First Kilogram-Scale Application of the Lanthanum Catalyzed Asymmetric Amination to Synthesis of the Chiral Succinimide Derivative, A Key Intermediate for the Preparation of AS-3201

Article abstract of DOI:10.1021/acs.oprd.6b00053

The process development of ethyl-(R)-3-amino-2,5-dioxopyrrolidine-3-carboxylate (2), the chiral intermediate for the manufacture of AS-3201 (1), is described. A practical and scalable Shibasaki asymmetric amination that generates the chiral quaternary center was developed and demonstrated on kilogram scale. A safe, convenient, and large-scale hydrogenation of the hydrazine intermediate was also developed.

Full text of DOI:10.1021/acs.oprd.6b00053

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Full Paper
First Kilogram-Scale Application of the Lanthanum Catalyzed
Asymmetric Amination to Synthesis of the Chiral Succinimide
Derivative, A Key Intermediate for the Preparation of AS-3201
Minoru Toshima, Shoji Watanabe, Katsuya Uchiyama, Tsuyoshi Takasaki, Nandkumar N
Bhogle, Hang Zhao, Mike Filios, Kazuhiko Takahashi, John R Snoonian, and Kostas Saranteas
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00053 • Publication Date (Web): 17 May 2016
Downloaded from http://pubs.acs.org on May 18, 2016
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First KilogramꢀScale Application of the Lanthanum
Catalyzed Asymmetric Amination to Synthesis of
the Chiral Succinimide Derivative, A Key
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Intermediate for the Preparation of ASꢀ3201
Minoru Toshima†, Shoji Watanabe†, Katsuya Uchiyama†, Tsuyoshi Takasaki†, Nandkumar N.
Bhogle*#, Hang Zhao#, Mike Filios#, Kazuhiko Takahashi†, John R. Snoonian#, and Kostas
Saranteas#
†Process Chemistry Research and Development Laboratories, Sumitomo Dainippon Pharma Co.,
Ltd., 3ꢀ1ꢀ98 Kasugadeꢀnaka, Konohanaꢀku, Osaka 554ꢀ0022, Japan.
#Chemical and Pharmaceutical Sciences, Sunovion Pharmaceuticals, Marlborough,
Massachusetts 01752, United States
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ABSTRACT. The process development of ethylꢀ(R)ꢀ3ꢀaminoꢀ2,5ꢀdioxopyrrolidineꢀ3ꢀ
carboxylate (2), the chiral intermediate for the manufacture of ASꢀ3201 (1), is described. A
practical and scalable Shibasaki asymmetric amination that generates the chiral quaternary center
was developed and demonstrated on kilogram scale. A safe, convenient and large scale
hydrogenation of the hydrazine intermediate was also developed.
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INTRODUCTION
ASꢀ3201 (1) is an aldose reductase inhibitor (ARI) that acts by reducing sorbitol accumulation in
the cells.1 ASꢀ3201 exhibits better efficacy and low toxicity compared to most other ARIs and is
currently in the Phase III clinical trials in Japan. ASꢀ3201 is a highly functionalized heterocycle
with a spirocyclic tetrasubstituted stereocenter and two imide moieties. The main synthetic
challenge is the construction of the chiral intermediate 2 (Figure 1).
Figure 1. Structures of AS-3201 and Chiral Intermediate 2
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2
Currently, 2 is produced by the route shown in the Scheme 1.1a Alkylation of ethyl
[(benzyloxycarbonyl)amino]cyanoacetate 3 with ethyl bromoacetate 4 furnished 5. Hydrolysis of
5 using hydrogen peroxide and sodium carbonate followed by cyclization produced succinimide
6. Resolution of 6 was carried out by forming cinchonidium salt 7. Crude salt 7 was crystallized
twice from ethanol to afford the diastereomerically enriched cinchonidium salt. This salt after
treatment with aqueous hydrochloric acid yielded 8 with >99.5% ee. Carbobezyloxy group of the
compound 8 was removed by hydrogenolysis with palladium on carbon to give 2. The overall
isolated yield of 2 is <12% due to the low yielding hydrolysis step, resolution step and two
recrystallizations of the diastereomeric salt. Additionally, difficulty in recycling the used
cinchonidine and limited world supply of cinchonidine make this route undesirable for the
commercial production of 2.
