Practical asymmetric hydrogenation-based synthesis of a class-selective histone deacetylase inhibitor

Article abstract of DOI:10.1021/op500250b

Two syntheses of the class-selective histone deacetylase inhibitor 1 are reported. In the first, eight-step entailing synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording trans-rac-5 and its resolution. In the

Full text of DOI:10.1021/op500250b

Article
pubs.acs.org/OPRD
Practical Asymmetric Hydrogenation-Based Synthesis of a Class-
Selective Histone Deacetylase Inhibitor
Junli Chen,†,‡ Tianqi Chen,⊥ Qiupeng Hu,⊥ Kurt Puntener,§ Yi Ren,‡ Jin She,‡ Zhengming Du,*,‡
̈
and Michelangelo Scalone*,§,∥
†Institute of Drug Discovery and Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062,
China
‡Roche Innovation Center Shanghai, Process Research & Synthesis, 720 Cailun Road, Building 5, Pudong, Shanghai, 201203, China
§Roche Innovation Center Basel, Process Research & Synthesis, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
∥F. Hoffmann-La Roche Ltd., Pharma Technical Development, Process Research & Development, Grenzacherstrasse 124, CH-4070
Basel, Switzerland
⊥School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
S
* Supporting Information
ABSTRACT: Two syntheses of the class-selective histone deacetylase inhibitor 1 are reported. In the first, eight-step entailing
synthesis, the key transformations were a highly efficient [3 + 2] dipolar cycloaddition affording trans-rac-5 and its resolution. In
the second, asymmetric approach, the key steps were a highly selective asymmetric hydrogenation to produce the cis-(S,S)-3,4-
disubstituted pyrrolidine 18 followed by an amide formation with simultaneous chiral inversion of the carboxy stereocenter to
generate the key intermediate trans-(R,S)-3,4-disubstituted pyrrolidine 19. The overall yield increased from ∼6% for the
resolution approach to ∼26% for the enantioselective approach.
chromatography. In spite of the improvements, however, the
loss of ca. 60% of the material during the resolution step and
the very low overall yield (6.3%) rendered this synthesis not
acceptable.
Therefore, a new, more efficient enantioselective sequence
was developed (Figure 1, lower route) which contained the
formation of the dihydropyrrole 17, its asymmetric hydro-
genation, and the subsequent coupling reaction with simulta-
neous inversion of the configuration of the adjacent center on
the pyrrolidine ring. Gratifyingly, the overall yield of this new
synthesis increased to 25.6%. Herein we report both routes to 1
and address the key process issues.
INTRODUCTION
■
Hepatocellular carcinoma (HCC) is a leading cause of cancer
deaths worldwide. The incidence of hepatocellular carcinoma is
highest in Asia and Africa, where the endemic high prevalence
of hepatitis B and hepatitis C strongly predisposes to the
development of chronic liver disease and subsequent develop-
ment of hepatocellular carcinoma.1 Histone deacetylase
(HDAC) is recognized as one of the promising targets for
cancer treatment as many HDAC inhibitors have entered
clinical trials for both solid and liquid tumors.2 With respect to
HDACs as potential targets for HCC treatment, HDAC1 in
particular has been found to be significantly overexpressed in
HCC patient tumor samples, and its expression in this context
is negatively correlated to overall survival.3 Our medicinal
chemists had discovered the class-selective histone deacetylase
(HDAC) inhibitor 1, which has excellent drug-like properties
while maintaining selectivity toward the class I HDAC family
with particular potency against HDAC1.4 The process
development described in this paper was conducted to provide
API in a quality which would allow to define safety and
pharmacological properties in the preclinical studies.
The original synthesis of 1 proceeded through the racemic
pyrrolidine 5 which was resolved by chiral chromatography
(Figure 1, upper route).4 A SFC chiral separation provided
indeed enough material for preliminary investigations but was
clearly unsuitable for larger scale production. Notably, the
synthesis suffered from low yield and safety issues in the [3 + 2]
dipolar cycloaddition. As a result, the initial process trouble
shooting work focused both on the optimization of the [3 + 2]
dipolar cycloaddition step and on finding a suitable resolving
agent to obtain enantiomerically pure (R,S)-5 without need for
RESULTS AND DISCUSSION
■
Classical Resolution Approach to HDAC Inhibitor 1.
(E)-3-(4-Bromophenyl) acrylic acid ethyl ester 4, the first
intermediate of the classical resolution synthesis (Scheme 1), is
not commercially available in bulk amounts. For its synthesis
the use of various bases (e.g., KOtBu or NaH,5 DBU, or
Verkade’s bicyclic triaminophosphine6) as well as various
methods such as solvent-free reaction using high-speed ball
milling7 or solid−liquid phase transfer with sodium hydroxide8
have been reported.
We have conducted the reaction using aqueous sodium
hydroxide in a THF/water mixture at 2−15 °C. The phosphate
byproduct was easily removed by a water extraction. On a 50 kg
scale, the crude product 4 was used directly in next step as an
Received: August 5, 2014
© XXXX American Chemical Society
A
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Figure 1. Classical resolution vs asymmetric hydrogenation route.
Scheme 1. Classical resolution-based synthesis of 1
a
Table 1. Effect of solvents and additives in the [3 + 2] dipolar cycloaddition
b
c
d
e
entry sarcosine (equiv) (CH2O)n (equiv)
solvent
toluene
additive (amount) T (°C) ratio 5/4
isolated yield of rac-5 [%] scale-up issues
1
2
3
4
5
6
7
8
9
4.5
6.8
4.8
4.8
4.8
4.8
4.8
4.8
4.8
4.8
4.8
4.8
4.5
4.8
4.8
2.3
20
30
16
16
16
16
16
16
16
16
16
16
20
16
16
2.0
110
80
40/60
n.a.
43
35
Y
cyclohexane
xylenes
Y
f
130
130
66
57/43
54/45
38/62
79/21
59/41
11/89
31/69
61/39
56/44
75/25
38/62
47/53
43/57
>99/1
Y
chlorobenzene
THF
Y
Y
2-Me-THF
1,4-dioxane
isopropanol
DMPU
80
Y
100
80
Y
Y
108
108
85
N
N
N
N
Y
10
11
12
13
14
15
16
DMEU
DMF
NMP
85
toluene
TsOH
AcOH
TsOH
110
85
70%
42%
43%
98%
DMF
N
N
N
NMP
85
NMP
110
a
Conditions: 5−10 g scale; molar equivalents relative to 4; sarcosine and paraformaldehyde were added in 2−4 portions for entry 1−14 and all at
b
c
d
once for entry 15. DMPU: 1,3-dimethyl-propyleneurea; DMEU: 1,3-dimethyl-ethyleneurea. 5 wt %. Ratio of HPLC A% normalized to 4 and 5.
e
f
The scale-up issues include stirring and clogging of the condenser. Water was removed azeotropically.
B
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a
easy-to-handle NMP solution (118 kg with 17.7 wt %
concentration) without further purification.
Table 2. Optimization of the Heck coupling of 7 and 8
time
(h)
ratio 9/7
d
The [3 + 2] dipolar cycloaddition reaction of N-methyl
glycine and paraformaldehyde (via in situ azomethine-ylide
formation) with alkenes to form N-methyl pyrrolidines had
been reported to proceed with 46% yield.9 The reaction had
originally been carried out in refluxing toluene. However, this
procedure gave a biphasic mixture containing a large amount of
sticky material which adhered to the reactor wall and the
agitator (Table 1, entry 1). Moreover, formaldehyde sublimed
and accumulated as a solid on the condenser walls. As a
consequence, a large excess of paraformaldehyde was needed to
drive the reaction to completion. Unfortunately, on scale-up the
condenser was clogged and had to be replaced. To solve this
safety issue, alternative solvents such as cyclohexane, xylene,
chlorobenzene, 2-Me-THF, THF, dioxane, and IPA were tested
but did not improve this aspect (Table 1, entries 2−8).
Fortunately, no blocking issues were observed in DMPU, DMF,
and NMP as solvents (Table 1, entries 9−12). Moreover,
attempts to lower the reaction temperature by using an acid as
an additive failed (Table 1, entries 13−15).10 Finally, running
the reaction in NMP at 110 °C without an additive led to high
conversion in the presence of only a small excess of
paraformaldehyde and sarcosine (Table 1, entry 16). With
the safety issue solved, the reaction was run in a 1000 L reactor
with excellent results (98% yield) which compare very favorably
with those reported previously for the same step.4 As already in
the previous step, trans-rac-5 was not isolated but telescoped as
an ethanolic solution directly into the next step.
