Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate

Article abstract of DOI:10.1021/acs.joc.0c02986

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.

Full text of DOI:10.1021/acs.joc.0c02986

pubs.acs.org/joc
Article
Weinreb Amide Approach to the Practical Synthesis of a Key
Remdesivir Intermediate
Yuanchao Xie, Tianwen Hu, Yan Zhang, Daibao Wei, Wei Zheng, Fuqiang Zhu, Guanghui Tian,
Haji A. Aisa,* and Jingshan Shen*
Cite This: J. Org. Chem. 2021, 86, 5065−5072
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sı Supporting Information
ABSTRACT: Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies
of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for
preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from
2
,3,5-tri-O-benzyl-D-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection,
and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable
PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable
production of the key remdesivir intermediate.
INTRODUCTION
consuming and costly, and it became even worse when
COVID-19 affected the whole world.
■
The newly emerged coronavirus, SARS-CoV-2, which leads to
a severe respiratory disease named COVID-19, has posed a
great threat to global public health. As COVID-19 numbers
continue to rise around the world, effective treatments are
urgently needed to combat this pandemic. Remdesivir
RDV), a 1′-cyano-substituted adenosine nucleotide analogue
prodrug that demonstrates broad-spectrum antiviral activity
against an array of RNA viruses, was found to be a potent
SARS-CoV-2 replication inhibitor and approved by the FDA
for COVID-19 treatment on October 22, 2020.
As a unique C-nucleoside analogue characterized by a 1′-α-
CN and an adenine-mimicking pyrrolotriazine base moiety, the
synthesis of RDV as well as its parent nucleoside, GS-441524,
is a great challenge. In 2016, a scalable approach for the
preparation of RDV was reported, involving multistep
reactions starting from 2,3,5-tri-O-benzyl-D-ribonolactone 3
Recently, Gilead scientists reported a large-scale cyanation
7
process to prepare 6 using continuous flow chemistry.
Moreover, an optimized synthetic method employing NdCl3/
n-Bu NCl to facilitate the critical C-glycosylation reaction
1
4
between 3 and 4a was provided, affording 5 in 69% yield.
Compound 5 is an upstream intermediate in RDV synthesis,
and its accessibility is fundamental for the bulky supply of
RDV. To date, the synthesis of 5 is mainly achieved by
coupling 3 with 4a or the bromide counterpart 4b. In the case
of using 4b as the starting material, the yield of 5 could reach
(
2
,3
4
,5
8
,9
10
60%, even up to 75%, reported in a newly published paper.
Nevertheless, an uncommon agent, 1,2-bis(chlorodimethyl-
silyl)ethane, was required to mask the amino group of 4b,
which made this approach unsuitable for large-scale
production.
In our lab, we had performed an extensive study on the
synthesis of 5 using the existing methods but were unable to
obtain acceptable yields (40−50%). Two main byproducts
and 4-amino-7-iodopyrrolo[2,1-f ][1,2,4]triazine 4a (Scheme
). In the first step, the addition reaction between 3 and 4a
6
1
needs to be performed under harsh reaction conditions, giving
the hemiacetal 5 only in a moderate to low yield (40%). The
following two steps suffered from serious disadvantages, such
as low reaction temperatures, use of hazardous and corrosive
reagents, and cumbersome workup. From 2, three steps were
required to synthesize RDV, with a total yield of 43%. The
entire process for the manufacturing of RDV was rather time-
Received: December 20, 2020
Published: March 18, 2021
©
2021 American Chemical Society
https://doi.org/10.1021/acs.joc.0c02986
5
065
J. Org. Chem. 2021, 86, 5065−5072

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Article
Scheme 1. Gilead’s Method for the Scalable Synthesis of RDV
Scheme 2. Two Main Byproducts (7 and 8) Identified in the Synthesis of 5 Using the Existing Methods
were identified, the deiodinated pyrrolotriazine 7 and the
overaddition product 8 (Scheme 2), accounting for at least
3.0 equiv of i-PrMgCl. This intermediate possessed a free 4-
hydroxyl group, which was supposed to be protected before
proceeding to the following step. Initially, TBS was chosen as
the protecting group in view of its tolerance to organometallic
reagents. This reaction was conducted in dimethylformamide
(DMF) with a combination of TBSCl and imidazole at 0 °C.
