Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.oprd.9b00138

An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available 1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient ruthenium-catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr and 99.7% ee on a 100 g scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to scale-up. This process not only gives a desirable total yield but also avoids hazardous conditions and chromatographic purification. The robustness of this synthesis was successfully performed on a multigram scale to afford 1 with >99.9% de and >99.9% ee in 56.8% overall yield in nine steps.

Full text of DOI:10.1021/acs.oprd.9b00138

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Full Paper
Development of an Efficient and Scalable Asymmetric Synthesis of
Eliglustat via Ruthenium (II)-catalyzed Asymmetric Transfer Hydrogenation
Guodong Sun, Weilin Jian, Zhonghua Luo, Tengfei Sun, Chao Li, Jiancun Zhang, and Zhongqing Wang
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 23 May 2019
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Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via
Ruthenium (II)-Catalyzed Asymmetric Transfer Hydrogenation
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Guodong Sun†,‡, Weilin Jian‖, Zhonghua Luo‖, Tengfei Sun‖, Chao Li‖, Jiancun Zhang†,*, Zhongqing Wang‖, §,
*
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†Guangzhou Institutes of Biomedicine and Heath, Chinese Academy of Sciences, 190 Kaiyuan Road, Guangzhou,
510530, P. R. China
‡University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing, 100049, P. R. China
‖HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China
§Anti-infection Innovation Department, New Drug Research Institute, HEC Pharma Group, Dong Guan 523871, P.
R. China
*E-mail:zhang_jiancun@gibh.ac.cn
*E-mail:wangzhongqing@hec.cn
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TOC Graphic:
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O
OH O
OH
N
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O
O
O
O
O
OH
OEt
DKR-ATH
N
HN
O
O
Ph Ph
7
5
eliglustat,1
telescoped processing
excellent stereoselectivity
high overall yield
>99.9% de, >99.9% ee
56.8% overall yield in 9 steps
mild conditions, easily operated
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ABSTRACT
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An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step
telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available
1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient Ruthenium catalyzed
DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr, and 99.7% ee on 100-
gram scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to
scale-up. This process not only gives desirable total yield, but also avoids hazardous conditions and
chromatographic purification. The robustness of this synthesis was successfully performed on multigram scale to
afford eliglustat (1) with >99.9% de, and >99.9% ee in 56.8% overall yield in nine steps.
KEYWORDS
eliglustat, asymmetric synthesis, Ruthenium catalyst, asymmetric transfer hydrogenation, dynamic kinetic resolution
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INTRODUCTION
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Eliglustat (1), an orphan drug developed by Genzyme, is a specific and potent inhibitor of glucosylceramide
synthase.1 In 2014, eliglustat tartrate (Cerdelga®) was approved by the FDA for the treatment of adults with
Gaucher disease type 1, a rare genetic disease caused by a deficiency of the lysosomal hydrolase acid β-
glucosidase.2 Due to the demonstrated efficacy in the long-term treatment with eliglustat (1), attention has been paid
to find efficient methods for its synthesis.
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To date, several approaches have been developed for the asymmetric synthesis of eliglustat (1), and the reported
analysis was summarized in Scheme 1.3 These methods showed a similar synthetic strategy using the key
intermediate 2, the synthesis of which was however the major challenge in the development of a robust processes.
Known methods of preparing this chiral aryl β-hydroxy α-amino acid derivative are poorly amenable to
manufacturing scale. In 2003, Genzyme disclosed the medicinal chemistry route of eliglustat (1) utilizing a
substrate-controlled chiral aldol reaction with 1,4-benzodioxan-6-carbaldehyde A and a chiral pool material B,
which was derived from (s)-2-phenylglycinol.3a This route could efficiently establish the two contiguous stereogenic
centers of 2. However, multiple chromatographic purifications were needed and the overall yield was very low
(9.5%, for 6 steps). Other approaches utilized D-serine derivative C3b,3c as chiral pool or chiral source E3d have also
been reported but were unlikely suitable for large scales as harsh conditions, such as microwave and cryogenic
condition were needed. Recently, Xu et al. 3e reported a concise synthesis of eliglustat involving an organocatalytic
asymmetric Henry reaction. This synthetic route was short and eliglustat (1) could be obtained in only three steps
starting from A and nitro compound F. Last year, another concise synthesis based on Crimmins aldol reaction
between A and Evans auxiliary G was reported by Liu and coworkers.3f Although these two methods seem
interesting and could shorten the synthetic steps, neither is suitable for scale up, because both suffer from safety
issues for the use of the potentially explosive reagents or toxic tin compound. Therefore, an efficient and readily
scalable asymmetric synthesis of eliglustat (1) with improved yield, without using harsh conditions or hazardous
reagents and chromatographic purification is highly desirable.