The enantioselective enzymatic hydrolysis of esters using the
food-grade subtilisin Carlsberg (alcalase) has been reported.11
We investigated its use in the selective hydrolysis of racemic 5.
Stirring the reaction mixture in a K2HPO4/KH2PO4 buffer (pH
= 7.8−8.2) at 35−40 °C for ca. 20 h led to complete hydrolysis
of the undesired (S,R) enantiomer. After workup, the ee value
of (R,S)-7 was up to 98.5%, but the isolated yield (30%) and
the purity of crude 7 (79% as sticky oil) were unsatisfactory.12
The purification could be achieved only by column
chromatography which again is not a preferred method on
the production scale.
entry
catalyst
Pd(PPh3)2Cl2
base
TEA
[%]
1
2
3
4
5
18
18
18
18
18
18
5
43/10
19/23
35/14
33/10
60/10
no product
85/2
Pd(OAc)2/PPh3 (1:3)
Pd(PPh3)4
TEA
TEA
TEA
TEA
TEA
Pd2(dba)3/PPh3 (1:5)
Pd2(dba)3/P(t-Bu)3 (1:5)
Pd2(dba)3/P(n-Bu)3 (1:5)
b
6
7
8
Pd2(dba)3/P(o-tolyl)3 (1:2) TEA
Pd2(dba)3/P(o-tolyl)3 (1:2) DIPEA
Pd2(dba)3/P(o-tolyl)3 (1:2) EtONa
Pd2(dba)3/P(o-tolyl)3 (1:2) DBU
Pd2(dba)3/P(o-tolyl)3 (1:2) Cs2CO3
Pd2(dba)3/P(o-tolyl)3 (1:2) NaHCO3
5
91/0
c
9
2
dec.
c
10
2
dec.
b
11
5
no product
59/5
12
5
a
Conditions: 1 g scale; DMF as solvent; 0.02 equiv of palladium
precursor, 2.5 equiv of base, 1.05 equiv of 8, 110 °C. For entries 6
and 11, a part of 7 decomposed, but 9 was not found. Decomposition
b
c
d
of 7 and 9 was observed. Determined by HPLC (A%).
the acid 10 was extracted into the n-butanol layer when the pH
reached 6.5−7.0. After removal of n-butanol as an azeotrope
with toluene, the addition of MTBE led to the precipitation of
10 which was isolated easily by filtration. The crude was further
purified by a reslurry in methanol.
For the amide formation reaction, coupling reagents HATU,
T3P, EDC/HOBt, diethyl chlorophosphate, DIC/HOBT, and
isobutyl chloroformate were tested. HATU gave the best result
when the amide formation was run in a mixture of DCM/THF
(14.4/1 wt/wt).13 Crystallization from acetonitrile afforded
amide 11 in 69% yield with 96.6% purity.
The last step of the sequence, the removal of the Boc
protecting group, was performed in a solution of HCl in
methanol (10 mol/L) at 0−5 °C for 1 h. The concentration of
the methanolic solution and addition of aqueous sodium
bicarbonate led to the precipitation of 1 which could be easily
isolated by filtration. After drying, the solid was suspended in a
methanol/water mixture to give the desired polymorph B. With
this synthesis, 913 g of API 1 was prepared.
Finally, the classical chemical resolution offered a viable
alternative. After optimization of the crystallization conditions,
the salt of 5 with D-DTTA afforded pure ester 7 in 99.6% ee.
For the subsequent Heck coupling of (R,S)-7 with
acrylamide 8, various palladium catalysts and bases were tested
(Table 2). As a result, the combination of Pd2(dba)3 and P(o-
tolyl)3 gave the most effective catalyst (Table 2, entry 7). The
best base was DIPEA (Table 2, entry 8). Sodium ethoxide and
DBU (Table 2, entries 9 and 10) brought about the
decomposition of both 7 and 9 (Table 2, entries 9 and 10).
Inorganic bases such as Cs2CO3 or NaHCO3 (Table 2, entries
11 and 12) led to low conversion. The production of 9 in the
pilot plant scale was carried out under the condition of entry 8.
The crude product 9 (3.43 kg, 65.2 wt %) was not isolated but
telescoped directly to the subsequent hydrolysis.
The hydrolysis of ester 9 proceeded uneventfully with
aqueous LiOH in methanol at room temperature. However,
after removing the solvent and adjusting the pH to 6.5−7.0
with 2 N HCl, the acid separated as a sticky solid. Prolonged
stirring did not help form a crystalline solid. A solvent screening
showed that acid 10 is poorly soluble in most organic solvents.
Finally, n-butanol was identified to be a good cosolvent to be
added before the neutralization of the reaction mixture. Thus,
Asymmetric Hydrogenation-Based Synthesis of 1. In
order to improve the supply efficiency, alternative asymmetric
syntheses were considered. Various enantioselective entries into
trans-3,4-disubstituted pyrrolidines had been reported. The [3
+ 2] dipolar cycloaddition using chiral auxiliaries proceeded
usually with moderate diastereoselectivity.14 The rhodium-
catalyzed asymmetric 1,4-arylation of pyrrolines with arylbor-
onic acids provided trans-3,4-disubstituted pyrrolidines in good
enantioselectivity but modest yields.15 The enantioselective
nitrile anion cyclization had been reported to form 3,4-
disubstituted pyrrolidines efficiently.16 In our hands, however,
this method failed to form the desired product. Finally, we
decided to use an approach which had been used previously at
Roche to prepare similarly substituted pyrrolidines in a highly
enantioselective manner.17 Accordingly, an asymmetric hydro-
genation-based synthesis of 1 was conceived (Scheme 2).
For the synthesis of the asymmetric hydrogenation substrate
17, the cynnamic ester 4 was chosen as starting material.18
Dibromination of 4 using bromine in tetrachloromethane or
organocatalysis have been reported.19 We have run this reaction
simply in DCM at room temperature and obtained the 2,3-
dibromoester 12 as a solid in 96% yield. In the subsequent
steps, the double HBr elimination followed by the esterification
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Scheme 2. Asymmetric hydrogenation-based synthesis of 1
of the intermediate acid 13 provided the acetylenic ester 14.
The double HBr elimination reaction was quite challenging due
to the formation of various impurities (Scheme 3). The product
With the alkyne 14 available, the [3 + 2] cycloaddition was
investigated to evaluate its scalability. Sarcosine and paraf-
ormaldehyde had been used in the first protocol of the [3 + 2]
reaction. However, this protocol led to low conversion and
poor selectivity. The use of N-methoxymethyl-N-methyl-1-
(trimethylsilyl)-methylamine 15 resulted to be much more
convenient. This reagent was not commercially available but
could be easily prepared from chloromethyl(trimethyl)silane 23
in two steps using modified literature conditions (Scheme 4).22
Scheme 3. Alkyne acid 13 formation by double hydrogen
bromide elimination/hydrolysis
Scheme 4. Formation of 15
A mixture of neat chloromethyl(trimethyl)silane and a large
excess of aqueous methylamine was stirred at 90 °C in a sealed
stainless steel reactor. The crude intermediate 24 was isolated
by phase separation and could be used directly in the
subsequent reaction. Typically the crude aminal 15 was used
immediately. If required, it could be stored at −20 °C for
months without substantial degradation.
The [3 + 2] cycloaddition between the alkyne ester 14 and
the crude amine 15 was then accrued. An excess amount of 15
was required to increase the conversion in the presence of TFA
as a catalyst. This caused the formation of 5−11% of the
bicyclic ester 25 as well as 2−8% of the pyrrole 26 (Figure 2).
However, the impurity levels could be kept within an
acceptable range by controlling the amount of 15. Sub-
sequently, the hydrolysis of 16 proceeded smoothly with aq 2N
NaOH in methanol. Under these conditions, the side products
25 and 26 were not hydrolyzed and could be easily removed by
was a mixture of Z- and E-3-bromo intermediates (20) when
TEA was used as a base. The reactions using NaH in toluene
and NaOtBu in 2-Me-THF gave a mixture of 13 and 21. In
methanol, ethanol, or mixed solvents such as ethanol/water and
IPA/water, the desired acid 13 was formed together with the
two major impurities 21 and 22.20 Finally, a clean reaction was
obtained in refluxing isopropanol as a solvent and KOH as a
base. After 3 h the solvent was partially removed and replaced
with water. A solid precipitated when the pH was adjusted to 2
by addition of conc. HCl. The alkyne acid 13 was isolated by
filtration in 96% yield with >98% purity.
The preparation of ester 14 by treatment of acid 13 with
diazomethane has been reported.19a We tried to run this
reaction under classical conditions (MeOH/cat. H2SO4) but
obtained no methyl ester 14. Finally, acid 13 could be
converted to the acyl chloride by treatment with (COCl)2/cat.