Unexpectedly, the product mixture contained a high level of 3
that was possibly derived from 10 due to the tendency to form
a stable five-membered ring. After purification, 11a was
obtained in 58% yield, and it proved to be stable under an
ambient atmosphere for weeks. With 11a in hand, the
literature glycosylation conditions were employed (4a was
first in situ silylated with TMSCl and PhMgCl, followed by
magnesium−iodide exchange in the presence of i-PrMgCl·LiCl
to form the heteroaryl Grignard reagent, and then reacted with
3
0% in the reaction mixture, as reported in recent research that
elaborately investigated the impurities of this glycosylation
1
1
step. 4a bearing a free primary amino group makes this
addition reaction complicated, and lactone 3 has an ester
functionality, which inevitably leads to the overaddition side
reactions. Use of PhMgCl as the deprotonating agent for in
situ TMS protection of the amino group of 4a could lead to an
equivalent amount of benzene that is undesirable from an
application perspective, as well as the potential impurities
associated with the addition of PhMgCl to 3 or 5. These issues
still remain in the optimized process for preparing 5.
As is known, Weinreb amides are excellent substrates for the
diverse synthesis of ketones by reaction with Grignard or
organolithium reagents. This approach is highly efficient, and
importantly, it could minimize or even preclude over-
1
1a), and it was encouraging to find that the reaction was
clean, except for the deiodinated byproduct 7, accounting for
20% in the mixture. Compound 12a was obtained by
1
2−14
addition.
Hence, we envisaged that using a Weinreb
∼
amide, instead of lactone 3, may gain superiority in accessing
the key intermediate of RDV. Herein, we describe our
discovery of a new approach for the preparation of 5. To
our surprise, this approach not only offers a high yield but also
eliminates the use of PhMgCl, which allows for an efficient and
practical synthesis of 5 at a large scale.
chromatographic purification on silica gel in 52% yield, and the
TBS protecting group was removed by trifluoroacetic acid
(
TFA) to furnish 5 in a yield of 80%.
The favorable outcome of the Weinreb amide-based
approach for the synthesis of 5 prompted us to optimize this
new method. First, to shorten the synthetic route that
consisted of four steps, we intended to directly prepare 5 in
the addition step by using an excess of hydrochloric acid as the
quenching agent to remove the TBS protecting group of 11a.
However, this group exhibited good stability and remained
unchanged for at least 2 h in the acidic solution (pH = 1) at
ambient temperature. We thought that TMS or TES that had
much lower acid stability may be removed automatically
RESULTS AND DISCUSSION
■
Given the commercial availability, we still used 3 as the starting
material, and the original route is shown in Scheme 3.
Transforming 3 into Weinreb amide 10 was readily achieved in
a quantitative yield (100%) using 1.5 equiv of N,O-
dimethylhydroxylamine hydrochloride 9 in the presence of
5
066
https://doi.org/10.1021/acs.joc.0c02986
J. Org. Chem. 2021, 86, 5065−5072

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Article
Scheme 3. Original Weinreb Amide-Based Approach for the Synthesis of 5
Scheme 4. Modified Weinreb Amide-Based Approach for the Synthesis of 5
during the workup. Along this line, we performed the addition
reaction using TES- and TMS-protected Weinreb amides (11b
and 11c), respectively, shown in Scheme 4. As we expected,
the reactions afforded 5 directly after being quenched with 1 M
HCl to a final pH of 1−2. In this way, the TMS-containing
adduct 11c could be easily (within 20 min to 1 h depending on
the scale) converted into 5 at ambient temperature in an
isolated yield of 65%, while prolonged reaction time (at least 4
h) was required to remove the TES group of 11b. Therefore,
TMS was identified as the best protecting group.
the optimal deprotonating agent for in situ TMS protection of
6
,11
4a to perform the addition reaction.
However, this reagent
could lead to toxic benzene, which is obviously a concern in
large-scale production. In another aspect, Grignard reagents
bearing bulky nucleophilic components may hamper the
deprotonation or the silylation process. Taking these
considerations into account, we chose three common Grignard
reagents (CH CHMgCl, EtMgCl, and MeMgBr) for
2
condition optimization of this step, and the result is shown
in Table 1. CH CHMgCl bearing a vinyl anion is similar to
2
Subsequently, we optimized the reaction condition of the
silylation step. With imidazole as the base, solvent screening
was done, including DMF, CH Cl , tetrahydrofuran (THF),
PhMgCl in the aspects of alkalinity and nucleophilicity. It was
observed that in the presence of 1.0 equiv of TMSCl, the two
reagents gave acceptable yields (∼65%, entries 1 and 3).
However, when the amount of TMSCl was increased to 2.0
2
2
and methyl tert-butyl ether (MTBE). For DMF and CH Cl ,
2
2
the reaction proceeded well at 0 °C with 1.2 equiv of TMSCl
equiv, PhMgCl led to a decreased yield (entry 2), and CH 
2
and 1.8 equiv of imidazole. However, the cyclization byproduct
CHMgCl provided a relatively better result, with byproduct 7
reduced to 14% (entry 4).