Scheme 1. Reported Retrosynthetic Analysis of Eliglustat (1)
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O
4
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O
O
O
O
N
+
NO2
O
F
O
A
TBSO
N
H
asymmetric
ref 3e
OH
ref 3d
Henry reaction
E
chiral source
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N
O
OH
N
H
chiral pool
Ph
N
O
O
O
O
O
O
+
NH2
HN
O
ref 3a
O
B
O
A
2
chiral pool
ref 3b,c
O
chiral auxiliary ref 3f
eliglustat, 1
O
BrMg
O
O
OMe
O
+
RO
N
O
X2
X1
N3
NHR
N
+
C
D
O
X = O or S
A
G
Asymmetric reduction via dynamic kinetic resolution (DKR) is regarded as a powerful synthetic method to
simultaneously set up two adjacent stereogenic centers in a single transformation from racemic substrates.4,5
Recently, we have developed an efficient asymmetric synthesis of enantiomeric pure syn-aryl β-hydroxy α-
dibenzylamino esters via a DKR asymmetric transfer hydrogenation (DKR-ATH) in high yields.6 Excellent
diastereoselectivity and enantioselectivity were obtained by using oxo-tethered Ru (II) catalyst that could be applied
to a wide range of substrates. Thus, we believed that this highly stereoselective reaction would be a promising
candidate for a practical synthesis of eliglustat (1). The novel approach envisioned for the synthesis of eliglustat (1)
based on the above-mentioned DKR-ATH reaction is displayed in the retrosynthetic strategy shown in Scheme 2.
Scheme 2. Retrosynthetic Strategy of Eliglustat Based on Ru-catalyzed DKR-ATH
OH
OH
N
OH
O
O
debenzylation
acylation
reduction
O
O
O
O
N
N
N
HN
O
NH2
Ph Ph
2
3
1
OH
O
OH
O
O
O
O
HN
O
O
O
O
O
DKR-ATH
steps
N
OEt
OEt
O
O
HO
N
N
N
O
Ph Ph
Ph Ph
Ph Ph
4
5
6
7
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As shown in Scheme 2, we envisioned that eliglustat (1) could be obtained through acylation of intermediate 2, of
which the free amino group could be released via debenzylation from 3. Compound 3 could in turn be generated
from reduction of amide 4, which was readily derived from the key intermediate 5. The key transformation from α-
dibenzylamino β-ketoester 6 to 5 with the introduction of the two adjacent stereogenic centers could be achieved by
the Ru-catalyzed DKR-ATH reaction. Compound 6 could be synthesized from the commercially available 1,4-
benzodioxane-6-carboxylic acid 7. Herein, we report our result of this efficient and readily scalable approach and
describe its implementation on multigram scale preparation of eliglustat (1).
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RESULTS AND DISCUSSION
Preparation of α-dibenzylamino β-ketoester 6
Our synthetic efforts started with the synthesis of the α-dibenzylamino β-ketoester 6 from commercially available
1,4-benzodioxane-6-carboxylic acid 7. Although this type of compounds could be easily obtained from the
corresponding acyl chloride in high yields in one step, cryogenic condition (-60 °C) was often required.7 With the
aim of developing a convenient and readily scalable process we need to explore an alternative approach avoiding
such harsh conditions. Thus, a three-step telescoped process was identified (Scheme 3). Acid 7 was activated by
CDI, and then underwent condensation reaction with potassium monoethylmalonate to afford β-ketoester 8. After
aqueous HCl and aqueous NaHCO3 washes the DCM solution of 8 was telescoped directly into the bromination step.
1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) was added portionwise to the DCM solution of 8 to suppress the
dibromide impurity. Upon completion of the bromination, the mixture was washed with aqueous NaHCO3 and the
organic phase was concentrated and the solvent was switched to MeCN. The amination of 9 was conducted with
dibenzylamine at reflux (80 °C) and mild base NaHCO3 was used, as high levels of debromination of 9 were
observed when stronger bases were used. The overall yield of 6 varied from 80% to 90% on small scales, and 85%
overall yield was achieved when the process was operated on 100-gram scale, demonstrating a good reproducibility.
With this robust scalable process, the remaining challenge remains on the downstream steps from 6 to the key
intermediate 2 in the synthesis of eliglustat (1).
Scheme 3. Preparation of α-dibenzylamino β-ketoester 6 from Acid 7
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O
O
O
O
O
O
O
1, CDI, DCM, 25 C
O
O
O
O
O
O
O
O
Bn2NH/NaHCO3
MeCN, 80 C
DBDMH
OH
OEt
OEt
OEt
Br
N
2, EtO2CCH2CO2K,
MgCl2, DMAP,Et3N,
DCM, 0~25 C
DCM
25 C
Ph Ph
6
7
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9
7
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9
three-step telescoped process
overall yield: 80-90%
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Asymmetric Synthesis of 6 via a Ru-Catalyzed DKR-ATH.
With substrate 6 in hand, the investigation of asymmetric transfer hydrogenation of 6 using Ru catalysts was
undertaken. Based on our experience in the field of Ru-catalyzed DKR-ATH reactions, we deliberately focused on
two class of Ru catalysts, oxo-tethered catalyst (R,R)-10 ((R,R)-Ts-DENEB) and catalyst (R,R)-11 (RuCl[(R,R)-
TfDPEN](p-Cymene)).4f,6 As expected, catalyst (R,R)-10 used in our previous work gave excellent stereoselectivity
with full conversion (entry 1, table 1), and catalyst (R,R)-11 resulted in moderate conversion (entry 2, table 1) under
the same condition. After fine-tuning of the reaction conditions, improved result (>33:1 dr and 99.7% ee, entry 3,
table 1) was obtained with catalyst (R,R)-11 when applying a slow addition of HCO2H over 15 h. As previously
reported, slow addition of HCO2H was shown to be favorable for achieving the high conversion and selectivity.8
Catalyst (R,R)-11 was therefore considered due to its excellent catalytic potency and cost-effective preparation at
larger scale.9 Upon the completion of the reaction (6 remained <5 A % by HPLC), the reaction mixture was
concentrated under vacuum and the crude residue was recrystallized from EtOH/H2O (9:1) to give product 5 in 90%
isolated yield with >99:1 dr, and 99.7% ee.