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Scheme 1. Current Supply Route for 2
RESULTS AND DISCUSSION
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Due to the limitations associated with the current route, we were interested in alternative routes
to key intermediate 2 that would provide 2 in higher efficiency and security of supply for larger
scale manufacture. The Shibasaki group has devised an elegant threeꢀstep sequence for the
asymmetric synthesis of 2 and further demonstrated it on multigram scale (Scheme 2)2. Imide 9
was subjected to the asymmetric Diels amination to produce 12 in high conversion and chiral
purity. Deprotection of 12 furnished 13 in 96% isolated yield and 91% ee (two steps).
Hydrogenation of 13 to cleave the nitrogenꢀnitrogen bond with Raney Ni (RaꢀNi) furnished
crude 2 that was further crystallized from 2ꢀpropanol to afford 2 in 63% overall yield with the
desired chemical and enantiomericpurities.
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Scheme 2. Shibasaki Asymmetric Synthesis of 2
We were encouraged by the results for the Shibasaki synthesis of 2. However, the conditions
described in the papers were found to present challenges for large scale manufacture. First, the
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deprotection reaction with HCl gas bubbling into a toluene solution of 12 followed by two
isolations of hydrazine 13 after toluene evaporation and trichuration with three different solvents
of makes this step somewhat lengthy and impractical. Second, RaꢀNi hydrogenation of the
nitrogenꢀnitrogen bond for the conversion of 13 to 2 was carried with large quantities of
pyrophoric RaꢀNi (substrate/RaꢀNi [dry] 2:1). All steps were further optimized to be able to
produce multiꢀkilogram quantities of 2. The details are described below.
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Optimization of imide 9 synthesis. Earlier batches of imide 9 were prepared by the following
route depicted in the Scheme 3.3 Low yield, use of dichloromethane for extraction and silica gel
chromatography for purification of the crude product 9 were the issues associated with this route.
Scheme 3. Original Route for Imide 9
Closer examination of this synthetic route revealed formation of two byproducts 16 (21%) and
17 (6%) due to over alkylation and partial hydrolysis of diethylmalonate respectively. Further
optimization with varying amounts of diethylmalonate and sodium ethoxide was conducted
(Table 1). Use of >2.0 equivalents of sodium ethoxide resulted in formation of byproducts 16
and 17 in higher content (entries 2 and 3). A screen of diethylmalonate equivalents with 2.0
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equivalents of sodium ethoxide revealed that the reaction proceeds with improved conversion
and selectivity with higher equivalents of diethylmalonate (entry 7). Using <2.0 equivalents of
sodium ethoxide with 5.0 equivalents of diethylmalonate resulted in lower conversion (entry 8).
The optimal results were obtained when 2.0 equivalent of sodium ethoxide and 5.0 equivalents of
diethylmalonate were used (entry 7). Higher conversion (>95%) and good selectivity were
observed (>85%)
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Table 1. Optimization of Imide 9 Synthesis
Entry NaOEt (eq.) Diethylmalonate (eq.) 14(%)a 9(%)a 16(%)a 17(%)a
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2
3
4
5
6
7
2.0
3.0
4.0
2.0
2.0
2.0
2.0
1.1
2.0
2.0
2.0
1.1
1.5
3.0
5.0
5.0
6.6
2.4
63.8
29.4
14.4
63.4
71.3
79.8
86.4
73.9
21.3
55.4
63.8
5.8
6.3
9.8
15.6
4.3
5.0
2.6
2.9
2.4
1.7
20.3
11.9
6.3
10.0
9.8
4.9
4.9
8
19.0
3.0
a. HPLC A%
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The sodium salt of 9 was isolated via filtration and further treated with 1M phosphate buffer.
Crude 9 was extracted with ethyl acetate, and the resulting extract was concentrated and then
crystallized from 2ꢀpropanol/ꢀnꢀheptane mixture to furnish imide 9 with good purity. This
procedure was scaled up to produce several 40 g batches of 9 with good yield (74%) and high
purity (98.9%).
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The optimized procedure was further employed for the kilo laboratory scaleꢀup. The yield and
quality data are depicted in the Table 2. The result of kilogram scale almost reproduced a result
of laboratory scale. The reaction filtration and wet cake washing of sodium salt of 9 was slow
enough that further attention is prudent to ensure success at larger scale.