3
was also produced, accounting for approximately 10% in the
reaction mixture. THF and MTBE were found to be
unfavorable for this reaction due to the incomplete conversion
of compound 10. Considering that the remaining DMF would
be detrimental to the addition reaction, CH Cl was chosen as
EtMgCl was recently investigated as an alternative
deprotonating agent but found to be inferior to PhMgCl for
11
the addition reaction. Similarly, in this study, we found that
EtMgCl gave a poor result with 5 and 7 in a ratio of nearly 1:1
(entries 5 and 6). MeMgBr is the simplest Grignard reagent
and supposed to be highly reactive to deprotonate the amino
group of 4a. When it was used, to our surprise, the reaction
went smoothly over an easily controlled temperature range
(−15 to 0 °C), and was completed within 1.5 h after
transferring 11c into the nascent Grignard reagent solution. In
the case of 2.0 equiv of TMSCl, the yield was up to 76% at a
10.0 mmol scale (entry 9), which was a little better than that of
the 1.0 equiv of TMSCl (entry 8). We further performed the
reactions at a larger scale (192 mmol) starting from 3, and the
product was obtained by crystallization in MTBE in a yield of
65% (entry 10). It is noteworthy that 7 was the primary
byproduct in the reaction and could be recycled by an acid−
base workup.
2
2
the solvent for further condition optimization. It was
discovered that when the reaction was conducted at a lower
temperature (−15 °C), there was no or only a slight amount of
3
in the product, which could be directly used for the following
addition reaction.
Coupling of 11c with 4a involved a complicated process and
constituted the most crucial step in the synthesis of 5. In
principle, total protection of the amino group of 4a was
favorable, as evidenced by the application of bis-
(
chlorodimethylsilyl)ethane for N-protection, which provided
10
a high yield for the addition step. With regard to the N-TMS
protection of 4a, we assumed that disilylation of the amino
group would be beneficial for the Mg−I exchange and the
subsequent addition reaction. PhMgCl has been considered as
5
067
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Article
Table 1. Summary of Results for the Coupling of 11c with 4a Using Different Deprotonating Grignard Reagents
yields [%]
a
b
entry
scale of 4a (mmol)
Grignard reagent
equiv of TMSCl
5
7
1
2
3
4
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
2.0
2.0
10.0
10.0
192.0
PhMgCl
PhMgCl
1.0
2.0
1.0
2.0
1.0
2.0
1.0
1.0
2.0
65
22
31
24
14
37
36
16
15
12
47
64
72
42
44
CH CHMgCl
2
CH CHMgCl
2
EtMgCl
EtMgCl
MeMgBr
MeMgBr
MeMgBr
MeMgBr
66
c
72
c
76
d
1
0
2.0
65
a
b
Determined by column chromatographic purification on silica gel unless otherwise specified. 7 was obtained from the acidic aqueous phase by
c
neutralization. 5 was synthesized from 3 in three steps. The majority of 5 was obtained by crystallization in MTBE, and the remaining portion was
obtained by column chromatography from the filtrate. Crystallization yield.
d
Scheme 5. More Simplified Weinreb Amide-Based Approach for the Synthesis of 5
In the course of the Weinreb amidation step, the product
was obtained in the form of magnesium alkoxide (proposed
structure 13), which was converted into 10 upon aqueous
workup. Because the hydroxyl group of 13 was deprotonated,
this intermediate could be used directly for the addition
reaction, therefore possibly further simplifying the synthetic
method. At first, we conducted the reaction by adding 13 into
the nascent heteroaryl Grignard reagent THF solution.
However, it went very slowly, affording only a very small
amount of 5 in the reaction mixture by thin-layer
chromatography (TLC) analysis. After quenching with 1 M
HCl, the predominant product was 7. We also attempted to
add the nascent Grignard reagent to the solution of 13 and it
gave a similar result. By accident, we discovered that when an
additional 1.0 equiv of i-PrMgCl was added to the freshly
prepared 13 (a total of 4.0 equiv of i-PrMgCl was used) and on
transferring the mixture into the Grignard reagent solution, the
reaction proceeded well and gave a remarkably increased yield
PrMgCl, adding the additional i-PrMgCl to the final reaction
mixture, and increasing the addition reaction temperature, but
no improvement was observed. Generally, this method did not
show an obvious advantage over the TMS-protection process
for the preparation of 5 despite being more simplified (Scheme
5).
Based on the above result, a three-step process for the
synthesis of 5 was finalized: Weinreb amidation, O-TMS
protection, and Grignard addition. Using the optimized
conditions, preparation of 5 at scales from 50 grams to
kilograms was successfully achieved in a stable yield (65%).
The overall yield was highly dependent on the quality of 13c in
the silylation step, where the cyclization impurity 3 should be
strictly controlled.