Table 1. Ru-Catalyzed DKR-ATH of Substrate 6a
OH
O
O
O
O
O
catalyst
(5 mol %)
O
O
OEt
OEt
NBn2
NBn2
HCO2H/Et2NH (5:2)
5
6
O
N
Ru
Ru
Tf
Ts
Cl
NH2
Cl
N
N
Ph
Ph
H
Ph
Ph
(R,R)-10
catalyst
(R,R)-11
drc (syn/anti)
entry
conv.b (%)
eed (%)
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(R,R)-10 e
(R,R)-11e
(R,R)-11f
99
86
96
>18:1
>29:1
>33:1
>99
>99
99.7
7
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aReaction conditions: compound 6 (22.4 mmol), Ru catalysts (5 mol %, (R,R)-10 was used directly, (R,R)-11 was generated with
R,R-TfDPEN and [Ru(p-cymene)Cl2]2) and used in situ), HCO2H (88.1 mmol), and Et2NH (35.2 mmol), stirred at 50 °C in
toluene (45 mL) for 40 h. bDetermined by HPLC. cDetermined by 1H NMR. dDetermined by chiral HPLC using a CHIRALPAK
IA column. eHCO2H was added over 10 min. f HCO2H was added over 15 h.
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Considering the variety of options within this strategy, we also synthesized an alternative substrate, racemic α-
dibenzylamino-β-ketoamide 13, which could be a more straightforward starting material for the synthesis of the key
intermediate 2 (Scheme 4). But, surprisingly, no conversion was observed when substrate 13 was applied under the
optimized DKR-ATH conditions. Based on these observations, we consequently focused our attention on using
compound 5 for the subsequent studies.
Scheme 4. Possible Routes toward Key Intermediate 2 via DKR-ATH
O
O
OH
O
O
O
O
O
DKR-ATH
OEt
OEt
N
N
Ph Ph
Ph Ph
6
5
O
O
OH
O
OH
O
O
O
O
DKR-ATH
O
O
N
N
N
N
N
NH2
Ph Ph
Ph Ph
13
2
4
Amide Synthesis.
Scheme 5. Direct Amidation
OH
O
OH
O
R1
NH
O
O
O
O
N
NR2
NR2
direct amidation
O
R=Bn or H, R1=Me or Et
At this stage, amidation of 5 with pyrrolidine would be the most direct way to obtain amide 4.10 (Scheme 5)
Unfortunately, this approach was unsuccessful in our case presumably due to the steric hindrance of the two bulky
Bn protecting groups. Alternative attempts by displacing the ethyl ester with methyl ester or subsequently
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deprotecting Bn groups were envisaged to promote this transformation. Indeed, the reaction proceeded to give amide
as the major product in pyrrolidine; however, decomposition via retro-aldol was then observed. In addition, the high
loss of the product during isolation in Bn deprotection process made this method unamenable to scale-up.
Therefore, we sought to explore the amide coupling through carboxylic acid 14 to prepare 4.( Scheme 6) We
decided to start with the widely used EDCI/HOBt, but low conversion was found. Our initial screen with other
coupling reagents (Table 2), such as CDI, EDCI/HOAt, and EDCI/HOSu, also gave poor results. It was rationalized
that sterically hindered Bn groups at the nitrogen atom possibly decreased the coupling efficiency. Literature
searching led us to examine the more active reagents, such as ethyl 2-cyano-2-(hydroxyimino) acetate (Oxyma),11 4-
(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methyl-morpholinium chloride (DMTMM),12 and recently reported
N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (TCFH),13 which are considered optimal reagents
for the couplings of sterically hindered carboxylic acids.14
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Scheme 6. Synthesis of Amide 4 from 5 through carboxylic acid 14
OH
O
OH
O
OH O
NH
O
O
O
O
O
O
NaOH
OEt
OH
N
NBn2
NBn2
NBn2
THF/EtOH
coupling agents
5
14
4
Table 2. Screening of Coupling Agents for Amidation Process
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Starting material
Product
Activated ester
Unknown impurities
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We subsequently found that the combination of Oxyma and other additives such as DIC and EDCI, displayed
superior coupling efficiency to TCFH and DMTMM (Table 2). Notably, the use of DMTMM led to considerable
amounts of recovered 14 and N-arylation impurity due to competitive addition of pyrrolidine. Considering the good
coupling efficiency and the lower risk of explosion harzard, DIC/Oxyma was chosen for the further development.