Table 2. Data for kilolab run
Input of chloroacetamide (kg)
Output of 9 (kg)
8.0
10.7
73.0
97.88
Isolated Yield (%)
Purity by HPLC (A%)
Optimization of Asymmetric Diels Amination. Effect of additives. Effect of additives on the
rate and selectivity of the reaction was explored. Water was proved to be detrimental. Addition
of 10 mol% of water to the reaction indicated erosion in the stereochemical purity of the product
and 30 mol% water in the reaction diminished the rate and selectivity significantly (Table 3,
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entry 2). While ethanol and triethylorthoformate did not improve the ee there was also no loss of
ee either (entries 3 and 4).
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Table 3. Asymmetric Diels amination- Effect of additives
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Entry
Additive
Quantity, mol% Conversion, %a
12, era
1
2
3
4
H2O
10
30
6
>99.5
62.0
95.2:4.8
H2O
61:39
96:4
EtOH
>99.5
>99.5
Triethylorthoformate
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96.2:3.8
a. HPLC A%
Catalyst preparation, di-t-butylazodicarboxylate addition and work-up of the reaction. The
ꢀvalineꢀOtBu successively to a
catalyst preparation involves addition of ligand 11 and Hꢀ
D
solution of (LaNO3)3.6H2O in ethyl acetate at 20ꢀ25 oC. The imide 9 is then added at 20ꢀ25 oC
and the resultant solution is then cooled to 0 oC and aged for 1h. Diꢀtꢀbutylazodicarboxylate is
then added in portions at 0 oC for the formation of the product 12. After completion the reaction
was quenched at 0 oC with the addition of 0.6M aqueous HCl and workedꢀup. Erosion of the
selectivity of the Diels amination was observed when reaction was carried out at 20ꢀ25 oC (er
93.4:6.6 vs 96:4)). Catalyst preparation, addition of diꢀtꢀbutylazodicarboxylate and aqueous HCl
workꢀup exhibited very mild exotherms (rise of 5ꢀ7 oC).
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Optimization of deprotection step. Evaporation of the amination reaction stream to dryness,
HCl gas bubbling for deprotection, two purification steps, low volumetric productivity and use of
four solvents were the major issues with this procedure. Thus, it was necessary to streamline and
telescope the deprotection step into the prior amination reaction for the development of a
practical process.
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Commercially available 5 M HCl in 2ꢀpropanol was employed in the deprotection step (Scheme
4). Process stream generated from 1g scale Diels amination reaction was subjected to
deprotection with 5M HCl (8 eq.) at 50 oC. The reaction proceeds through formation of two
mono Boc intermediates 18 and 19 and was found to be complete in about 10 h. The reaction
slurry was filtered to afford the hydrazine HCl salt 13 as white solid in 86% yield (2 steps) and
>98% purity.
Scheme 4. Deprotection of 12
O
O
O
O
HCl/2-propanol (5M)
EtOAc
NH
NH
NH
NH
HCl/2-propanol (5M)
EtOAc
+
O
O
O
O
EtO2C
NBoc
EtO2C
NH HCl
NHBoc
EtO2C
NBoc
NH2
EtO2C
NH
50 o
C
50 o
C
NHBoc
HCl
NH2
13
HCl
12
(Prcoess stream in EtOAc)
18
19
Prior to deprotection, the organic phase derived from Diels amination is washed with water and 5
wt% sodium chloride solution successively, and is then dried via azeotropic distillation under
reduced pressure to achieve well below the target maximum of 0.50% water. HCl equivalence
and reaction completion data from significant scale laboratory experimentation are summarized
here in Table 3. With 4.5 eq. of HCl the reaction is essentially complete in about 13 h at 50oC.
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Fortunately, most of the impurities are soluble in the reaction solvents. The high isolated yields
5
6
and purities of hydrazine 13 were observed (Table 4).
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Table 4. Deprotection of 12 at 50oCa
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Entry Imide 9 Eq. of HCl Reaction Time (h) Isolated yield of Purity of isolated
13 (%)
13 (%)b,c
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2
3
30 g
8.8
4.3
4.5
9
94
95
94
99.0
180 g
200 g
10
13
99.1
99.0
a. After completion of Diels amination reaction workꢀup the process stream was subjected to azeotropic distillation
and then exposed to HCl/IPA. b. HPLC A%. c. remainder is only one impurityꢀmono BOC intermediate.
Both the asymmetric Diels amination and deprotection reactions worked very well at kilogram
scale. Robustness of the process was evident by good performance and reproducibility.