DMF and then quenched with excess MeOH to produce ester
14 as a light yellow solid in 98% yield. As a potentially shorter
alternative, the alkyne 14 formation was also attempted by Pd-
catalyzed cross coupling of propynoic acid methyl ester (via its
in situ conversion into alkynylzinc derivative) and aryl iodide.21
However, the conversion was only ca. 60%, and the side
products could be removed only by chromatographic
purification. Therefore, the four steps synthesis of the alkyne
14 was used for further scale-up.
Figure 2. Side products of the [3 + 2] cycloaddition.
D
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Scheme 5. Asymmetric hydrogenation of 17
extraction with MTBE. The targeted unsaturated acid 17 was
then crystallized from water at 0 °C upon adjusting the pH to
6.8 by conc. HCl. An easy filtration afforded 17 as a white solid
in 60% yield from alkyne ester 14.
Asymmetric Hydrogenation. The asymmetric hydro-
genation of 17 was the key transformation for the second-
generation synthesis (Scheme 5). A variety of chiral ruthenium
catalysts were evaluated (Table 3). Only the ruthenium
lowest chemoselectivity (entry 6), 28 was isolated as a reference
for analytical purposes. The rate of the hydrogenation in the
presence of [Ru(OAc)2(R)-L2)] (29) was strongly dependent
on the pH. In acidic medium the reaction was almost
suppressed, whereas it proceeded with highest rate in neutral
to slightly basic medium (Table 4). These findings strongly
a
Table 4. Influence of pH on the hydrogenability of 17
pH
3.67
2
4.05
10
6.35
20
6.53
45
6.7
7.81
91
8.45
56
a
Table 3. Ru-catalyzed hydrogenation of 17
conv. %
100
b
b
a
(S,S)/(R,R)-18
(S,R)/(R,S)-27
The pH was measured in methanol; it was adjusted to 3.67−6.70 by
b
entry
catalyst
(%)
(%)
28 [%]
HCl (conc. in water) or to 7.81−8.45 by sodium methoxide. The
1
2
Ru(OAc)2((R)-L1)
Ru(OAc)2((R)-L2)
Ru(OAc)2((R)-L3)
Ru(OAc)2((R)-L4)
Ru(OAc)2((R)-L5)
Ru(OAc)2((R)-L6)
Ru(OAc)2((R)-L7)
Ru(OAc)2((R)-L8)
Ru(OAc)2((S)-L9)
97.2/2.0
100/−
0.7/−
−/−
−/−
−/−
−/−
conversion was determined by HPLC (A%).
3
95.0/2.7
39.9/18.5
85.5/5.1
41.5/13.8
68.6/3.2
73.5/2.8
0.5/85.6
56.9/3.8
2.2
suggest that the coordination of the carboxylate group to the
metal is a condition for the fast hydrogenation of the double
bond. An analogous behavior has been observed in the
asymmetric hydrogenation of an acrylic acid containing a
tetra-substituted double bond.24 The hydrogenation under the
conditions of entry 2 of Table 3 could be easily scaled up. On a
20 g scale the hydrogenation was complete after 3 h at S/C 500
to afford (S,S)-18 with >99.9% ee and in 89.4% isolated yield
after crystallization.
The ruthenium complex 29 is so far unreported in the open
literature. In was prepared according to a reported procedure.25
Treatment of [Ru(OAc)2(p-cymene)] with (R)-2-furyl-MeO-
BIPHEP in toluene afforded 29 as a yellow solid in 93% yield
after crystallization. Its solid state structure has been
determined by X-ray diffraction (Figure 4). The structure is
very similar to that of [Ru(OAc)2(L1)] both as to the geometry
around the ruthenium atom (a distorted octahedron) and as
the most significative bond lengths and angles.26
4
26.3
9.1
5
6
−/−
44.3S)
25.6
14.6
4.3
7
2.0/−
1.8/0.6
1.0/1.0
1.7/-
8
9
10
Ru(OAc)2((R)-
L10)
36.2
11
12
Ru(OAc)2((R)-
L11)
1.8/92.1
5.3/65.5
0.5/0.4
1.6/0
1.6
Ru(OAc)2((S,S)-
L12)
22.8
a
Conditions: 100 mg of 17, S/C 50, MeOH (2 mL), 45 °C, 40 bar H2,
18 h. Conversion was ≥98% in all cases except in entry 4 with 95%.
b
Determined by HPLC on chiral column (A%).
catalysts containing (R)-MeOBIPHEP (L1) and (R)-2-furyl-
MeOBIPHEP (L2) (Figure 3) afforded the desired (3S,4S)-4-
(4-bromo-phenyl)-1-methyl-pyrrolidine-3-carboxylic acid (18)
with high chemo- (100% in both entries 1 and 2, no
decarboxylated side product 28 formed), enantio- (96.0% and
100% ee, respectively), and diastereoselectivity (0.7% and no
27 formed, respectively).23 With all other catalytic systems both
the ee and the de values were unsatisfactory with variable
amounts of 28 being formed. From the hydrogenation with the
Synthesis of the Amide 19 and API 1. With the cis-
(3S,4S)-4-(4-bromophenyl)-1-methyl-pyrrolidine-3-carboxylic
acid (18) in hand, the trans-(3R,4S)-amide 19 formation was
originally conducted in three steps, which included the
formation of the acyl chloride, the coupling with 4-chloroani-
line in DCM to give cis-(3S,4S)-amide 30 and epimerization
under basic conditions (Scheme 6). Various bases and solvents
Figure 3. Ligands used in the asymmetric hydrogenation of 17.
E
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Table 6. Relation between chiral conversion and aging time
time (h)
0.5
1
2
4
12
a
19/30
85/15
90/10
94/6
98/2
>99/1
a
A%: determined by HPLC (A%).
Figure 4. X-ray structure of 29; a DCM molecule has been removed
for clarity.
Figure 5. N-acylurea side products.
resolution of the resulting rac-5 to give the pure chiral
compound 7. With this route 913 g of 1 were prepared to
supply the first series of preclinical tox studies. In view of the
successive campaign, a very efficient enantioselective synthesis
was demonstrated which entailed three well scaleable and high
yielding steps: a [3 + 2] dipolar cycloaddition, a ruthenium
catalyzed asymmetric hydrogenation, and a subsequent
simultaneous coupling/epimerization to generate the chiral
amide 19, which was easily converted into the final product 1.
Accordingly, the overall yield was improved from 6.3% to
26.5%.
were evaluated in the chiral inversion step. Organic bases
(DIPEA, N-methyl-bicyclohexylamine) did not epimerize the
chiral center. In contrast, K2CO3 promoted the epimerization
reaction in DMF or in ethylene gylcol/water (5/1). The best
condition was identified as using 0.2 equiv of DBU in DMF/
ethylene glycol (10/1) at 120 °C for 7 h to achieve 94% of
conversion to 19. However, the overall yield over these three
steps was only 56%.
Surprisingly, the amide formation with EDC/HOBt as
coupling reagent gave both compounds 30 and 19. This result
enabled the alternative one-step entry into 19 from 18 directly.
At first, acid 18, EDC (1.5 equiv), and HOBt (0.2 equiv) were
combined to form the active intermediate which was aged for
some time before adding 4-chloroaniline. It is not surprising
that the 19/30 ratio became higher with a longer holding time
and reached 98/2 after 4 h (Table 6). However, a significant
amount of N-acylurea side products was detected (Figure 5).
Increasing the amount of HOBt was expected to minimize the
N-acylurea formation but could also have reduced the
racemization during the amide bond formation.27 Fortunately,
in our case favorable effects were observed. When 1.0 equiv or
more of HOBt was added, the competing N-acylurea formation
was completely suppressed, while the chiral inversion still did
proceed such that only 19 was obtained after addition of 4-
chloroaniline. From a mechanistic point of view two pathways
are likely (Figure 6). The initially formed O-acylisourea
intermediate (A) can epimerize to the thermodynamically
more stable trans-HOBt activated intermediate (D) via Pathway
2 or via the cis-HOBt activated intermediate (C′) in Pathway 1.
In the next step, the Heck coupling between acrylamide 8
and aryl bromide 19 reached quantitative conversion with 1
mol % of Pd2(dba)3, 2 mol % of P(o-tolyl)3, and 1.3 equiv of N-
methyl dicyclohexyl amine. The final deprotection reaction was
performed according to the first generation process to give
compound 1 in 86% yield with ≥98% purity.
EXPERIMENTAL SECTION
■
General. All commercially available reagents and solvents
were used without further purification unless otherwise noted.