Preliminary research showed that the main impurities detected in this transformation were N-acylurea 15 and
activated ester 16. Consequently, the equivalents of DIC and pyrrolidine and order of addition were screened with
the aim of suppressing these impurities. We found that the formation N-acylurea 15 was significantly suppressed by
addition of DIC to the mixture of 14 and Oxyma in CH2Cl2 followed by pyrrolidine (Table 3, entry 3). Further
process optimization identified a telescoped sequence from hydrolysis step to amide 7, which obviated the need for
isolation and further streamlining the process. After saponification was completed, the reaction mixture was
concentrated to remove the solvent and acidified with aqueous HCl solution, then carboxylic acid 14 was telescoped
into the amide formation as a CH2Cl2 solution. Under the optimized conditions, the desired amide 4 was readily
crystallized from EtOH with excellent yield (94% over two steps) and no detectable amounts of the other
diastereomers were found.
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Table 3. Optimization of Amidation Process Using DIC/Oxyma
OH
O
N
O
O
O
NH
OH
O
OH O
NBn2
15
NH
O
O
O
O
OH
N
OH
Bn2N
16
O
NBn2
NBn2
Oxyma, DIC, DCM
O
N
14
4
NH
O
O
DIC
equiv.
1.0
pyrrolidine
equiv.
1.0
Conv. c
(%)
entrya
15b
16b
1
2
3
NDd
NDd
NDd
9.6
0.4
99.4
93.2
100
1.0
2.0
1.8
2.0
NDd
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aOrder of addition: entries 1-3, DIC was added to a mixture of 14 and Oxyma in CH2Cl2 followed by addition of pyrrolidine;
entry 4, Oxyma was added to a mixture of 14 and DIC in CH2Cl2 followed by addition of pyrrolidine; entry 5, DIC was added to
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c
d
a mixture of 14, Oxyma and pyrrolidine in CH2Cl2. Area percent by HPLC analysis. Determined by HPLC analysis. Not
detected.
Amide Reduction
With a reliable process in place to prepare 4, we next focused our efforts on amide reduction step. In the Genzyme
route, amide reduction was conducted using LiAlH4, which also worked well with amide 4 in our case (Table 4,
entry 1). However, considering the safety issue related to LiAlH4 for pilot-scale manufacturing,15 alternative
reagents were investigated (Table 4, entries 2-8). Early work showed that NaBH4/TFA gave low conversion in
amide reduction (Table 4, entry 2). The combination of NaBH4 and other additives also led to poor results (Table 4,
entries 3-7). Gratifyingly, reduction of amide 4 using Red-Al gave 3 smoothly with a good impurity profile (Table 4,
entry 8). As a result, Red-Al was identified for this amide reduction process and toluene was chosen as the solvent.
The reaction using 2.8 equiv. of Red-Al in toluene at 60°C achieved complete conversion in 4 h. After basic quench
and workup, 3 was afforded as an oil in >95 A% HPLC and used in the next step without any further purification.
Table 4. Screening of Amide Reducing Agentsa
OH
O
OH
O
O
O
O
Reduction
N
N
NBn2
NBn2
4
3
entry
reagent
additive
none
solvent
4 (area %)b
3 (area %)b
1
2
3
4
6
7
8
THF
THF
NDc
52
74
34
LiAlH4 (3.0 equiv)
NaBH4 (6.5 equiv)
NaBH4 (10 equiv)
NaBH4 (20 equiv)
NaBH4 (20 equiv)
NaBH4 (20 equiv)
Red-Al (5.0 equiv)
TFA (3.0 equiv)
TiCl4 (5.0 equiv)
AlCl3 (10 equiv)
LiCl (20 equiv)
I2 (10 equiv)
none
DME
THF
82
NDc
16
47
THF
4
NDc
11
THF
78
toluene
NDc
86
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aReactions were performed with 4 (0.3 mmol), reducing agents and additives in 10 mL solvents at 70°C. b Detected by HPLC.
cNot detected.
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The subsequent debenzylation of 3 was conducted with Pd/C as catalyst under hydrogen atmosphere. From a
8
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preliminary screen of reaction conditions, the use of 5.0 mol % of Pd/C under 1 atm of H2 at room temperature in
ethanol, in the presence of 2.5 equiv. of aqueous HCl, was found to be optimal in debenzylation reaction. Initially,
the desired product 2 was isolated by filtration after workup in 89% yield over two steps with >97 A% HPLC purity.
However, a formylated impurity 17 (Figure 1) was observed (up to 1 A% HPLC). The formation of 17 might be
attributed to the presence of residual isopropylurea, which was reduced by Red-Al and further coupled with 2 under
the acidic condition. Although recrystallization of the isolated solid from a mixture of ethyl acetate and cyclohexane
could upgrad the purity to >99 A% HPLC, reduction of the yield was also observed during recrystallization.
Fortunately, we subsequently found that recrystallization was not necessary because of efficient purging in
downstream processing.
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OH
N
O
O
HN
O
H
17
Figure 1. Structure of formylated impurity 17
Synthesis of Eliglustat (1)
The final step involves condensation of 2 with 2,5-dioxopyrrolidin-1-yl octanoate to afford eliglustat (1).
Originally, the amidation reaction was performed under the previously reported condition in absence of a base.3a
Further process development revealed a beneficial effect when base was introduced. The reaction using 2.0 equiv. of
Et3N showed better impurity profiles in this transformation. Upon reaction completion, the reaction mixture was
subjected to an aqueous workup to remove N-hydroxysuccinimide. The crude product was recrystallized from n-
hexane/MTBE to afford eliglustat (1) in 90% yield and >99 A% HPLC with >99.9% de, and >99.9% ee. The overall
synthetic route of eliglustat (1) was summarized in Scheme 7.