CONCLUSIONS
■
In summary, we explored a Weinreb amide approach for the
synthesis of a key RDV intermediate in the C-glycosylation
step with the aim of eliminating the overaddition side
reactions. Initially, this idea was implemented in a four-step
sequence with compound 7 as the main byproduct. After
process optimizations, the synthesis of 5 was achieved in three
steps, and the crystallization yield could reach 65% at a
kilogram scale. In particular, the undesirable PhMgCl was
replaced by MeMgBr, which provided a superior yield for the
addition reaction. Besides, a more simplified route consisting
of two steps was developed and worthy of further optimization.
(
(
60% yield). However, the reaction took a relatively long time
5−6 h) even at room temperature.
Considering that the excess of magnesium ion may facilitate
the addition reaction, we conducted the reaction using 1.0
equiv of MgCl2 instead of the additional i-PrMgCl.
Disappointingly, it did not afford the desired product, which
was contrary to our expectations. The role of the additional i-
PrMgCl in the reaction was confusing. Nevertheless, efforts
were still made to improve the reaction yield or shorten the
reaction time, such as further increasing the amount of i-
5
068
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+
Overall, our work provides an alternative method for the
preparation of the key remdesivir intermediate.
25.7, 17.8, −4.7, −5.0. HRMS (ESI) m/z: [M + H] calcd for
+
C H NO Si , 594.3245; found 594.3252.
34 48
6
(
2R,3S,4R)-2,3,5-Tris(benzyloxy)-4-((triethylsilyl)oxy)-N-methoxy-
N-methylpentanamide (11b). Following the above procedure of
synthesizing 11a, the reaction of compound 10 (7.0 g, 14.6 mmol)
with TESCl (2.6 g, 17.5 mmol) in the presence of imidazole (1.79 g,
EXPERIMENTAL SECTION
■
General Experimental Details. 2,3,5-Tri-O-benzyl-D-ribonolac-
tone 3 and 4-amino-7-iodopyrrolo[2,1-f ][1,2,4]triazine 4a were
provided by Topharman Shanghai Co., Ltd. with a purity of ≥95%.
The other materials and reagents, including N,O-dimethylhydroxyl-
amine hydrochloride 9, tert-butyldimethylsilyl chloride (TBSCl),
chlorotriethylsilane (TESCl), chlorotrimethylsilane (TMSCl), imida-
zole, 2.0 M isopropylmagnesium chloride (i-PrMgCl) THF solution,
26.3 mmol) in DMF afforded crude product 11b, which could be
used in the next step without further purification. Alternatively, the
crude product was subjected to column chromatography on silica gel
using acetone and petroleum ether as the eluent (acetone/petroleum
1
ether = 1:20−1:8) to give 11b as an oil (8.1 g, 93%). H NMR (500
MHz, DMSO-d ) δ 7.38−7.18 (m, 15H), 4.74−4.61 (m, 2H), 4.50−
6
4
.44 (m, 3H), 4.42 (d, J = 11.4 Hz, 1H), 4.37 (d, J = 11.7 Hz, 1H),
.27−4.22 (m, 1H), 3.82 (d, J = 8.5 Hz, 1H), 3.71 (dd, J = 10.0, 4.5
1
.3 M isopropylmagnesium chloride−LiCl complex (i-PrMgCl·LiCl)
THF solution, 2.0 M phenylmagnesium chloride (PhMgCl) THF
4
Hz, 1H), 3.51 (s, 3H), 3.48 (dd, J = 10.0, 6.8 Hz, 1H), 3.12 (s, 3H),
solution, 1.0 M vinylmagnesium chloride (CH CHMgCl) THF
2
13
1
0
.91 (t, J = 8.0 Hz, 9H), 0.61−0.54 (m, 6H). C{ H} NMR (151
solution, 3.4 M ethylmagnesium chloride (EtMgCl) 2-methyl-THF
solution, and 3.0 M methylmagnesium bromide (MeMgBr) 2-methyl-
THF solution, were commercially available. Extra dry THF (with
molecular sieves, water ≤ 50 ppm) was purchased from Energy
Chemical. CH Cl (AR) and DMF (AR) were used as received. The
MHz, DMSO-d ) δ 170.7, 138.35, 138.30, 137.7, 128.05, 128.03,
6
1
7
27.97, 127.5, 127.42, 127.38, 127.29, 127.22, 82.0, 73.5, 73.3, 72.4+,
2.0, 71.7, 71.1, 61.0, 31.6, 6.6, 4.5. HRMS (ESI) m/z: [M + H]
+
calcd for C H NO Si , 594.3245; found 594.3247.