Significant loss of volatile hydrogen chloride which drives deprotection was observed and is
attributed to evolution of 2 equivalents each of nonꢀcondensable reaction byproducts carbon
dioxide and isobutene. The impact of hydrogen chloride loss on the reaction profile was
mitigated by a modified addition of HCl/2ꢀpropanol solution such that some acid is added only
after partial conversion (and nonꢀcondensable gas evolution) is achieved. As indicated in the
Table 5 both the kilolab runs produced 13 consistently in high yield and good quality with
complete removal of Lanthanum.
Table 5. Data for kilolab runs
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Item
Run 1
2.0
Run 2
2.0
Input of imide 9 (kg)
Output of 13 (kg)
Isolated yield (%)
Purity by HPLC (A%)
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2.66
95.8
99.13
2.67
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98.95
96:4
<0.1
Chiral purity (er, HPLC A%)
Lanthanum, ppm
96.2:3.8
<0.1
Hydrogenation of hydrazine-Conversion of 13 to 2. The Shibasaki group utilized RaꢀNi
catalyst for the hydrogenation step (Scheme 5).2a This procedure was carried out at 12 g scale of
13 with 6 g of RaꢀNi(dry basis) and at a hydrogen pressure of 50 psi. The crude product isolated
after workꢀup was subjected to recrystallization with 2ꢀpropanol to afford 2 in 66% yield with
the desired purity. Two areas of focus for optimization for this step were to first, lower catalyst
loading for the hydrogenation and second, integrate the workꢀup and isolation to simplify the
isolation procedure.
Scheme 5. Hydrogenation of hydrazine 13
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Optimization of Ra-Ni catalyzed hydrogenation. The effect of variations in RaꢀNi quantity,
reaction temperature and water content were explored for the rate and conversion of the reaction.
Higher catalyst loading resulted in better reaction profile and higher conversions (Table 6, entries
1, 2 and 3). Higher temperature was better for reaction conversions (entries 4 and 6).
Concentration of the reaction did not have much impact on the conversion (entries 4 and 5; 6 and
7; 8 and 9). Larger catalyst loadings at moderate temperature, the conditions reported by the
Shibasaki group, were found to perform better than other conditions (entry 1).
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Table 6. Hydrogenation at different catalyst loadings, temperature and concentrationa
Entry
13
T oC
Ratio of
2 (%)c
13 (%)c
13/Raney Ni
(dry basis)b
1
0.290 g
50
2/1
97.2
0
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2
0.120 g
0.400 g
0.154 g
0.466 g
0.195 g
0.546 g
0.256 g
0.556 g
0.280 g
50
50
70
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70
4/1
6/1
4/1
4/1
6/1
6/1
8/1
8/1
10/1
84.7
73.3
91.2
90.2
87.8
88.5
79.5
82.6
77.0
6.3
20.6
0.3
0.1
0.3
0.3
0.5
0.3
1.1
3
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10
a. The substrate was dissolved in 5 mL of EtOH and hydrogenated at 115 psi for 5h. b. EtOH wash performed to
remove water from the catalyst. c. HPLC A%
Effect of water. Presence of water in the reaction was found to be detrimental. Higher content of
water produced more impurities, thus, affecting the conversion to 2 (Figure 2). Since RaꢀNi is a
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50% water wet slurry a good wash procedure is required to remove most of the water from the
catalyst.
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100%
90%
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80%
2 (%)
70%
60%
Major byproduct
(%)
50%
40%
30%
20%
10%
0%
0.0%
1.0% 2.0%
Water content of reaction
3.0%
Figure 2: Effect of water on hydrogenation of 13 to 2
Scale up of hydrogenation. Larger catalyst loadings [(2:1, substrate:RaꢀNi (dry basis)] and
moderate temperature of 50 oC were used for further scale up of hydrogenation at 90 psi. For
practical purposes water content of the hydrogenation mixture was set at not more than 1.0% at
the ethanol wash step. Further dilution of the reaction mixture with absolute ethanol was
expected to bring the water content of the reaction well below 1%. After maximum amount of
liquid was removed from the settled RaꢀNivia a dip tube under positive nitrogen pressure
absolute ethanol was added to the RaꢀNi and the slurry was stirred for 10ꢀ15 minutes and
allowed to settle. The supernatant ethanol was removed repeating the above procedure. After
performing the ethanol wash procedure three more times the water content of the RaꢀNi slurry in
ethanol was consistently found well below 1%.
