-
7
8
9
°
carboxaldehyde (0.34 kg, 3.52 mol) were mixed in toluene (39.0 L) at 20-25 C. To this stirred
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slurry, trifluoroacetic acid (1.81 kg, 15.9 mol) and then trifluoroacetic acid anhydride (0.55 L, 3.82
°
mol) were added sequentially while maintaining the temperature below 30 C. The biphasic
mixture was vigorously stirred at 20-25 °C for 30 minutes. Triethylsilane (0.60 L, 3.82 mol) was
°
then added and the reaction mixture was stirred at 20-25 C until the reaction was completed.
Ethanol-water (99:1, 19.5 L) was added and the resulting solution was polish-filtered. The solution
was heated to 60 °C. Methanesulfonic acid (0.23 L, 3.51 mol) was added and a white slurry formed.
The slurry was cooled to 20-25 °C over 1 h and stirred for an additional 2 h. The resulting white
crystalline solid was filtered and washed with cold anhydrous ethanol (6.5 L). The wet cake was
°
dried in a vacuum oven at 70 C to afford 1.72 kg of the desired product as a white, crystalline
solid in 92% yield. m.p. 104.0-105.0 °C.1
(R)-N-(1-hydroxy-3-phenylpropan-2-yl)thiophene-2-sulfonamide 28. The title compound is a
byproduct (5-25% based on reaction condition) for preparation of 13 and was isolated by
1
chromatography for identification. H NMR (400 MHz, DMSO-d6)  7.86 (br d, J=7.8 Hz, 1H),
7.80 (dd, J=5.0, 1.5 Hz, 1H), 7.35 (dd, J=3.8, 1.5 Hz, 1H), 7.11-7.23 (m, 3H), 7.08 (m, 2H), 7.04
(dd, J=5.0, 3.8 Hz, 1H), 4.80 (t, J=5.4 Hz, 1H), 3.26-3.40 (m, 2H), 3.17-3.26 (m, 1H), 2.84 (dd,
J=13.4, 6.1 Hz, 1H), 2.49 (dd, J=13.4, 6.4 Hz, 1H). 13C NMR (101 MHz, DMSO-d6)  143.3,
138.9, 132.5, 131.6, 129.7 (2C), 128.7 (2C), 128.0, 126.6, 63.1, 57.9, 37.5.
AUTHOR INFORMATION
Corresponding Authors
* Email: zhongping.shi@bms.com
* Email: junying.fan@bms.com
ORCID
Zhongping Shi: 0000-0003-2019-5792
Funding
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This work was supported by Bristol-Myers Squibb Co.
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Notes
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The authors declare no competing financial interest.
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Acknowledgement
The authors wish to thank the BMS pilot plant operations and Analytical R & D staff for their
valuable support during our scale up runs. In addition, we thank Dr. Albert DelMonte and Thomas
La Cruz for helpful discussion during the preparation of the manuscript.
Reference
1.
Hunt, John T.; Ding, Charles Z.; Batorsky, Roberta; Bednarz, Mark; Bhide, Rajeev; Cho,
Young; Chong, Saeho; Chao, Sam; Gullo-Brown, Johnni; Guo, Peng; et al. Discovery of (R)-7-
Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-
1H-1,4-benzodiazepine (BMS-214662), a Farnesyltransferase Inhibitor with Potent Preclinical
Antitumor Activity. Journal of Medicinal Chemistry, 2000, 43(20), 3587-3595.
2.
Ding, Charles Z.; Hunt, John T.; Kim, Soong-hoon; Mitt, Toomis; Bhide, Rajeev;
Leftheris, Katerina; Imidazole-containing benzodiazepines and analogs as inhibitors of farnesyl
protein transderase. PCT Int. Appl. 1997, WO 9730992 A1 19970828.
3.
Baldwin, Jack E.; Cha, Jin K.; Kruse, Lawrence I. Total synthesis of antitumor agent AT-
125, (αS,5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid. Tetrahedron, 1985, 41 (22),
5241-5260.
4.
Velaparthi, Upender; Liu, Peiying; Balasubramanian, Balu; Carboni, Joan; Attar, Ricardo;
Gottardis, Marco; Li, Aixin; Greer, Ann; Zoeckler, Mary; Wittman, Mark D.; Vyas, Dolatrai,
Imidazole moiety replacements in the 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors
of insulin-like growth factor receptor-1 (IGF-1R) to improve cytochrome P450 profile. Bioorganic
& Medicinal Chemistry Letters, 2007, 17(11), 3072-3076.