3
4
48
6
2
2
(
2R,3S,4R)-2,3,5-Tris(benzyloxy)-4-((trimethylsilyl)oxy)-N-me-
melting points were recorded using a melting point apparatus in
thoxy-N-methylpentanamide (11c). Compound 10 obtained from
the reaction of 3 (4.18 g, 10.0 mmol) with 9 (1.56 g, 16.0 mmol)
using the above-described procedure was dissolved in CH Cl (30
1
13
1
capillary tubes and uncorrected. H NMR and C{ H} NMR spectra
were determined on a Brucker 500 Hz or 600 Hz instrument in
DMSO-d or CDCl with TMS as a reference. High-resolution mass
2
2
6
3
mL) and cooled to −15 °C. Imidazole (1.23 g, 18.0 mmol) was
added, followed by the slow addition of TMSCl (1.30 g, 12.0 mmol).
The mixture was continuously stirred at −15 °C. About 2 h later, the
temperature gradually increased to 0 °C and TLC showed that the
material had completely disappeared. The reaction mixture was
diluted with CH Cl (30 mL) and washed with water. The organic
spectra (HRMS) were recorded on a Q-TOF mass spectrometer
Agilent Technologies 6520) using the electron spray ionization
mode. All reactions were monitored by thin-layer chromatography
TLC) on 25.4 mm × 76.2 mm silica gel plates (GF-254).
2R,3R,4R)-2,3,5-Tris(benzyloxy)-4-hydroxy-N-methoxy-N-meth-
ylpentanamide (10). To a mixture of 2,3,5-tri-O-benzyl-D-ribono-
lactone 3 (20.0 g, 47.8 mmol) and N,O-dimethylhydroxylamine
hydrochloride 9 (7.0 g, 71.7 mmol) in extra dry THF (70 mL), 2 M i-
PrMgCl THF solution (71.7 mL, 143.4 mmol) was slowly added in an
ice bath over 30−40 min under a nitrogen atmosphere using a
balloon. Note that obvious gas generation was observed if the
dropping speed was too fast. After that, the mixture was continuously
stirred in the ice bath for 3 h, and TLC showed that the reaction was
(
(
(
2
2
layer was separated and concentrated. The obtained oil product was
dissolved in MTBE (60 mL), which was subsequently washed with
water and brine. The organic layer was separated, dried over Na SO ,
2
4
and evaporated to give crude product 11c, which could be used in the
next step without further purification. Alternatively, the crude product
was subjected to column chromatography on silica gel using acetone
and petroleum ether as the eluent (acetone/petroleum ether = 1:20−
1
1
:8) to give 11c as an oil (5.0 g, 91% over two steps). H NMR (500
completed. The mixture was poured into a saturated NH Cl aqueous
solution (150 mL) and extracted with ethyl acetate (200 mL). The
organic phase was separated, washed with water, brine, dried over
4
MHz, DMSO-d ) δ 7.40−7.20 (m, 15H), 4.71−4.64 (m, 1H), 4.61
6
(
d, J = 11.4 Hz, 1H), 4.51−4.45 (m, 3H), 4.43 (d, J = 11.4 Hz, 1H),
.38 (d, J = 11.7 Hz, 1H), 4.24−4.20 (m, 1H), 3.77 (dd, J = 8.0, 2.1
Hz, 1H), 3.67 (dd, J = 10.1, 4.0 Hz, 1H), 3.53 (s, 3H), 3.49 (dd, J =
4
1
Na SO , and evaporated to give 10 (24.1 g, yield 100%) as an oil. H
2
4
NMR (500 MHz, DMSO-d ): δ 7.39−7.20 (m, 15H), 5.09 (d, J = 4.9
13
1
6
10.0, 7.0 Hz, 1H), 3.12 (s, 3H), 0.08 (s, 9H). C{ H} NMR (126
Hz, 1H), 4.71 −4.62 (m, 2H), 4.51−4.42 (m, 4H), 4.38 (d, J = 11.5
Hz, 1H), 4.12−4.04 (m, 1H), 3.82 (dd, J = 7.8, 2.9 Hz, 1H), 3.66 (dd,
MHz, DMSO-d ) δ 138.5, 138.3, 137.7, 128.3, 128.24, 128.17, 127.7,
6
1
7
27.59, 127.56, 127.48, 127.40, 127.37, 81.3, 73.5, 73.0, 72.3, 71.8,
J = 9.9, 4.5 Hz, 1H), 3.53 (s, 3H), 3.49 (dd, J = 9.9, 6.5 Hz, 1H), 3.12
13
1
1.6, 71.1, 61.1, 30.8, 0.4. C{ H} NMR (126 MHz, CDCl ) δ 171.9,
3
1
(
1
7
s, 3H). 13C{ H} NMR (126 MHz, DMSO-d ) δ 171.2, 139.0, 138.2,
6
138.6, 138.5, 137.7, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.5,
27.4, 82.1, 74.2, 73.4, 73.2, 72.3, 72.1, 72.0, 61.2, 32.1, 0.4. HRMS
28.6, 128.5, 128.1, 128.0, 127.90, 127.87, 127.77, 82.1, 74.4, 73.7,
1
+
+
+
2.8, 71.8, 71.5, 69.9, 61.5, 32.4. HRMS (ESI) m/z: [M + H] calcd
(ESI) m/z: [M + H] calcd for C H NO Si , 552.2776; found
31 42 6
+
6
for C H NO , 480.2381; found 480.2392.