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Hydrogenation scaleꢀup experiments were conducted on 25 g scale of 13. The reactions were
stirred under hydrogen at about 25oC for 30 minutes and then warmed to 50oC and continued for
about 4.5 h. Good conversion with very little side reactions were observed (Table 7). After
completion the reaction was passed through Celite and mass balance of 2 in the reaction solution
was determined by wt/wt% HPLC assay.
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Table 7. Scale up of Hydrogenationa
Entry
Raney Ni
(dry basis)
12.5 g
H2O wt%b ToC
Time
2 (%)c 13 (%)c Mass balance
of 2 (Wt %)c
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2
0.94
0.57
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0.5 h
4.5 h
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4.5 h
96.8
96.7
0
90
91
12.5 g
0.5
a. 25 g of 13 was added to the catalyst slurry in 300 mL of EtOH and hydrogenated at 90 psi. b. Water Wt%
determined after catalyst wash with EtOH. c. HPLC A%
Isolation of 2. Major impurities present in the hydrogenation process stream are the undesired
enantiomer of 2 (~4%) and NH4Cl (1 equivalent). The undesired enantiomer is formed in the
asymmetric Diels amination reaction in about 4% and then it is carried through deprotection and
hydrogenation steps finally converting to the undesired enantiomer of 2. Recrystallization of
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crude 2 from 2ꢀpropanol removes the undesired enantiomer efficiently but it does not remove
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residual NH4Cl completely. Usually about 1% NH4Cl is detected in the final isolated sample of
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2.
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The process stream obtained after 25 g scale hydrogenation of 13 was workedꢀup, concentrated
and subjected to a crystallization screen. The slurry of substrate in ethyl alcohol was heated up
to 60 oC, then nꢀheptane was added and the mixture was heated up to 70 oC. After 30 minutes at
70 oC, the insoluble solid (NH4Cl) was filtered off, washed with corresponding hot solvent
mixture. The filtrate was cooled linearly to room temperature. The solid was filtered, washed,
dried to give the final product. 2 was obtained in 56ꢀ59% yield with >99.5% purity. Further,
hydrogenation was performed on 70 g scale and the crystallization was conducted with ethyl
alcohol/ nꢀheptane (1:1). The product was isolated with good yield (65%) and high purity
(chemical and chiral purities>99.5% with <0.1% NH4Cl)
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Three runs of hydrogenation of 13 were conducted in the kilo laboratory. Safe RaꢀNi handling
and water removal procedures developed in the laboratory were demonstrated successfully in
these runs. The integrated hydrogenation and crystallization steps worked smoothly in the
kilolab. The undesired enantiomer of 2 was rejected with high efficiency during the
crystallization. The yield and quality data for the kilolab runs are depicted in the Table 8.
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Table 8. Data for kiloab runs
Item
Run 1
1.86
Run 2
1.55
Run 3
1.64
Input of 13 (kg)
Output of 2 (kg)
0.80
0.67
0.73
Isolated yield (%)
Purity by HPLC (A%)
Chiral purity (er, HPLC A%)
Ammonium chloride, wt%
55.2
55.8
56.8
99.94
99.93:0.07
<0.1
100.00
99.93:0.07
<0.1
99.84
99.89:0.11
<0.1
Scheme 6. Improved procedure for synthesis of 2
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CONCLUSIONS
In summary, practical procedures for synthesis of imide 9, Shibasaki asymmetric amination, Nꢀ
Boc deprotection and hydrogenation of the hydrazine 13 were developed (Scheme 6). The
amination step was successfully telescoped into the deprotection step thus obviating the need for
isolation of the amination product 12. Hydrazine 13 was isolated with high yield (96%) and high
purity (chem. purity 99%, er 96:4). Safe procedures for handling large quantities of RaꢀNi were
introduced. Hydrogenation followed by robust crystallization that rejects impurities with high
efficiency was also developed. The target compound 2 was isolated with overall yield of 54%
yield (3 steps) with high chemical (>99.5%) and chiral purities (>99.7%).