5.
Mishra, Jitendra Kumar; Garg, Puja; Dohare, Preeti; Kumar, Ashutosh; Siddiqi,
Mohammad Imran; Ray, Madhur; Panda, Gautam, Amino acid-based enantiomerically pure 3-
substituted 1,4-benzodiazepin-2-ones: A new class of anti-ischemic agents. Bioorganic &
Medicinal Chemistry Letters, 2007, 17(5), 1326-1331.
ACS Paragon Plus Environment

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Organic Process Research & Development
1
2
3
4
6.
a, Amati, Alessandro; Dosualdo, Gabriele; Zhao, Lihua; Bravo, Anna; Fontana, Francesca;
Minisci, Francesco; Bjorsvik, Hans-Rene, Catalytic Processes of Oxidation by Hydrogen Peroxide
in the Presence of Br2 or HBr. Mechanism and Synthetic Applications. Organic Process Research
& Development, 1998, 2(4), 261-269. b. Yi, Bing; Chen, Hong-biao; Lin, Yuan-bin; Zhao, Hong-
bin, New method for bromination of α-H in alkylbenzenes. Yingyong Huaxue, 2001, 18(6), 501-
503.
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
32
33
34
35
36
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.
a. Michael.Vetelino and Jotham W.Coe, A mild method for the conversion of activated aryl
methyl groups to carboxaldehydes via the uncatalyzed periodate cleavage of enamines.
Tetrahedron Lett., 1994, 35, 219-222. b. Riesgo, Elvira C.; Jin, Xiaoqing; Thummel, Randolph
P. Introduction of Benzo[h]quinoline and 1,10-Phenanthroline Subunits by Friedländer
Methodology. Journal of Organic Chemistry, 1996, 61, 3017-3022.
8.
Philippe, Nicolas; Denivet, Francois; Vasse, Jean-Luc; Sopkova-de Olivera Santos, Jana;
Levacher, Vincent; Dupas, Georges, Highly stereoselective Friedel–Crafts type cyclization. Facile
access to enantiopure 1,4-dihydro-4-phenyl isoquinolinones. Tetrahedron, 2003, 59(40), 8049-
8056.
9.
Nag, Somnath; Mishra, Amita; Batra, Sanjay, A facile route to the synthesis of
pyrimido[2,1-b]quinazoline core from the primary allyl amines afforded from Baylis–Hillman
adducts. Tetrahedron, 2008, 64(44), 10162-10171.
10.
a. Lanman, Brian A.; Myers, Andrew G. Efficient, Stereoselective Synthesis of trans-2,5-
Disubstituted Morpholines. Organic Letters, 2004, 6(6), 1045-1047. b. Kato, Yuzo; Yen, Dinh
Hoang; Fukudome, Yasuhiro; Hata, Takeshi; Urabe, Hirokazu, Aryl(sulfonyl)amino Group: A
Convenient and Stable Yet Activated Modification of Amino Group for Its Intramolecular
Displacement. Organic Letters, 2010, 12(18), 4137-4139.
11.
Scott G. Nelson and Paul M. Mills, Catalytic Asymmetric Acyl halide-aldehyde
cyclocondensation reaction. Organic Synthesis, 2005, 82, 170-178.
12.
Gu, Tao; Rachwal, Bogumila; Siddiqui, Ozair; Rachwal, Stanislaw; Kitahara, Isamu;
Simavoryan, Sergey; Wang, Peng; Yamamoto, Michiharu, Assignee Nitto Denko Corporation,
Japan, Chromophores for photochromic compositions useful for three dimensional display
applications. 2015, WO 2015164390 A1 20151025.
13.
Redemann, C. T.; Redemann, C. E. “5-amino-2,3-dihydro-1,4-phthalazinedione”.
Organic Synthesis, 1955, Collective Volume, 3, 69.
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14.
Chen, Bang-Chi; Sundeen, Joseph E.; Guo, Peng; Bednarz, Mark S.; Zhao, Rulin, Novel
triethylsilane mediated reductive N-alkylation of amines: improved synthesis of 1-(4-
imidazolyl)methyl-4-sulfonylbenzodiazepines, new farnesyltransferase inhibitors . Tetrahedron
Letters, 2001, 42(7), 1245-1246.
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