28
34
552.2781.
(
2R,3S,4R)-2,3,5-Tris(benzyloxy)-4-((tert-butyldimethylsilyl)oxy)-
N-methoxy-N-methylpentanamide (11a). Compound 10 (7.19 g,
5.0 mmol) and imidazole (1.84 g, 27.0 mmol) were dissolved in
DMF (20 mL) in an ice bath, followed by the addition of TBSCl
2.71 g, 18.0 mmol) in one portion. The mixture was allowed to warm
to room temperature and stirred for about 6 h. TLC showed that the
reaction was completed. The reaction mixture was poured into water
150 mL) and extracted with ethyl acetate (150 mL). The organic
layer was washed with water, brine, dried over Na SO , and
evaporated to give a mixture of 11a and 3, which were subjected to
column chromatography on silica gel using acetone and petroleum
Synthesis of 5 from 11a. Under nitrogen protection, 4a (0.52 g,
.0 mmol) was added in extra dry THF (3.0 mL) and cooled to 0 °C.
2
1
TMSCl (0.22 g, 2.0 mmol) was added, and about 20 min later, the
mixture was cooled to −15 °C; 2.0 M PhMgCl (2.0 mL, 4.0 mmol) in
THF was added, and after about 30 min, 1.3 M i-PrMgCl·LiCl (1.7
mL, 2.2 mmol) in THF was added. Then, the reaction mixture was
stirred at −15 to −10 °C until the material was completely converted
into the Grignard reagent (the conversion was monitored using TLC
by taking samples in methanol). To this mixture, 11a (1.19 g, 2.0
mmol) dissolved in extra dry THF (3.0 mL) was slowly added. After
the addition, the reaction mixture was stirred at 0 °C for about 1 h
(
(
2
4
ether as the eluent (acetone/petroleum ether = 1:20−1:8) to give 11a
5.17 g, yield 58%) as an oil, and 3 (2.0 g, yield 32%) as a solid. H
and the reaction was quenched with a saturated NH Cl aqueous
4
1
(
solution and extracted with ethyl acetate. The organic phase was
separated, washed with diluted hydrochloric acid and brine, then
dried over Na SO , and concentrated. The residue was subjected to
NMR (600 MHz, DMSO-d ) δ 7.33−7.15 (m, 15H), 4.71−4.63 (m,
6
1
2
4
3
1
1
H), 4.60 (d, J = 11.4 Hz, 1H), 4.46−4.38 (m, 3H), 4.36−4.30 (m,
H), 4.22−4.17 (m, 1H), 3.74 (d, J = 8.6 Hz, 1H), 3.62 (dd, J = 10.0,
.1 Hz, 1H), 3.49−3.41 (m, 4H), 3.06 (s, 3H), 0.82 (s, 9H), 0.00 (s,
2
4
column chromatography on silica gel using ethyl acetate and
petroleum ether as the eluent (ethyl acetate/petroleum ether =
1
3
1
1
H), −0.01 (s, 3H). C{ H} NMR (126 MHz, DMSO-d ) δ 170.7,
1:5−1:1) to give 12a as a solid (0.69 g, 52% yield); mp 70−73 °C; H
6
38.3, 138.2, 137.6, 128.13, 128.11, 128.0, 127.6, 127.43, 127.35,
27.33, 127.26, 81.7, 73.12, 73.06, 72.3, 72.0, 71.8, 71.1, 61.1, 31.7,
NMR (500 MHz, DMSO-d ) δ 8.09 (s, 2H), 7.96 (s, 1H), 7.39−7.22
6
(m, 11H), 7.18−7.07 (m, 3H), 6.96−6.85 (m, 3H), 5.40 (d, J = 7.6
5
069
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pubs.acs.org/joc
Article
Hz, 1H), 4.63−4.53 (m, 2H), 4.52−4.42 (m, 3H), 4.34 (d, J = 11.7
Hz, 1H), 4.26−4.17 (m, 1H), 3.91 (dd, J = 7.6, 1.6 Hz, 1H), 3.83 (dd,
J = 10.2, 3.5 Hz, 1H), 3.51 (dd, J = 10.2, 7.3 Hz, 1H), 0.83 (s, 9H),
Synthesis of 5 from 11c Using MeMgBr. A representative
procedure at a 10.0 mmol scale was provided. 4a (2.6 g, 10.0
mmol) was added in extra dry THF (30 mL) under nitrogen
protection and cooled to −15 °C. TMSCl (1.1 g, 10.0 mmol) or (2.2
g, 20.0 mmol) was slowly added, and after stirring for about 20 min, 3
M MeMgBr in 2-methyl-THF (20.0 mmol, 6.7 mL) was added slowly.