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EXPERIMENTAL SECTION
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All reactions were carried out under a nitrogen atmosphere. All solvents and reagents were
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9
purchased from commercial sources and were used without further purification. Chiral ligand 11
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was prepared according to literature procedure.2a Hꢀ ꢀvalineꢀOtBu .HCl was purchased from
D
Watanabe Chemical Company, Hiroshima, Japan. It was neutralized with aqueous sodium
bicarbonate and the free base was isolated after extraction with dichloromethane followed by
evaporation of the solvent. 1H and 13C NMR chemical shifts were reported relative to residual
proton solvent peaks. All yields are corrected for purity and determined by reverseꢀphase HPLC
using purified standards. Chiral purities of 13 and 2 were determined by analysis of NꢀBoc
derivative of 13 and NꢀCbz derivative of 2 respectively.
HPLC method for 9 (reaction/purity): YMC ODSꢀA Aꢀ303, 5 ꢁm (4.6 mmφ × 250 mm). Solvent
A: phosphate buffer [(KH2PO4 (2.94 g) and K2HPO4 (2.94 g) were dissolved in H2O (800 mL)
and this solution was diluted fivefold]. Solvent B: acetonitrile. Gradient program; solvent A /
solvent B hold 70:30 for 10 min, 70:30 to 10:90 over 5 min, 10:90 to 70:30 over 0 min hold 15
min, flow 0.5 mL/min, at 30 °C, detection at 210 nm, RT 8.3 min.
HPLC method for 12 (reaction/purity) and 13. (reaction/purity): YMC ODSꢀA Aꢀ303, 5 ꢁm (4.6
mmφ × 250 mm). Solvent A: phosphate buffer [(KH2PO4 (2.94 g) and K2HPO4 (2.94 g) were
dissolved in H2O (800 mL) and this solution was diluted fivefold]. Solvent B: acetonitrile.
solvent A / solvent B 50:50, 30 min, flow 0.5 mL/min, at 30 °C, detection at 210 nm, RT 11.1
min (12), RT 5.1 min (13).
Chiral HPLC method for asymmetric Diels amination reaction. Daicel Chiralpak ADꢀH,
methanol/hexane 5:95, flow 1.0 mL/min, at 40 °C, detection at 210 nm, RT 9.5 min (major) and
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12.5 min (minor).
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9
Chiral HPLC method for NꢀBoc derivative of 13. Daicel Chiralcel OJꢀH 2ꢀpropanol/hexane 1/9,
flow 1.0 mL/min, at 40 °C, detection at 254 nm, RT 9.3 min (minor) and 12.1 min (major).
HPLC method for 2 (reaction): YMC ODSꢀA Aꢀ303, 5 ꢁm (4.6 mmφ × 250 mm). Solvent A:
phosphate buffer [(KH2PO4 (2.94 g) and K2HPO4 (2.94 g) were dissolved in H2O (800 mL) and
this solution was diluted fivefold]. Solvent B: acetonitrile. Gradient program; solvent A / solvent
B 90 : 10 to 20 : 80 over 20 min, 20 : 80 to 90 : 10 over 0 min, hold 10 min, flow 0.5 mL/min, at
30 °C, detection at 210 nm, RT 9.8 min.
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HPLC method for 2 (purity): SUMIPAX ODS Dꢀ210SLP, 3 ꢁm (3.0 mmφ × 150 mm). Solvent
A: phosphate buffer [KH2PO4 (0.74 g) and K2HPO4 (0.74 g) were dissolved in H2O (1000 mL)].
Solvent B: acetonitrile. Gradient program; solvent A / solvent B 100 : 0 to 90 : 10 over 10 min,
90 : 10 to 40 : 60 over 20 min, 40 : 60 to 100 : 0 over 0 min, hold 15 min, flow 0.5 mL/min, at 25
°C, detection at 220 nm, RT 9.1 min.
Chiral HPLC method for NꢀCbz derivative of 2. Daicel Chiralpak ASꢀH, ethanol/hexane 1/9,
flow 2.0 mL/min, at 40 °C, detection at 254 nm, RT 11.0 min (major) and 16.8 min (minor).
3-Ethoxycarbonylpyrrolidin-2,5-dione (9). Chloroacetamide (8.00 kg, 85.6 mol), diethyl
malonate (68.5 kg, 428 mol, 5.00 eq.) and ethanol (100 kg) were charged at room temperature.