Scheme 7. The Overall Synthetic Route of Eliglustat(1)
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O
O
O
O
O
O
O
1, CDI, DCM, 25 C
O
O
O
O
O
O
O
O
Bn2NH/NaHCO3
MeCN, 80 C
DBDMH
OH
OEt
OEt
OEt
Br
NBn2
2, EtO2CCH2CO2K,
MgCl2, DMAP,Et3N,
DCM, 0~25 C
DCM
25 C
7
8
9
6
85% yield over 3 steps
105 g scale
9
OH
O
OH
O
OH
O
11
(R,R)-
pyrrolidine
DIC, Oxyma
DCM, 28C
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11
12
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14
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O
O
O
O
O
O
HCO2H, Et2NH
toluene, 50C
NaOH aq
EtOH/THF, 25C
OH
N
OEt
NBn2
NBn2
NBn2
5
14
4
90% yield
>99:1 dr, 99.7% ee
100 g scale
94% yield over 2 steps
O
O
N
OH
N
Pd/C
H2 (1atm)
3N HCl
OH
OH
O
O
O
O
O
O
Red-Al
toluene, 60C
2,5-dioxopyrrolidin-1-yl octanoate
Et3N, DCM, 28C
N
N
HN
O
O
NBn2
MeOH, 28C
NH2
O
3
2
1
Eliglustat ( )
89% yield over 2 steps
90% yield
>99.9% de, >99.9% ee
CONCLUSION
In conclusion, we have successfully developed an efficient and readily scalable asymmetric synthesis of eliglustat.
This process features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall
yield on 100-gram scale. The key intermediate 5 was obtained via an efficient Ruthenium catalyzed DKR-ATH
reaction, which afforded the desired product in 90% isolated yield with >99:1 dr, and 99.7% ee. The Ru-catalyst was
successfully switched to a cheaper catalyst (R,R)-11, due to its excellent catalytic performance and cost-effective
preparation at large scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized to allow
for scale-up. Our process not only gives desirable total yield, but also avoids hazardous conditions and
chromatographic purification, which could be amenable to large scale manufacture. The robustness of this synthesis
was successfully performed on multigram scale to afford eliglustat (1) with >99.9% de, and >99.9% ee in 56.8%
overall yield in nine steps.
EXPERIMENTAL SECTION
General. Commercially available materials purchased from Alfa Aesar or Kelong (China) were used as received.
Catalyst (R,R)-10 ((R,R)-Ts-DENEB) was purchased from Sino compound Catalysts Co., Ltd. (China) and (R,R)-
TfDPEN] for the preparation of (R,R)-11 was synthesized in house. If no special treatments are indicated, all
reagents and solvents were used without further purification. NMR spectra were measured on a Bruker Avance 400
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spectrometer or 600 spectrometer in solvents indicated; chemical shifts are reported in units (ppm) by assigning
1
TMS resonance in the H spectrum as 0.00 ppm, CDCl3 resonance in the 13C spectrum as 77.0 ppm. Coupling
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constants are reported in Hz with multiplicities denoted as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet
of doublets); m (multiplets), and etc. HRMS were performed on Fourier Transform Ion Cyclotron Resonance Mass
Spectrometer. Analytical HPLC for liquid phase was carried out on an Agilent HPLC workstation, equipped with a
Chiral MX (2) column (purchased from FLM Inc. Guangzhou, China). Optical rotations were measured using a 1
mL cell with a 1 dm path length on a Jasco P-1030 polarimeter and are reported as follows: [α]2D0 (c in g per 100 mL
solvent).
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Ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (8). To an agitated DCM (1.5 L) slurry of
potassium monoethyl malonate (118.1 g, 693.8 mmol) and magnesium chloride (79.3 g, 832.6 mmol) in Reactor A
was added DMAP (1.9 g, 13.9 mmol), followed by addition of Et3N (56.2g, 555.1 mmol). The mixture was
maintained at 25°C for 3-4 h. Reactor B was charged with 7 (50 g, 277.5 mmol) in DCM (400 mL) to afford a clear
solution. CDI (74.3 g, 457.9 mmol) was added portionwise at 25°C over a period of 20 min (CAUTION! CO2
evolution!). The reaction mixture was stirred at 25°C for 2 h. Then the mixture of Reactor B was transferred to
Reactor A using an addition funnel under nitrogen atmosphere at 0°C over a period of 30 min. After stirred for
additional 3 h, the mixture was cooled to 10-15°C at which point 2 M HCl solution (500 mL) was slowly added over
a period of 35 min and the mixture was stirred at 25°C for about 45 min. The organic layer was separated, washed
with 5 wt% NaHCO3 (450 mL) and saturated NaCl solution (600 mL). The resulting biphasic mixture was allowed
to settle for 20 min, and the organic layer was collected and used for the next step directly.