The solvents for hydrogenation reactions were distilled under
argon prior to use. All complexes, solvents, and additives used
for the hydrogenation reactions were stored and used in a
glovebox under an argon atmosphere (<2 ppm of O2).
1H NMR and 13C NMR spectra were measured on a Bruker
400 MHz NMR spectrometer at 400 and 100 MHz,
respectively, or on a Bruker 600 MHz spectrometer at 600
and 150 MHz with TMS as an internal reference. IR spectra
(cm−1) were recorded neat on Thermo NICOLET AVATAR
370 spectrometer. Melting points were performed on TA
Instruments DSC Q 2000. HRMS mass spectra were acquired
on Agilent QTOF 6350 spectrometer. Optical rotation data
were obtained on RUDOLPH AUTOPOL V autometric
polarimeter. HPLC and chiral LC were measured on an
Agilent 1200 and Shimadzu LC-20A spectrometer. Details on
HPLC analyses are reported in the Supporting Information.
(E)-3-(4-Bromophenyl)-acrylic Acid Ethyl Ester (4). To
a 500 L reactor equipped with a condenser, mechanical stirrer,
temperature probe, and nitrogen inlet, 4-bromobenzaldehyde
(2, 20.7 kg, 111.9 mol), triethyl phosphonoacetate (3, 30.0 kg,
133.8 mol), and THF (100 kg) were charged. The mixture was
stirred at 0−5 °C. A solution of NaOH (5.80 kg, 145 mol) in
water (8.9 kg) was charged to the mixture over 1.4 h to
In summary, we have demonstrated the viability of two
processes for production of the HDAC inhibitor 1. The first
comprised a [3 + 2] dipolar cycloaddition followed by the
Scheme 6. Amide 19 formation by acyl chloride coupling and chiral inversion
F
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Figure 6. Possible pathways for the selective formation of amide 19.
maintain the reaction temperature at 2−15 °C. After addition,
the mixture was stirred for an additional 30 min at 10−15 °C.
HPLC analysis (Method A: 2 RT 7.2 min, RRT 0.48; 4 RT
15.2 min, RRT 1.0) showed that 2 was not detected. MTBE
(34.0 kg) and water (45.0 kg) were charged, while the batch
temperature was maintained at 10−15 °C. The organic layer
was separated, and the aqueous layer was extracted with MTBE
(2 × 22 kg). The combined organic layers were washed with
water (32 kg) and aqueous NaCl (2 × 21 kg, 15%) and then
dried over Na2SO4 (3.2 kg). The suspension was filtered, and
the cake was washed with MTBE (15 kg). The filtrate was
concentrated at <40 °C under reduced pressure (60−80 mbar).
To the residue, NMP (81 kg) was added. The mixture was
concentrated at <40 °C under reduced pressure (40−60 mbar)
to further remove MTBE and THF. The product solution was
transferred to a plastic drum, the reactor was rinsed with NMP
(15.2 kg), and the washings transferred to the same drum to
give a solution of 4 in NMP (118.4 kg, 98.7A% (HPLC method
A), 17.7 wt %, 73% yield), which was used directly in the next
step.
trans-rac-4-(4-Bromophenyl)-1-methyl-pyrrolidine-3-
carboxylic Acid Ethyl Ester (5). To a 1000 L reactor
equipped with a condenser, mechanical stirrer, temperature
probe, and nitrogen inlet, N-methyl glycine (14.7 kg, 165 mol),
paraformaldehyde (4.80 kg, 159.8 mol), and NMP (72 kg)
were charged, and the mixture was stirred at 20−25 °C. A
solution of 4 in NMP (118.4 kg, 17.7 wt %, 82.3 mol) was
charged. The mixture was stirred at 100−110 °C for 1.0 h and
then slowly cooled to ca. 40 °C. IPC by HPLC analysis
(method A: 4 RT 15.2 min, RRT 1.14; 5 RT 13.3 min, RRT
1.0)) showed that 4 was not detected. The mixture was diluted
with EtOAc (152 kg) and water (335 kg) and the aqueous layer
was separated. The aqueous layer was then extracted with
EtOAc (3 × 153 kg). Combined organic layers were washed
with water (3 × 70 kg), aqueous NaCl (25 wt %, 42 kg), and
dried over Na2SO4 (7.5 kg). The suspension was filtered, and
the cake was washed with EtOAc (22 kg). The filtrate was
concentrated to ca. 40 L at <45 °C under reduced pressure
(35−55 mbar). Ethanol (106 kg) was charged, and the mixture
was concentrated again to ca. 40 L at <45 °C under reduced
pressure (30−50 mbar) to further remove EtOAc. The
resulting solution was transferred to a plastic drum. The
reactor was washed with ethanol (11 kg), and the washings
were transferred to the same drum to give a solution of 5 in
ethanol (49.2 kg, 98.A% (HPLC method A), 51.1 wt %, 98%
yield). Analytically pure 5 (oil) was obtained by preparative
HPLC. IR (neat) 1731, 1488, 1372, 1246, 1179, 1157, 1126,
822 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.3 Hz,
2H), 7.20 (d, J = 8.3 Hz, 2H), 4.21−4.07 (m, 2H), 3.69−3.56
(m, 1H), 3.06−2.95 (m, 3H), 2.92−2.82 (m, 1H), 2.67 (dd, J =
6.5, 9.3 Hz, 1H), 2.40 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H);13C
NMR (100 MHz, CDCl3) δ 173.5, 142.7, 131.2, 128.9, 120.0,
63.5, 60.5, 59.2, 52.0, 46.6, 41.6, 13.9 HRMS m/z [M + H]+
calcd for C15H23N2O, 311.0521; found, 311.0524.
(3R,4S)-4-(4-Bromophenyl)-1-methyl-pyrrolidine-3-
carboxylic Acid Ethyl Ester (7). To a 500 L reactor equipped
with a condenser, mechanical stirrer, temperature probe, and
nitrogen inlet, ditoluoyl-D-tartaric acid (31 kg, 80.2 mol), a
solution of 5 in ethanol (49.2 kg, 51.1 wt %, 80 mol), and
ethanol (165.0 kg) were charged. Under agitation, the reaction
mixture was heated to 76 °C over 1 h and maintained at that
temperature for 10 min. The mixture was cooled to 15 °C over
2 h and maintained for 1 h at 10−15 °C. The crude chiral salt 6
was centrifuged, and the cake was washed with ethanol (26.0
kg). The cake and fresh ethanol (188 kg) were charged back
into the reaction vessel and stirred for 10 min at 75 °C. The
suspension was cooled to 10−15 °C and maintained for 1 h at
this temperature. The solid was centrifuged, and the cake was
washed with ethanol (14 kg) to give 24.8 kg of chiral salt 6. The
wet cake was dried for ca. 12 h at 40−45 °C under reduced
pressure (25−40 mbar) to give 6 (23.4 kg, 99.7A% (HPLC
method A), 42.0% yield). The chiral assay (method B: 7 (free
from salt 6) RT 11.2 min, RRT 1.0; isomer (3S, 4R)-5 RT 9.1
min, RRT 0.82) gave 99.6% ee for isolated 6; mp (DSC): peak
1
154.38 °C. H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.3
Hz, 4H), 7.47 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 4H),
7.28 (d, J = 8.5 Hz, 2H), 5.73 (s, 2H), 4.08−3.93 (m, 2H), 3.62
(q, J = 8.8 Hz, 1H), 3.46−3.23 (m, 4H), 3.08 (t, J = 10.0 Hz,
G
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1H), 2.64 (s, 3H), 2.38 (s, 6H), 1.08 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 171.6, 168.7, 165.3, 144.5,
139.9, 131.8, 130.4, 129.9, 127.0, 120.7, 72.6, 61.2, 61.1, 57.1,
50.1, 46.3, 21.7, 14.4.