20% sodium ethoxide in EtOH (58.2 kg, 171 mol, 2.00 eq.) was added over 20 minutes and the
mixture was stirred at 25°C for 23 h (HPLC condition A). The reaction slurry was filtered and
the residue was washed with ethyl acetate (40.0 kg). The filtered residue was collected as sodium
salt of 9 and ethyl acetate (80.0 kg) was added. The phosphate buffer (1 M, pH 6) was added and
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adjusted pH to 8.2. The organic layer was removed and the aqueous layer was extracted with
ethyl acetate (80 kg) two times. The combined organic layer was concentrated under reduced
pressure below 40°C to a weight of 22.2 kg 2ꢀpropanol (80.1 kg) was added to the concentrated
residue and the mixture was concentrated under reduced pressure below 40°C to a weight of 22.2
kg. The concentrated residue was filtered and washed with 2ꢀpropanol to a weight of 29.3 kg nꢀ
heptane (7.32 kg) was added to the concentrated oil at room temperature and seed crystals of 9
(8.02 g) were added at 25°C. The mixture was stirred for 25°C and nꢀheptane (36.6 kg) was
added over 1 h. The mixture was cooled to ꢀ10°C over 1 h and stirred for 1 h. The white slurry
was filtered and the wet cake was washed with 2ꢀpropanol/nꢀheptane (1.78 kg/14.2 kg) at ꢀ10oC.
The wet cake was dried under reduced pressure under 40°C for 21 h to give 9 as offꢀwhite solid
in 73% yield (10.7 kg, 97.9% HPLC purity). 1H NMR (400MHz, CDCl3): 9.06 (brs, 1H), 4.28 (q,
J = 7.2 Hz, 2H), 3.85 (dd, J = 4.8, 9.6 Hz, 1H), 3.15 (dd, J = 4.8, 18.4 Hz, 1H), 2.95 (dd, J = 9.6,
18.4 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 176.0, 172.8, 167.3,
62.8, 47.9, 33.4, 14.1. The NMR data are in agreement with the previously reported data.3
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Preparation of ethyl-(R)-3-hydrazinyl-2,5-dioxopyrrolidine-3-carboxylate hydrochloride
(13). To a stirred solution of LaNO3.6H2O (51 g, 0.12 mol) in ethyl acetate (3.32 L) ligand 11
(40 g, 0.12 mol) and Hꢀ
ꢀvalineꢀOtBu (61.2 g, 0.36 mol were added successively. The solution
D
was stirred for about 15 minutes until a thin white slurry was formed. Ethyl acetate (22.2 L) was
added to get a clear solution. Imide 9 (2.0 kg, 11.8 mol) was added and the resulting solution
was cooled to about 0 oC and aged for 1 h. Diꢀtꢀbutylazodicarboxylate (3.24 kg, 14.1mol) was
added maintaining the reaction temperature below 5 oC. The addition was complete in about 15
minutes. The reaction was stirred at 0ꢀ5 oC until <0.5% imide 9 remained in the reaction as
judged by HPLC method (~ 1 h). It was then quenched with addition of 0.6M aqueous HCl (8.0
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kg). After the separation of the lower aqueous phase the reaction stream was washed
successively with water (1x8.0 kg) and 5% aqueous NaCl (2x8.0 kg) and subjected to azeotropic
distillation under vacuum maintaining the batch temperature below 50 oC. The distillation was
continued until the water content of the process stream was <0.5%. The process stream was then
cooled to about 22 oC and polish filtered to a clean reactor. The batch was warmed to about 50
oC and 5M HCl in 2ꢀpropanol (8.0 kg, 60 mol) was added over a period of 1h. Caution! vigorous
gas evolution occurs due to byproducts carbon dioxide and isobutene. Gas evolution can be
controlled by reducing addition rate or pausing addition to allow vigorous evolution to subside.