Ethyl 2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (9). To the above obtained solution
of 8 in DCM was added DBDMH (40.5 g, 141.5 mmol) at 25°C over a period of 1 h. The reaction mixture was
stirred at 25°C for additional 30-60 min. Then 10 wt% solution of Na2S2O3 (300 mL) was added and the mixture
stirred at 25°C for 30 min. The organic layer was separated and washed with H2O (320 mL) followed by complete
distillation under vacuum to afford the crude compound 9, which was used for the next step directly. 1H NMR (400
MHz, CDCl3) δ 7.51 (dd, J = 12.1, 9.9 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 5.61 (s, 1H), 4.32 (ddd, J = 14.2, 8.2, 4.8
Hz, 6H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 186.59, 165.27, 149.16, 143.62, 126.97, 123.46,
118.71, 117.55, 64.80, 64.06, 63.20, 46.17, 13.89.
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Ethyl 2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (6). MeCN (600 mL) was
added to the above obtained 9, followed by addition of NaHCO3 (37.3g, 444.1 mmol) and dibenzylamine (76.7g,
388.5 mmol). The reaction mixture was heated to 80°C for about 4 h and then cooled to room temperature. The
mixture was diluted with toluene (500 mL) and H2O (750 mL), and stirred for 20 min. The aqueous layer was
separated and extracted with 200 mL of toluene. The combined organic phase was washed with water (2 × 400 mL),
and concentrated to afford crude compound. MeOH (250 mL) was added and the mixture was stirred at 40-45°C for
1h. The mixture was then cooled to 10-20°C, the obtained solid was filtered and washed with MeOH (100 mL)
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1
followed by vacuum drying to afford the title compound 6 (105.2 g, 85.1% yield). Mp 124-126°C. H NMR (400
MHz, CDCl3) δ 7.40 (d, J = 2.0 Hz, 1H), 7.31 (dt, J = 7.9, 4.0 Hz, 5H), 7.26 (dd, J = 7.6, 6.2 Hz, 6H), 6.83 (d, J =
8.5 Hz, 1H), 4.89 (s, 1H), 4.41 – 4.25 (m, 6H), 3.94 (q, J = 13.7 Hz, 4H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 194.14, 169.66, 148.42, 143.27, 138.92, 129.35, 129.28, 128.33, 127.32, 123.61, 118.74, 116.86,
67.32, 64.77, 64.06, 60.77, 55.38, 14.32.
(2S,3R)-Ethyl 2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoate (5). To
a
solution of (R,R)-11 (6.9 g, 11.2 mmol) and 6 (100 g, 224.5 mmol) in toluene (400 mL), was added Et2NH (26.3 g,
359.2 mmol) at 20-30°C. HCO2H (47.1 g, 901.6 mmol) was then added slowly over 15 h. The reaction mixture was
stirred at 50°C until >95% conversion was obtained. Upon reaction completion (6 remained <5 A % by HPLC), the
mixture was subjected to distillation under vacuum at 50-55 °C to give the crude product. Then, 90% EtOH (200
mL) was added and the mixture was heated to 70-75°C for dissolution. After cooling to 15-20°C, the resulting slurry
was stirred for another 1 h. The solid was filtered and washed with 90% EtOH (100 mL) followed by drying to
afforded the desired product 5 (90.5 g, 90% yield) with >99:1 dr and 99.7% ee. The enantiomeric excess was
determined by chiral HPLC method: Chiral MX (2) column, 4.6 x 250 mm x 5μm; flow rate 0.8 mL/min;
temperature: 20°C; detection wavelength: 210 nm; eluent: Hexane/Ethanol/Isopropanol = 40/30/20; retention time:
20
1
8.70 min (syn-5) and 13.14 min (ent-syn-5). Mp 91-93°C. [α] -54.1, (c = 0.28, MeCN). H NMR (400 MHz,
D
CDCl3) δ 7.43 – 7.29 (m, 10H), 6.69 (ddd, J = 13.6, 10.1, 5.1 Hz, 3H), 4.86 (d, J = 10.0 Hz, 1H), 4.28 – 4.06 (m,
9H), 3.49 (d, J = 13.3 Hz, 2H), 3.38 (d, J = 10.0 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
169.36, 143.26, 143.19, 138.00, 133.55, 129.26, 128.65, 127.61, 120.57, 116.86, 116.27, 69.09, 67.58, 64.32, 64.24,
60.37, 54.82, 14.42. HRMS (ESI) calcd for C27H30NO5 [M+H]+: 448.2108, found 448.2115. Analysis by ICP-MS
showed 144 ppm Ru.
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(2S,3R)-2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoic acid (14). To a
reaction vessel was charged 5 (90.4 g, 204.2 mmol), THF (140 mL), and EtOH (280 mL). A solution of NaOH (16.2
g, 405.0 mmol) in 140 mL of water was added, and the mixture was stirred at 24-28 °C for 15 h. After that the
reaction mixture was adjusted to pH=5~6 with 4M HCl solution, the solvent was removed by distillation under
reduced pressure. Dichloromethane (400 mL) and water (100 mL) were added into the residue. The organic phase
was washed with brine (200 mL), and used for the next step directly. An analytical sample of 14 was obtained by
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crystallization from ethanol: white solid. Mp 76-78°C. [α] 20 -110.6, (c = 0.26, MeOH). 1H NMR (400 MHz, CDCl3)
D
δ 7.49 – 7.30 (m, 10H), 6.76 (d, J = 8.5 Hz, 2H), 6.69 (dd, J = 8.3, 1.7 Hz, 1H), 5.00 (d, J = 9.0 Hz, 1H), 4.20 (s,
4H), 4.09 (d, J = 13.2 Hz, 2H), 3.70 (d, J = 13.2 Hz, 2H), 3.52 (d, J = 9.0 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ
172.66, 143.34, 143.31, 136.98, 133.32, 129.40, 128.82, 127.98, 120.40, 117.10, 116.25, 68.93, 67.04, 64.30, 64.24,