condenser, mechanical stirrer, temperature probe, and nitrogen
inlet, a solution of 9 (2.99 kg, 65.2 wt %, 3.95 mol) in methanol
(7.18 kg) was charged. With agitation, a solution of LiOH·H2O
(332 g, 7.91 mol) in H2O (4.2 kg) was added while maintaining
the batch temperature at 10−30 °C. The resulting mixture was
stirred at 18−23 °C for 2 h. HPLC (method C: 9 RT 13.6 min,
RRT 1.31; 10 RT 10.4 min, RRT 1.0) showed complete
consumption of 9. MeOH was removed at 30−35 °C under
reduced pressure (30−50 mbar). The residue was diluted with
water (30 kg), and the solution was extracted with EtOAc (2 ×
2.4 kg). The aqueous layer was diluted with n-butanol (10.5
kg), then the pH was adjusted to 6.5 by slow addition of
aqueous HCl (2N) at 10−20 °C. The aqueous layer was
separated and further extracted with n-BuOH (2 × 5.4 kg). The
combined organic layers were washed with water (2 × 3 kg)
and concentrated at 45−50 °C under reduced pressure (20−40
mbar). Toluene (10.5 kg) was added to the resulting
suspension and concentrated in vacuo to further remove the
n-butanol. After addition of MTBE (12.5 kg), the solid was
isolated by filtration and dried in a vacuum oven at 40−50 °C/
20−30 mbar for 8 h. The solid was reslurried in methanol (12
kg) and filtered. After drying in vacuo at 40−50 °C/20−30
mbar for 48 h, 10 (1.64 kg, 92.1 A% (HPLC method C), 88.9
wt %, 63% yield) was obtained as an off-white solid. Analytically
pure 10 (solid) was obtained by preparative HPLC. IR (neat)
1711, 1626, 1512, 1437, 1159, 1022, 826 cm−1; 1H NMR (400
MHz, DMSO-d6) δ 9.84 (br. s., 1H), 8.56 (br. s., 1H), 7.70−
7.51 (m, 5H), 7.41 (d, J = 8.0 Hz, 2H), 7.24−7.06 (m, 2H),
6.93 (d, J = 15.8 Hz, 1H), 3.63 (q, J = 7.0 Hz, 2H), 3.08−2.92
(m, 3H), 2.89−2.79 (m, 1H), 2.65−2.55 (m, 1H), 2.33 (s, 3H),
1.48 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 175.6, 164.6,
153.6, 146.7, 140.6, 133.2, 131.4, 130.3, 128.5, 128.4, 125.48
(br), 125.0, 124.4, 124.3, 121.8, 79.8, 64.0, 59.7, 52.1, 47.4,
42.0, 28.5; HRMS m/z [M + H]+ calcd for C26H31N3O5,
To a 30 L reactor equipped with a condenser, mechanical
stirrer, temperature probe, and nitrogen inlet, chiral salt 6 (8.00
kg, 11.5 mol) and water (10 kg) were charged. The agitation
was started, and aqueous NaOH (10 wt %, 9 kg) was added
slowly to adjust pH (aqueous layer) to 7.5−8.0 while
maintaining the batch temperature at 10−25 °C. After addition,
the mixture was stirred at 20−25 °C for additional 40 min. The
resulting white suspension was filtered, and the filtrate was
extracted with EtOAc (3 × 6 L). The combined organic layers
were dried over Na2SO4. After filtration, the filtrate was
concentrated to give 7 (3.71 kg, 99.9 A% (HPLC method A),
assay 93.8 wt %, 97.2% yield) as light yellow oil. IR (neat) 1731,
1488, 1372, 1245, 1179, 1158, 1010, 823 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.42 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.5 Hz,
2H), 4.22−4.06 (m, 2H), 3.67−3.57 (m, 1H), 3.07−2.92 (m,
3H), 2.91−2.81 (m, 1H), 2.67 (dd, J = 6.5, 9.3 Hz, 1H), 2.39
(s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 174.1, 143.4, 131.9, 129.5, 121.7−117.7 (m), 64.2, 61.1, 59.9,
52.6, 47.3, 42.2, 14.5; HRMS m/z [M + H]+ calcd for
20
C15H23N2O, 311.0521; found, 311.0524. [α]D = +65.49°
(0.488, MeOH).
(3R,4S)-4-{4-[(E)-2-(2-tert-Butoxycarbonylamino-phe-
nylcarbamoyl)-vinyl]-phenyl}-1-ethyl-pyrrolidine-3-car-
boxylic Acid Ethyl Ester (9). To a 20 L reactor equipped with
a condenser, mechanical stirrer, temperature probe, and
nitrogen inlet, 7 (1.96 kg, 92.8 wt %, 5.93 mol), (2-
acryloylamino-phenyl)-carbamic acid tert-butyl ester (8, 1.56
kg, 5.95 mol), Pd2(dba)3 (54.8 g, 59.8 mmol), tri(o-tolyl)-
phosphine (36.4 g, 0.119 mol), DMF (8.0 L), and DIPEA (1.93
kg, 14.9 mol) were charged. The mixture was stirred at 105−
110 °C for 5 h and cooled to 50 °C. HPLC analysis (method
C: 7 RT 3.7 min, RRT 0.27; 8 RT 11.8 min, RRT 0.87; 9 RT
13.6 min, RRT 1.0) showed that 1.9% of 7 was unreacted. The
resulting mixture was concentrated at 80 °C under reduced
pressure (20−30 mbar) to remove DMF. The residue was
diluted in EtOAc (8.0 L) and then filtered through Celite. The
filtrate was washed with water (2 × 5.0 L) and aqueous NaCl
(15%, 2 × 4.0 L). The combined aqueous layers were filtrated
through Celite and then extracted with EtOAc (4 × 3.0 L). The
combined organic layers were concentrated under reduced
pressure (30−50 mbar). The resulting brown gummy residue 9
(3.43 kg, 79.0 A% (HPLC method C), 65.2 wt %, 76% yield)
was used directly in the next step. Analytically pure 9 (sticky
oil) was obtained by preparative HPLC. IR (neat) 1730, 1516,
1455, 1367, 1244, 1158, 1023, 825 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ 9.70 (s, 1H), 8.48 (s, 1H), 7.65−7.50 (m, 5H),
7.39 (d, J = 8.0 Hz, 2H), 7.19−7.07 (m, 2H), 6.89 (d, J = 15.6
Hz, 1H), 4.07 (quin, J = 6.8 Hz, 2H), 3.61−3.51 (m, 1H),
3.12−3.02 (m, 1H), 2.91 (td, J = 8.7, 13.2 Hz, 2H), 2.84−2.77
(m, 1H), 2.59−2.52 (m, 1H), 2.29 (s, 3H), 1.46 (s, 9H), 1.16
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 173.4,
164.1, 153.1, 145.8, 140.2, 132.9, 131.0, 129.8, 128.0, 127.9,
125.1, 124.5 (br), 123.9, 123.8−123.7 (m), 121.4, 79.4, 63.6,
20
465.2264; found, 465.2258; [α]D = +56.07° (0.283, MeOH).
[2-((E)-3-{4-[(3S,4R)-4-(4-Chlorophenylcarbamoyl)-1-
methyl-pyrrolidin-3-yl]-phenyl}-acryloylamino)-phenyl]-
carbamic Acid tert-Butyl Ester (11). To a 30 L reactor
equipped with condenser, mechanical stirrer, temperature
probe and nitrogen inlet, 10 (800 g, assay 88.9%, 1.53 mol),
DCM (20.8 kg,) and THF (1.44 kg) were charged. To the
stirred suspension was added HATU (784 g, 2.06 mol)
followed by triethylamine (435 g, 4.30 mol), and the mixture
was stirred at 20−23 °C for 20 min. Then 4-chloroaniline (230
g, 1.80 mol) was added, and the mixture was stirred at same
temperature for additional 3 h. HPLC analysis (method C)
showed that more than 10% of 10 was still unreacted.
Additional HATU (2 × 196 g, 0.515 mol) was added and
the mixture stirred overnight. The second IPC (method C: 10
RT 10.4 min, RRT 0.75; 11 RT 13.9 min, RRT 1.0) showed
that the amount of residual 10 had decreased to 3.3%. Aqueous
Na2CO3 (10 wt %, 5 L) was added to quench the reaction. The
phases were separated. The organic layer was washed with aq.
Na2CO3 (10 wt %, 5 L) and dried over Na2SO4. After filtration,
the filtrate was concentrated under reduced pressure (40−60
mbar) to give the crude 11 (2.70 kg). The residue was slurried
in CH3CN (2.5 kg) at 20 °C for 1 h; the solid was collected by
filtration to give 11 (627 g, 89.5 A% (HPLC method C), 96.6
wt %, yield 69%) as an off-white solid. Analytically pure 11
(solid) was obtained by preparative HPLC. IR (neat) 1737,
1654, 1525, 1453, 1242, 1160, 826 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ 10.04 (s, 1H), 9.69 (s, 1H), 8.48 (s, 1H), 7.68−
7.52 (m, 7H), 7.41−7.28 (m, 4H), 7.22−7.04 (m, 2H), 6.88 (d,
60.3, 58.8, 51.1, 47.1, 41.5, 28.0, 14.0; HRMS m/z [M + H]+
20
calcd for C28H35N3O5, 493.2577; found, 493.2575; [α]D
+67.13° (0.301, MeOH).