About 30 min later, 1.3 M i-PrMgCl·LiCl in THF (10.8 mL, 14.0
mmol) was added. The resulting mixture was stirred at −15 to −10
°C for about 1 h (conversion of 4a into the Grignard reagent was
monitored by taking samples in methanol). When 4a was completely
converted into the Grignard reagent, 11c (10 mmol) in extra dry
THF (20 mL) prepared according to the above-described procedure
was transferred into the reaction mixture. The resulting mixture was
allowed to warm to 0 °C and stirred for about 1 h; 1 M hydrochloric
acid was added to adjust the pH to 1−2. After stirring for 1 h, the
organic layer was separated and concentrated. The residue was
dissolved in ethyl acetate and washed with water and brine. The
organic layer was dried over Na SO and evaporated. MTBE was
added to give a clear solution, which was held overnight. The solid
was obtained by filtration and dried to afford 5 (3.3 g for 1.0 equiv of
TMSCl and 3.6 g for 2.0 equiv of TMSCl). The filtrate was
concentrated, and the residue was purified by column chromatog-
raphy on silica gel using methanol and dichloromethane as the eluent
(methanol/dichloromethane = 1:50−1:15) to give the remaining
portion (0.7 g for 1.0 equiv of TMSCl and 0.6 g for 2.0 equiv of
TMSCl). For the experiment with 1.0 equiv of TMSCl, 4.0 g of 5 was
obtained, 72% yield; for the experiment with 2.0 equiv of TMSCl, 4.2
g of 5 was obtained, 76% yield.
1
3
1
0
1
1
7
.02 (s, 3H), −0.05 (s, 3H). C{ H} NMR (126 MHz, DMSO-d ) δ
6
88.4, 155.8, 149.0, 138.5, 138.1, 137.9, 128.6, 128.2, 128.1, 127.8,
27.54, 127.49, 127.3, 127.1, 127.0, 118.9, 117.5, 102.3, 82.6, 79.8,
2.7, 72.42, 72.36, 71.8, 71.4, 25.7, 17.8, −4.6, −5.0. HRMS (ESI) m/
+
+
z: [M + H] calcd for C H N O Si , 667.3310; found 667.3321.
3
8
47
4
5
To a solution of 12a (0.69 g, 1.0 mmol) in THF (10 mL), a 50%
TFA aqueous solution (1.5 mL) was added. The mixture was stirred
at room temperature until the staring material disappeared
completely. Water (15 mL) was added, and the mixture was extracted
with ethyl acetate. The organic layer was separated, washed
successively with water, saturated NaHCO3 solution, and brine,
then dried over Na SO , and concentrated. The residue was purified
2
4
by column chromatography on silica gel using methanol and
dichloromethane as the eluent (methanol/dichloromethane = 1:50−
1
1
:15) to give 5 as a foam (0.44 g, 80% yield); mp 57−59 °C; H
2
4
NMR (500 MHz, DMSO-d ) δ 8.07 (s, 2H), 8.00 (s, 1H), 7.38−7.23
6
(
m, 11H), 7.20−7.13 (m, 3H), 7.04−6.98 (m, 2H), 6.95 (d, J = 4.5
Hz, 1H), 5.39 (d, J = 5.9 Hz, 1H), 5.06 (d, J = 5.3 Hz, 1H), 4.61−
4
5
.54 (m, 2H), 4.51−4.43 (m, 4H), 4.05−3.98 (m, 1H), 3.94 (t, J =
.2 Hz, 1H), 3.70 (dd, J = 10.2, 3.4 Hz, 1H), 3.48 (dd, J = 10.2, 6.4
15
+
+
Hz, 1H). HRMS (ESI) m/z: [M + H] calcd for C H N O ,
3
2
33
4
5
5
53.2445; found 553.2480.
Synthesis of 5 from 11c Using PhMgCl. Under nitrogen
protection, 4a (0.52 g, 2.0 mmol) was added in extra dry THF (3.0
mL) and cooled to 0 °C. TMSCl (0.22 g, 2.0 mmol) was added, and
about 20 min later, the mixture was cooled to −15 °C; 2.0 M PhMgCl
Synthesis of 5 from 3 in Two Steps. To a mixture of 3 (24.1 g,
57.7 mmol) and 9 (8.4 g, 86.6 mmol) in extra dry THF (80 mL), 2 M
i-PrMgCl THF solution (86.5 mL, 173.1 mmol) was slowly added in
an ice bath under nitrogen protection. The mixture was stirred in the
ice bath until the conversion was completed. Then, an additional 2 M
isopropylmagnesium chloride THF solution (29.0 mL, 57.7 mmol)
was added, and the resulting mixture was held in the ice bath.