54.91. HRMS (ESI) calcd for C25H26NO5 [M+H]+: 420.1793, found 420.1804.
(2S,3R)-2-(dibenzylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-1-(pyrrolidin-1-yl)propan-
1-one (4). Oxyma (28.7 g) was added to the DCM solution of acid 14, followed by the addition of DIC (45.9 g).
The mixture was stirred and cooled to 5-10 °C. Pyrrolidine (28.7 g) was added dropwise over 20 min while
maintaining the temperature below 15°C. After the completion of addition, the mixture was warmed to room
temperature, and stirring was continued for 5 h. The solvent was removed by distillation under reduced pressure.
95% Ethanol (330 mL) was added, and the mixture was heated to 60-70°C for 45 min, then the mixture was cooled
to 10-15°C and stirred for another 1 h. The product was collected by filtration and washed with EtOH/H2O (1:1, 2 ×
110 mL), then dried at 60°C under vacuum for 10 h to afford 4 as a white solid (89.4 g, 94% yield, >99.9 %
ee, >99:1 dr). The enantiomeric excess was determined by chiral HPLC method: Chiral MX (2) column, 4.6 x 250
mm x 5μm; flow rate: 0.6 mL/min; temperature: 20°C; detection wavelength: 210 nm; eluent: Hexane/Ethanol =
35/65; retention time: 8.57 min (anti-4), 9.27 min (syn-4), 10.12 min (ent-anti-4) and 13.24 min (ent-syn-4). Mp
132-134°C. [α] 20 -36.4, (c = 3.5, MeCN). 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 9H), 6.88 (d, J = 1.4 Hz, 1H), 6.76
D
(dt, J = 16.3, 5.0 Hz, 2H), 5.30 (s, 1H), 5.01 (d, J = 9.7 Hz, 1H), 4.38 (d, J = 14.4 Hz, 2H), 4.28 (s, 1H), 4.19 (s, 4H),
3.66 (d, J = 14.4 Hz, 2H), 3.46 (d, J = 9.7 Hz, 1H), 3.36 (m, 2H), 2.57 (m, 1H), 1.88 (m, 1H), 1.69 (m, 1H), 1.54 (m,
2H), 1.33 (td, J = 12.5, 6.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 168.64, 143.18, 143.08, 139.21, 133.67, 128.59,
128.55, 127.29, 119.69, 116.75, 115.33, 70.40, 66.83, 64.31, 54.83, 53.40, 45.85, 45.27, 25.88, 23.97. HRMS (ESI)
calcd for C29H33N2O4 [M+H]+: 473.2428, found 473.2433.
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(1R,2R)-2-(dibenzylamino)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol
(3).
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Toluene (400 mL) and 4 (89 g) were charged to a reaction vessel. Red-Al (168 g, 70% solution in toluene) was
added to the solution over a 60-min period using an addition funnel under nitrogen atmosphere. The reaction
mixture was stirred at 60°C for 4 h. The mixture was cooled to 5°C and quenched with 20% sodium hydroxide (660
mL), while keeping the temperature below 15°C. The aqueous layer was separated and extracted with 200 mL of
toluene. The combined organic phase was washed with water (3 × 300 mL), and concentrated to afford 3 as an oil
9
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(>95 A% HPLC), which was directly used in the next step without further purification. Mp 102-104°C. [α] 20 -35.5,
D
(c = 3.0, MeCN). 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8.6, 5.3 Hz, 8H), 7.28 (dd, J = 7.8, 4.1 Hz, 2H), 6.67
(ddd, J = 17.5, 10.0, 5.0 Hz, 3H), 5.53 (s, 1H), 4.27 (d, J = 8.4 Hz, 1H), 4.22 (s, 4H), 3.90 (d, J = 13.2 Hz, 2H), 3.80
(d, J = 13.2 Hz, 2H), 3.18 – 2.95 (m, 2H), 2.51 – 2.27 (m, 4H), 2.24 (d, J = 8.9 Hz, 1H), 1.74 (s, 4H). 13C NMR (101
MHz, CDCl3) δ 143.09, 142.90, 139.59, 135.96, 129.05, 128.43, 127.13, 120.66, 116.77, 116.39, 72.68, 64.32,
64.28, 61.55, 54.35, 54.30, 53.00, 23.65. HRMS (ESI) calcd for C29H35N2O3 [M+H]+: 459.2637, found 459.2644.