=
(3R,4S)-4-{4-[(E)-2-(2-tert-Butoxycarbonylamino-
phenylcarbamoyl)-vinyl]-phenyl}-1-methyl-pyrrolidine-
3-carboxylic Acid (10). To a 30 L reactor equipped with a
H
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J = 15.8 Hz, 1H), 3.83−3.62 (m, 1H), 3.19−3.02 (m, 2H), 2.88
(t, J = 8.7 Hz, 1H), 2.75 (dd, J = 5.8, 9.0 Hz, 1H), 2.65−2.57
(m, 1H), 2.32 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz,
DMSO-d6). 13C NMR (101 MHz, DMSO-d6) δ 171.6, 164.1,
153.0, 146.5, 140.2, 138.0, 132.8, 130.9, 129.8 (br), 128.6,
128.0, 127.9, 126.8, 125.0 (br), 124.5 (br), 123.9, 123.9−123.7
(m), 121.3, 120.7, 79.4, 63.3, 60.5, 53.8, 46.7, 41.6, 28.0; HRMS
m/z [M + H]+ calcd for C32H35ClN4O4, 574.2347; found,
with Na2SO4. The mixture was concentrated under reduced
pressure at 20−30 °C under reduced pressure (40−50 mbar) to
give the crude 4 (254.6 g, 99.0 A%, yield 96%) as a light-yellow
oil which was used directly in the next step. A reference sample
1
of 4 was isolated by chromatography. Its H NMR spectrum
was in agreement with literature data.6a 1H NMR (400 MHz,
CD3Cl) δ 1.29 (t, J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H),
6.37 (d, J = 16.0 Hz, 1H), 7.33(d, J = 8.4 Hz, 2H), 7.46 (m, J =
8.4 Hz, 2H), 7.56, (d, J = 16.0 Hz, 1H).
20
574.2352; [α]D = +200.45° (0.313, MeOH).
(3R,4S)-4-{4-[(E)-2-(2-Aminophenylcarbamoyl)-vinyl]-
phenyl}-1-methyl-pyrrolidine-3-carboxylic Acid (4-
Chlorophenyl)-amide (1). To a 30 L reactor equipped with
a condenser, mechanical stirrer, temperature probe, and
nitrogen inlet, 11 (1.69 kg, 2.94 mol) and MeOH (2.70 kg)
were charged. The internal temperature was adjusted at 0−5
°C. To the suspension was added a solution of HCl in
methanol (10 mol/L, 6.25 kg) at 0−5 °C under stirring over 1
h. After the addition, the reaction mixture was stirred at 0−5 °C
for 3 h. IPC by HPLC analysis (method C: 11 RT 13.9 min,
RRT 1.13; 1 RT 12.3 min, RRT 1.0) to show that 1.2% of 11
was unreacted. Most of the MeOH and excess HCl was
removed at 15−20 °C under reduced pressure (30−50 mbar).
The oily residue was dissolved in MeOH (5.10 kg) and
concentrated again at 15−20 °C bath temperature; then it was
dissolved in MeOH (40.56 kg). Saturated aqueous Na2CO3 was
added to the solution at 10−20 °C with stirring until the pH of
the reaction mixture was 8.0. Saturated aqueous NaHCO3 (25.4
kg) was added, and the suspension was stirred for 30 min. After
filtration, the filter cake was slurried in water (5.07 kg) for 1 h.
After filtration, the filter cake was dried in a vacuum oven at
45−50 °C for 2 days. Thereafter, the dried solid was reslurried
in methanol (7.6 kg) and stirred at 60−65 °C for 20 min; the
slurry was cooled to 5−10 °C and filtered. The filter cake was
dried in a vacuum oven at 45−50 °C/25 mbar for 24 h. The
dried solid was reslurried in MeOH (11.8 kg) and stirred at
50−55 °C for 3 h; then water (16.9 kg) was added to the
suspension at 40−55 °C slowly. The slurry was cooled to 5−10
°C and filtered. The filter cake was dried in a vacuum oven at
45−50 °C/30 mbar for 2 days to give 1 (913 g, 98.2 A%
(HPLC method C), yield 65.5%, >99% ee (HPLC method D: 1
RT 13.5 min, RRT 1.0; isomer (3S,4R)-1 RT 19.8 min, RRT
1.47) as an off-white solid with the desired polymorph B. Mp
(DSC): peak 233.32 °C. IR (neat) 1655, 1529, 1494, 1226,
2,3-Dibromo-3-(4-bromophenyl)-propionic Acid Ethyl
Ester (12). To a 2 L flask equipped with a mechanical stirrer,
thermometer, and condenser, 4 (253.4 g, 0.993 mol) and DCM
(800 mL) were charged. The internal temperature was
controlled at to 0−5 °C with an ice−water bath. Bromine
(166.6 g, 1.04 mol) was added to the mixture at 0−10 °C over
30 min, and then the batch was stirred at 25 °C for 30 min.
After completion, sat. NaHSO3 (200 mL) was added to quench
the reaction. The mixture was washed with brine (20%, 300
mL) and then concentrated at 25−35 °C under reduced
pressure (30−50 mbar) to give 12 (371.2 g, 98.8 A%
diastereoisomer mixtures, yield 90%) as an oil, which became
off-white solid on standing in refrigerator overnight. The crude
was used directly in the next step. A reference sample of 12 was
1
isolated by chromatography. Its H NMR spectrum was in
agreement with literature data.19b 1H NMR (400 MHz, CD3Cl)
δ 1.10 (t, J = 8.0 Hz, 0.6H), 1.40 (t, J = 8.0 Hz, 3H), 4.06 (q, J
= 8.0 Hz, 0.4H), 4.38 (q, J = 8.0 Hz, 2H), 4.74 (d, J = 8.0 Hz,
0.2H), 4.78 (d, J = 8.0 Hz, 1H), 5.25 (d, J = 8.0 Hz, 0.2H), 5.32
(d, J = 8.0 Hz, 1H), 7.15−7.32(m, 2.2H), 7.50, (d, J = 8.0 Hz,
0.4H), 7.55 (d, J = 8.0 Hz, 2H).
(4-Bromophenyl)-propynoic Acid (13). To a 5 L four-
neck flask equipped with a mechanical stirrer, thermometer,
and condenser, potassium hydroxide (85 wt %, 197.0 g, 2.98
mol) and 2-propanol (2.1 L) were charged. The batch was
stirred under cooling in an ice−water bath to keep the internal
temperature about 5−10 °C. 12 (312.5 g, 0.753 mol) was
charged in portions to maintain the batch temperature below
60 °C, and then the mixture was heated at reflux for 3 h. After
completion of the reaction, the resulting mixture was
concentrated at 40 °C under reduced pressure (30−50 mbar)
to remove 1.2 L of 2-propanol. The residue was diluted with
water (1.2 L) and cooled in an ice bath; then the pH was
adjusted to 2 using 35% hydrochloric acid while keeping the
batch temperature below 25 °C. The resulting slurry was
filtered, and the solid was washed with water (1.2 L). The wet
solid was dried in vacuum oven at 40 °C/25 mbar to give 13
(162.2 g) as a white solid (99.0 A%, yield 96%). 1H NMR (400
MHz, DMSO-d6) δ 7.62 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6
Hz, 1H).
(4-Bromophenyl)-propynoic Acid Methyl Ester (14).
To a 5 L four-neck flask equipped with a mechanical stirrer,
thermometer, and nitrogen inlet, 13 (161.2 g, 0.716 mol),
DCM (1.6 L), and DMF (anhyd., 1.54 mL) were charged. The
suspension was stirred in an ice−water bath, and oxalyl chloride
(100 g, 0.787 mol) was added dropwise over 15 min at 10−15
°C. The mixture was held at this temperature for 15 min; then
it was warmed to room temperature and stirred for additional 2
h. A sample was taken and quenched with methanol. HPLC
analysis showed that acid 13 was consumed. The resulting
solution was cooled to 0−5 °C, and methanol (160 mL) was
added dropwise over 30 min. The mixture was stirred at room
temperature for 1 h and then diluted with water (400 mL). The
organic phase was separated, washed with sat. aq. NaHCO3
1
973, 827 cm−1; H NMR (400 MHz, DMSO-d6) δ 10.05 (s,
1H) 9.38 (s, 1H), 7.62−7.51 (m, 5H), 7.38−7.33 (m, 5H),
7.94−6.85 (m, 2H), 6.76 (d, J = 8.0, 1H), 6.58 (t, J = 8.0, 1H),
4.95 (s, 2H), 3.76−3.71 (m, 1H), 3.13−3.08 (m, 2H), 2.90−
2.86 (m, 1H), 2.77−2.74 (m, 1H), 2.65−2.60 (m, 1H), 2.33 (s,
3H); HRMS m/z [M + H]+ calcd for C27H27ClN4O2,
474.1823; found, 474.1817; [α]D20 = +244.24° (0.264, MeOH).