After the addition reaction was further stirred at 50±2 oC until <0.05% 13 and <0.75% of monoꢀ
Boc intermediate 19 remained in the reaction as judged by HPLC method (~ 12h). The reaction
slurry was cooled linearly to 20±2 oC over a period of 1 h and filtered. The cake was washed
with successively with ethyl acetate (6 L)/2ꢀpropanol (1.9 L) mixture, 2ꢀpropanol (7.9L) and
ethyl acetate (8L) and dried in vacuo at 40±2 oC until constant weight to give 2.66 kg (95.8%
yield) of 13 as white solid. 1H NMR (400 MHz, CD3OD) δ 4.31ꢀ4.37 (m, 2H), 3.20 (d, J = 18.4
Hz, 1H), 2.87 (d, J = 18.4 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ
176.1, 175.2, 170.0, 69.0, 65.3, 41.5, 14.8. The NMR data are in agreement with the previously
reported data.2a, b
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Preparation of (R)-ethyl 3-amino-2,5-dioxopyrrolidine-3-carboxylate (2). 50% wet Raney Ni
(1.515 kg) was charged to a reactor and allowed to settle. Degassed ethanol (12 kg) in a charge
pot was transferred to the reactor. The system was purged with nitrogen and the catalyst slurry
was stirred for 10 minutes and allowed to settle. The supernatant ethanol was removed with the
aid of a dip tube utilizing positive pressure of nitrogen. Another catalyst wash with degassed
ethanol (8 kg) was performed. The analysis of water content of the ethanol washes indicated that
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most of the water has been removed from the catalyst and ~1% water remains with the last
ethanol wash. A slurry of 13 (1.55 kg, 6.52 mol) in ethanol (11.33 kg) was charged to the reactor
and the reactor was purged with nitrogen. The reaction slurry was warmed to 25±5 oC with
agitation and the reactor was pressurized with hydrogen to 90 psi. Hydrogenation was continued
for about 0.5 h with monitoring of hydrogen gas uptake. Hydrogenation was further continued at
40±5 oC for about 1.5 h and at 50±5 oC for about 4h. The catalyst and residual ammonium
chloride was filtered at 50±5 oC and the process stream was further concentrated to about 6.8L
via vacuum distillation maintaining the batch temperature below 60 oC. nꢀheptane (4.2 kg) was
charged to the reactor and the resulting slurry was heated to 70±2 oC. Reaction mixture was
filtered at 70±2 oC to remove residual ammonium chloride and cooled to about 47 oC and aged
for about 15 minutes. The resultant slurry was further cooled linearly to 20±2 oC over a period
of 1h, aged for about 0.5 h and filtered. The cake was washed twice with ethanol (0.93 kg)/nꢀ
heptane (0.77 kg) mixture and dried in vacuo at 40±2 oC until constant weight to give 0.674 kg
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1
(55.6% yield) of 2 as a white to offꢀwhite solid. H NMR (400 MHz, CD3OD) δ 4.22 (q, J = 7.0
Hz, 2H), 3.20 (d, J = 18.0 Hz, 1H), 2.67 (d, J = 18.0 Hz, 1H), 1.26 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CD3OD) δ 179.3, 177.8, 172.0, 65.9, 64.3, 43.9, 14.8. The NMR data are in
agreement with the previously reported data.2a
AUTHOR INFORMATION
Corresponding Author
Telephone: +1ꢀ508ꢀ357ꢀ7581. Fax: +1ꢀ508ꢀ357ꢀ7808. Eꢀmail:
Nandkumar.bhogle@sunovion.com
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Notes
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The authors declare no competing interest.
ACKNOWLEDGMENT
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We thank Mr. Takayuki Miyake for large scale manufacturing and Dr. Robert Bujalski for
analytical support.
REFERENCES
(1) (a) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.;
Suzuki, K.; Matsumoto, J.ꢀI. J. Med. Chem. 1998 41, 4118. (b) Kurono, M.; Fujiwara, I.;
Yoshida, K. Biochemistry 2001, 40, 8216. (c) Bril, V.; Buchanan, R. A. Diabetes Care 2004, 27,
2369. (d) Kurono, M.; Fujii, A.; Murata, M.; Fujitani, B.; Negoro, T. Biochem. Pharmacol. 2006,
71, 338. (e) Giannoukakis, N. Curr. Opin. Investig. Drugs 2006, 7, 916. (f) Matsumoto, T.; Ono,
Y.; Kurono, M.; Kuromiya, A.; Nakamura, K.; Bril, V. J. Pharmacol. Sci. 2008, 107, 231. (g)
Bril, V.; Buchanan, R. A. Diabetes Care 2006, 29, 68–72. (h)Vera Bril, Toshiyuki Hirose,
Sasagu Tomioka, Robert Buchanan, Diabetes Care. 2009 July; 32(7): 1256–1260
(2) (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 11342. (b) Mashiko, T.; Kumagai, N.; Shibasaki, M. Org. Lett. 2008, 10,
2725. (c) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 14990.
(3) (a)Tanaka, D. PCT Int Appl. WO2008 / 004415 A1, 2008. (b) Tanaka, D. US Patent Appl.
US20090253917A1
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