(1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (2). MeOH (450
mL) and 4N HCl (145 mL) was added to the above obtained crude 3. Activated Pd/C (0.77 mmol) was charged and
the mixture was stirred under H2 atomosphere (1 atm) at 25-30°C. Upon reaction completion, the mixture was
filtrated to remove Pd/C and washed with MeOH (50 mL) and water (50 mL). Then the filtrate was subjected to
distillation under vacuum. After completion of distillation, water (50 mL) was added followed by addition of 2N
aqueous HCl (10 mL). The resulting mixture was washed with ethyl acetate (2 × 100 mL). The organic layer was
discarded. The aqueous layer was cooled to 5-10°C, 15% aqueous NaOH (160 mL) was added over 30 min below
10°C to adjust pH 12-13. The reaction mixture was stirred for an additional 1 h. Then solid was collected by
filtration, and washed with water and dried under reduced pressure at 25-28°C to give the desired product 2 (46.5 g,
89% yield). Mp 87-89°C. [α] 20 +22.2, (c = 1.50, MeCN). 1H NMR (400 MHz, CDCl3) δ 6.83 (ddd, J = 9.7, 6.3, 1.3
D
Hz, 3H), 4.55 (d, J = 2.9 Hz, 1H), 4.26 (s, 4H), 3.12 (dd, J = 8.6, 6.6 Hz, 1H), 2.57 (m, 9H), 1.78 (s, 4H). 13C NMR
(151 MHz, CDCl3) δ 143.36, 142.69, 135.84, 119.25, 116.95, 115.22, 75.75, 64.39, 64.36, 60.11, 54.72, 54.43,
23.59. HRMS (ESI) calcd for C15H23N2O3 [M+H]+: 279.1694, found 279.1702. Analysis by ICP-MS showed 4.7
ppm Al, 310 ppm Pd.
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N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide
(Eliglustat, 1). 2 (45 g) was dissolved in anhydrous dichloromethane (360 mL) and the solution was cooled to
10°C. Triethylamine (24.5 g) was added to the mixture. A solution of 2,5-dioxopyrrolidin-1-yl octanoate (39.4 g) in
anhydrous dichloromethane (200 mL) was added over 30 minutes. Then the mixture was stirred at room temperature
for 14-16 hours. After completion of reaction, the reaction mixture was cooled to 5-10°C. 1M NaOH solution (230
mL) was added slowly to maintain the internal temperature below 15°C. After stirring for 30 min, the organic layer
was separated and washed with 5 wt% NaCl solution (2 × 250 mL). The organic layer was dried with anhydrous
Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was again dissolved
in MTBE (90 mL) and n-hexane (460 mL). After stirring for 30 min, the slurry was filtered. The product was
washed with n-hexane (2 × 200 mL) and dried under reduced pressure to afford Eliglustat (1) free base as a white
solid (58.7 g, 90% yield, >99.9 % ee, >99:1 dr). The enantiomeric excess was determined by chiral HPLC method:
chiral MX (2) column, 4.6 x 250 mm x 5μm; flow rate: 0.8 mL/min; temperature: 25°C; detection wavelength: 210
nm; eluent: Hexane/Ethanol (0.1% diethylamine) = 80/20; retention time: 11.08 min (syn-1), 13.05 min (anti-1),
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14.18 min (ent-syn-1) and 16.03 min (ent-anti-1). Mp 85-87°C. [α] 20 +7.3, (c = 3.00, MeCN). 1H NMR (400 MHz,
D
CDCl3) δ 6.95 – 6.67 (m, 3H), 5.87 (d, J = 7.2 Hz, 1H), 4.92 (d, J = 3.0 Hz, 1H), 4.26 (s, 4H), 4.20 (dt, J = 8.2, 4.0
Hz, 1H), 2.88 – 2.75 (m, 2H), 2.73 – 2.58 (m, 4H), 2.12 (t, J = 7.5 Hz, 2H), 1.80 (s, 4H), 1.61 – 1.44 (m, 2H), 1.39 –
1.15 (m, 9H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 173.47, 143.41, 142.80, 134.53, 118.92,
116.98, 115.06, 75.31, 64.33, 57.79, 55.14, 52.34, 36.81, 31.63, 29.08, 28.98, 25.65, 23.65, 22.60, 14.05. HRMS
(ESI) calcd for C23H37N2O4 [M+H]+: 405.2733, found 405.2746. Analysis by ICP-MS16 showed <3 ppm Al, <1
ppm Ru, <3 ppm Pd.
ASSOCIATED CONTENT
Supporting Information
1
Copies of H and 13C NMR spectra of compounds 1−6, 9, 14 and HPLC spectra for compounds 1,4 and 5. This
material is available free of charge via the internet at http://pubs.acs.org
AUTHOR INFORMATION
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Corresponding Authors
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E-mail: zhang_jiancun@gibh.ac.cn.
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E-mail: wangzhongqing@hec.cn.
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Notes.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the Anti-infective Drug National Key Laboratory Open Grant (No.
SKLAID201805). We also gratefully acknowledge financial support from the Key Science & Technology
Brainstorm Project of Dongguan (No. 2019622102009). We gratefully thank Guozhu Liu (HEC pharm Co., Inc.) for
NMR assistance, Baolei Luan and Yanling Liu (both HEC pharm Co., Inc.) for HPLC assistance.
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(16) Metal residues (Ru, Al and Pd) for compound 1 were detected by ICP-MS. According to the ICH Q3D
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guideline, all results were acceptable (less than 10 ppm).
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