(E)-3-(4-Bromophenyl)-acrylic Acid Ethyl Ester (4)
(Improved Lab Procedure). To a 5 L flask equipped with
a condenser, mechanical stirrer, temperature probe, and
nitrogen inlet, 4-bromobenzaldehyde (191.9 g, 1.04 mol)
triethyl phosphonoacetate (279.0 g, 1.24 mol) and THF (1.1
L) were charged. The internal temperature was controlled at
0−10 °C with an ice−water bath. A solution of NaOH (54.0 g,
1.35 mol) in water (90 g) was charged slowly to the mixture at
10−15 °C, and then the mixture was stirred under the same
conditions for 2 h. After completion, MTBE (400 mL) was
charged, and the reaction mixture was well-stirred. The organic
layer was separated, and the aqueous layer was extracted with
MTBE (2 × 400 mL). The combined organic layers were dried
I
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(400 mL) and brine (20%, 400 mL), and then dried over
Na2SO4. After filtration, the filtrate was concentrated at 25−35
°C under reduced pressure (30−50 mbar) to give 14 (168.7 g,
in an ice−water bath for 30 min, and the solid was isolated by
filtration. The cake was washed with water (14 mL) and dried
in vacuum oven at 45 °C/25 mbar to give 17 (70.8 g, 99.6 A%,
yield 60%) as off-white solid. IR (neat) 1630, 1487, 1372, 1327,
1
98.4 A%, yield 98%) as a light-yellow solid. H NMR (400
1
MHz, CDCl3) δ 7.58−7.51 (m, 2H), 7.48−7.41 (m, 2H), 3.85
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 154.2, 134.3, 132.0,
125.5, 118.4, 85.2.
817 cm−1; H NMR (400 MHz, MeOD + D2O) δ 7.57−7.50
(m, 2H), 7.47−7.41 (m, 2H), 4.54 (br. s., 2H), 4.43 (br. s.,
2H), 3.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 179.8,
148.5, 143.9, 140.2, 138.9, 137.3, 129.1, 75.2, 73.6, 51.6; HRMS
m/z [M + H]+ calcd for C12H12BrNO2, 281.0051; found,
281.0046.
Methyltrimethylsilanylmethylamine (24). A 2 L stain-
less steel autoclave was charged with chloromethyltrimethylsi-
lane (23, 264 g, 2.15 mol) and aqueous methylamine (40%,
1.15 L). The mixture was stirred at 90 °C in an oil bath for 6 h
and then cooled to room temperature. The organic phase was
separated, washed with water (2 × 150 mL) and brine (150
mL), and dried over Na2SO4. After filtration, the crude 24 (221
g, 98 A% by GC (FID), 88%) was isolated as a yellow oil which
was used directly in the next step.
N-Methoxymethyl-N-methyl-1-(trimethylsilyl)-meth-
ylamine (15). To a 2 L three-neck flask equipped with a
mechanical stirrer, thermometer, and nitrogen inlet, 37%
aqueous formaldehyde (138 mL) was charged. 24 (149.8 g,
1.27 mol) was added dropwise over 45 min at 5−10 °C.
Methanol (98.5 mL) was added dropwise over 10 min and
followed by portion-wise addition of K2CO3 (67 g, 0.486 mol)
such that the temperature was kept below 15 °C. The mixture
was stirred in an ice−water bath for additional 2 h. tert-Butyl
methyl ether (150 mL) was added, and the organic layer was
separated and dried over K2CO3 (51 g). After filtration, the
filtrate was concentrated at 40 °C under reduced pressure (100
mbar) to give crude 15 (177 g) as a light-yellow oil which was
used directly in the next step.
4-(4-Bromophenyl)-1-methyl-2,5-dihydro-1H-pyrrole-
3-carboxylic Acid Methyl Ester (16). To a 2 L three-neck
flask equipped with a mechanical stirrer, thermometer, and
nitrogen inlet, 14 (100.0 g, 0.418 mol) and tert-butyl methyl
ether (1.0 L) were charged. To the suspension trifluoroacetic
acid (7.2 g, 62.7 mmol) and 15 (202.5 g) were added dropwise
in sequence over 30 min at 0−10 °C. The mixture was then
stirred at room temperature for 40 min. HPLC showed 6.8% of
14 was detected. The batch was concentrated at 35−45 °C
under reduced pressure (35−55 mbar) to give crude 16 (162.0
g) as a light-yellow oil (78.8 A%) which was used directly in the
next step. Analytically pure 16 (oil) was obtained by flash
chromatography. IR (neat) 1731, 1488, 1372, 1246, 1179,
1157, 1126, 822 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.48 (d,
J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 3.91−3.83 (m, 4H),
3.67 (s, 3H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.11, 149.82, 132.63, 131.11, 129.74, 126.49, 122.91, 67.10,
63.36, 51.41, 42.20; HRMS m/z [M + H]+ calcd for
C15H23N2O, 311.0521; found, 311.0524.
4-(4-Bromophenyl)-1-methyl-2,5-dihydro-1H-pyrrole-
3-carboxylic Acid (17). To a 1 L three-neck flask equipped
with a mechanical stirrer, crude 16 (162.0 g) and methanol
(405 mL) were charged. The solution was cooled in an ice−
water bath, and aq. NaOH (2 N, 418 mL, 0.836 mol) was
added over 10 min while maintaining the temperature below 20
°C. The mixture was stirred at room temperature for additional
3 h until the conversion was complete. The batch was
concentrated at 25−35 °C under reduced pressure (30−40
mbar) to remove the methanol. The residue was diluted with
water (34 mL) and extracted with tert-butyl methyl ether (3 ×
135 mL). The aqueous layer was separated, and its pH was
adjusted to 6.8 by slow addition of conc. HCl while maintaining
the batch temperature below 20 °C. The suspension was stirred
(3S,4S)-4-(4-Bromophenyl)-1-methyl-pyrrolidine-3-
carboxylic Acid (18). A 380 mL stainless steel autoclave was
charged with 17 (15.20 g, 53.9 mmol), [Ru(OAc)2((R)-2-furyl-
MeOBIPHEP)] (82.1 mg, 0.108 mmol) and methanol (150
mL) in a glovebox (O2 content <2 ppm) under argon. The
autoclave was removed from the glovebox and attached to a
hydrogen line. The argon in the system was replaced with
hydrogen, and then the reaction mixture was stirred under
constant hydrogen pressure (40 bar) at 45 °C. After 3 h, the
autoclave was cooled to room temperature, the pressure was
released, and the reaction mixture (a yellow suspension) was
sampled under vigorous stirring. HPLC analysis showed 99%
conversion, 100% selectivity, and 100% ee for 18 as well as no
presence of trans byproduct 27 or decarboxylated byproduct
28. The yellow suspension was removed from the autoclave
with aid of methanol (50 mL) and rotary concentrated at 35−
45 °C under reduced pressure (40−60 mbar) to a total weight
of ca. 60 g. The precipitated product was isolated by filtration.
The filter cake was washed with methanol (15 mL) and dried at
the rotavap at 50 °C/10 mbar to constant weight to give 18
(13.69 g, 98.0 A%, 100% ee (method E: (S,S)-18 RT 2.95 min,
RRT 1.0; (R,R)-18 RT 3.61 min, RRT 1.22), yield 89.4%) as a
1
white solid. IR (neat) 1630, 1161, 1109, 964, 836 cm−1; H
NMR (600 MHz, DMSO-d6) δ 11.9 (bs, 1H), 7.42 (m, 2H),
7.25 (m, 2H), 3.63 (m, 1H), 3.34 (m, 1H), 2.92 (m, 2H), 2.77
3
3
(dd, J = 9.0 Hz, 1H), 2.63 (dd, J = 9.0, 6.5 Hz, 1H), 3.34 (s,
3H); 13C NMR (150 MHz, DMSO-d6) δ 173.8, 141.4, 131.3,
131.1, 120.0, 62.6, 57.9, 48.9, 46.3, 42.2, 40.6; HRMS m/z [M +
H]+ calcd for C12H14BrNO2, 283.0208; found, 283.0212; [α]D
20
= −63.80° (0.326, MeOH).
(3S,4S)-4-(4-Bromophenyl)-1-methyl-pyrrolidine-3-
carboxylic Acid (4-Chlorophenyl)-amide ((3S,4S)-19). To
the suspension of 18 (2.48 g, 8.73 mmol) in DCM (18 mL)
and DMF (18 uL), cooled in an ice−water bath, oxalyl chloride
(1.34 g, 10.5 mol) was added in portions while maintaining the
temperature below 10 °C. After stirring at room temp for 30
min, the reaction mixture was concentrated under reduced
pressure at 20 °C/30−40 mbar. The residue was redissolved in
DCM (15 mL) and cooled in an ice−water bath. 4-
Chlorophenylamine (1.18 g, 9.00 mmol) was added and
followed by addition of triethylamine (1.83 g, 18.1 mol) in
portions. The mixture was stirred at room temperature for 30
min to complete the reaction. After dilution with DCM (30
mL), the resulted mixture was washed with water (20 mL) and
brine (20 mL) and then dried over Na2SO4. After filtration,
DCM was removed by vacuum distillation, and the crude
product was recrystallized from ethyl acetate and heptane (v/v,
1/2). The product was collected by filtration, and the filter cake
was dried in vacuum oven at 40 °C/25 mbar to give 19 (2.2 g,
95.0 A%, yield 62.1%) as an off-white solid. Analytically pure 19
(solid) was obtained by preparative HPLC. Mp (DSC): onset
180.46 °C, peak 181.13 °C. IR (neat) 1667, 1525, 1492, 1010,
1
821 cm−1; H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H),
J
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7.36−7.29 (m, 2H), 7.26−7.13 (m, 6H), 3.75−3.64 (m, 1H),
3.69−3.67 (m, 1H), 3.49−3.37 (m, 1H), 3.01−2.91 (m, 2H),
4.33 mmol) and MeOH (26 mL) were charged under nitrogen.
The suspension was stirred at 0−5 °C in an ice−water bath. A
solution of HCl in ethyl acetate (3 mol/L, 30 mL) was added at
0−5 °C over 10 min. The batch was stirred at 0−5 °C for 3 h
until the reaction was complete. Solvents and excess HCl was
removed at 20 °C under reduced pressure (35−45 mbar). The
residual oil was diluted in MeOH (20 mL) and concentrated
again. The crude was redissolved in MeOH (40 mL). Aqueous
Na2CO3 (10%) was added to the solution at 10−20 °C with
stirring until the pH of the reaction mixture was 8.0. Water (25
mL) was added to the suspension and stirred for 30 min. The
solid product was collected by filtration, washed with water, and
then dried in a vacuum oven at 45−50 °C/30 mbar to give
crude 1 (2.50 g). The solid was reslurried in reflux ethanol (16
mL) for 1 h. The suspension was cooled to 5−10 °C and
filtered. The filter cake was dried in a vacuum oven at 45−50
°C for 1 day. The solid was reslurried in MeOH (12.5 mL) at
50−55 °C for 3 h, and water (35 mL) was added. The
suspension was cooled to 5−10 °C and filtered. The filter cake
was dried in a vacuum oven at 45−50 °C/30 mbar to give 1
(1.80 g, 98.5 A%, yield 86.5%) as a light yellow solid with the
desired polymorphic form B.
2.89−2.80 (m, 1H), 2.67 (t, J = 8.3 Hz, 1H), 2.36 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6) δ 170.1, 139.8, 137.5, 130.7,
130.3, 128.2, 126.5, 120.8, 119.3, 61.7, 57.1, 49.5, 46.7, 41.8;
HRMS m/z [M + H]+ calcd for C18H18BrClN2O, 392.0291;
20
found, 392.0293; [α]D = −135.13° (0.335, MeOH).
(3R,4S)-4-(4-Bromophenyl)-1-methyl-pyrrolidine-3-
carboxylic Acid (4-Chlorophenyl)-amide (19). To a 1 L
three-neck flask equipped with a mechanical stirrer, temper-
ature probe, and nitrogen inlet, 18 (98%, 85.4 g, 0.300 mol),
HOBt (40.5 g, 0.300 mol), and DMF (430 mL) were charged.
The suspension was stirred at room temperature, and EDC
(90.8 g, 0.45 mol) was charged in four portions while
maintaining the batch temperature below 26 °C. The mixture
was then stirred at room temperature, and after 4 h 4-
chlorophenylamine (42.1 g, 0.330 mol) was added. The batch
was heated at 50 °C; after 2 h HPLC analysis showed 18 was
consumed. The resulting solution was concentrated at 50 °C
under reduced pressure (10−20 mbar) to remove 254 mL of
DMF. The residue was diluted by the addition of water (680
mL) and stirred at room temperature for 10 min. NaOH (20 wt
%, 60 g) was added dropwise over 10 min, and the batch was
stirred at room temperature for additional 2 h. The solid was
collected by filtration and reslurried in acetonitrile/water (v/v =
1/2, 680 mL) for 1 h. Finally, the product was collected by
filtration and dried in vacuum oven at 45 °C/25 mbar for 2
days to give 19 (106 g, 99.6 A%, >99% ee method F: (S,R)-19
RT 4.37 min, RRT 1.0; (R,S)-19 RT 6.39 min, RRT 1.46, yield
90%) as an off-white solid. Mp (DSC): onset 199.25 °C, peak
199.79 °C. IR (neat) 1660, 1528, 1399, 1092, 1012, 825 cm−1;
1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.60 (d, J =
9.0 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H),
7.26 (d, J = 8.5 Hz, 2H), 3.73−3.61 (m, 1H), 3.14−2.99 (m,
2H), 2.84 (t, J = 8.5 Hz, 1H), 2.70 (dd, J = 5.5, 9.0 Hz, 1H),
2.62−2.52 (m, 1H), 2.31 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 171.51, 143.93, 137.93, 131.28, 129.48, 128.53,
126.76, 120.71, 119.29, 63.25, 60.38, 53.90, 46.28, 41.55;
HRMS m/z [M + H]+ calcd for C18H18BrClN2O, 392.0291;
ASSOCIATED CONTENT
* Supporting Information
■
S
General analytical methods and copies of 1H and 13C NMR for
compounds 1, 5, 6, 7, 9, 10, 11, 13, 14, 16, 17, 18, 19, and 29;
synthesis of [Ru(OAc)2((R)-furyl-MeOBIPHEP)] (29), crys-
tallographic data (tables of bond lengths and angles, complete
atomic coordinates, anisotropic displacement coefficients, and
isotropic displacement coefficients for hydrogen atoms) and
1
analytical data (HRMS, H NMR, 31P NMR, IR, and Raman).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: michelangelo.scalone@roche.com.
*E-mail: zhengming.du@roche.com.
■
20
found, 392.0288; [α]D = +186.14° (0.280, MeOH).
Notes
[2-((E)-3-{4-[(3S,4R)-4-(4-Chlorophenylcarbamoyl)-1-
methyl-pyrrolidin-3-yl]-phenyl}-acryloylamino)-phenyl]-
carbamic Acid tert-Butyl Ester (11). To a 1 L three-neck
flask equipped with a mechanical stirrer, temperature probe,
and argon inlet, 19 (80 g, 0.203 mol), (2-acryloylamino-
phenyl)-carbamic acid tert-butyl ester (58.2 g, 0.224 mol), and
DMF (400 mL) were charged. The solution was sparged with
argon for 20 min. N-Methyl-dicyclohexylamine (51.6 g, 0.264
mol), Pd2(dba)3 (1.86 g, 20.3 mmol), and tri(o-tolyl)phosphine
(1.24 g, 40.6 mmol) were added in sequence. The mixture was
stirred at 80 °C for 1.5 h until the reaction was complete and
then concentrated at 50−60 °C under reduced pressure (20
mbar) to remove DMF (300 mL). The residue was diluted with
EtOAc (1.6 L) and filtered through Celite. The filtrate was
washed with water (800 mL) and brine (20 wt %, 400 mL) and
then concentrated under reduced pressure to remove the
EtOAc. The residue was reslurried in MTBE (800 mL) at room
temperature overnight. The solid product was collected by
filtration and dried in vacuum overn at 40 °C/25 mbar for 30 h
to give 11 (92.1 g, 98.9 A%, yield 79%) as an off-white solid.
(3R,4S)-4-{4-[(E)-2-(2-Aminophenylcarbamoyl)-vinyl]-
phenyl}-1-methyl-pyrrolidine-3-carboxylic Acid (4-
Chlorophenyl)-amide (1). To a 50 mL flask 11 (2.60 g,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Mr. Zhifeng Li (Wuxi Apptech) is gratefully acknowledged for
providing manufacturing data. We also thank Ms. Lucy Lu for
her assistance with chiral analysis. The experimental assistance
of Mr. Arthur Meili, Mr. Etienne Trachsel, and Mr. Daniel
Spiess is gratefully acknowledged. We thank Dr. Beat Wirz for
̀
helpful discussions on enzymatic reactions and Mr. Andre M.
Alker for determining the X-ray structure of ruthenium
complex 29. We thank also all colleagues in the central
analytical laboratories for their precious support.
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