4a (15.0 g, 57.7 mmol) was added in extra dry THF (60 mL) under
nitrogen protection and cooled to −10 °C. TMSCl (12.5 g, 115.4
mmol) was slowly added, and after stirring for about 20 min, 3 M
MeMgBr in 2-methyl-THF (38.5 mL, 115.4 mmol) was added slowly.
About 30 min later, 1.3 M i-PrMgCl·LiCl in THF (62.2 mL, 80.8
mmol) was added. The resulting mixture was stirred at −10 °C for
about 1 h (conversion of 4a into the Grignard reagent should be
monitored). When 4a was completely converted into the Grignard
reagent, the Weinreb amide 13 solution was transferred into the
reaction mixture. The resulting mixture was allowed to warm to room
temperature and stirred for 5−6 h; 1 M hydrochloric acid was added
to adjust the pH to 1−2. After stirring for 1 h, the organic layer was
separated and concentrated. The resulting residue was dissolved in
ethyl acetate and washed with water and brine. The organic layer was
dried over Na SO and evaporated. MTBE was added to give a clear
(2.0 mL, 4.0 mmol) in THF was added, and after about 30 min, 1.3 M
i-PrMgCl·LiCl (1.7 mL, 2.2 mmol) in THF was added. Then, the
reaction mixture was stirred at −15 to −10 °C until the material was
completely converted into the Grignard reagent. To this mixture, 11c
(1.10 g, 2.0 mmol) dissolved in extra dry THF (3.0 mL) was slowly
added. The reaction mixture was stirred at 0 °C for about 1 h and
quenched with 1 M hydrochloric acid to a final pH of 1−2. The
mixture was stirred for 30 min at room temperature and extracted
with ethyl acetate. The organic phase was separated, washed with
diluted hydrochloric acid and brine, then dried over Na SO , and
2
4
concentrated. The residue was purified by column chromatography
on silica gel using methanol and dichloromethane as the eluent
(
methanol/dichloromethane = 1:50−1:15) to give 5 as a foam (0.72
g, 65% yield). The acidic aqueous phase was neutralized with a
saturated Na CO solution and extracted with ethyl acetate. The
2
3
organic phase was separated, washed with brine, and concentrated.
The solid residue was slurried with petroleum ether to give 7 as a light
gray solid (0.059 g, 22% yield); mp 219−222 °C.
With respect to the reaction with 2.0 equiv of TMSCl (0.43 g, 4.0
mmol), the procedure was the same as described above, but more i-
PrMgCl·LiCl (3.1 mL, 4.0 mmol) was required for the formation of
the Grignard reagent. After workup, 5 (0.52 g, 47% yield) and 7
2
4
solution, which was held overnight. The solid was obtained by
filtration and dried, and combined with the solid obtained from the
filtrate to afford 5 (19.1 g, 60% yield).
(
0.083 g, 31% yield) were obtained in the same way.
Synthesis of 5 from 11c Using CH CHMgCl. The procedure was
2
the same as described above. The reaction of 4a (0.52 g, 2.0 mmol)
and 11c (1.10 g, 2.0 mmol) in the presence of TMSCl (0.22 g, 2.0
Procedure for the Scale-Up Synthesis of 5 (50 g, 1 kg, and 20 kg
Scales of 4a). The glass flasks and the reactors were dried before use.
The glass flasks were dried using an electric heating air-blowing drier.
For the large-scale reactions, the cleaned reactor was charged with
extra dry THF, which was evaporated under reduced pressure. The
addition and removal of THF were repeated two more times. Then,
the reactor was filled with nitrogen gas and held at the indicated
temperature; 3 (1.0 equiv) and 9 (1.8 equiv) were mixed in extra dry
THF (3.0 vol), and stirred at 0 °C under a nitrogen flow; 2 M
isopropylmagnesium chloride tetrahydrofuran solution (3.6 equiv)
was added. After the addition, the mixture was continuously stirred at
mmol), 1.0 M CH CHMgCl (4.0 mL, 4.0 mmol), and 1.3 M i-
2
PrMgCl·LiCl (2.2 mL, 2.8 mmol) afforded 5 (0.71 g, 64% yield) and
7
(0.064 g, 24% yield), respectively. Another experiment using 2.0
equiv of TMSCl (0.43 g, 4.0 mmol) was conducted in parallel, and
gave 5 (0.80 g, 72% yield) and 7 (0.038 g, 14% yield) in the same
way.
Synthesis of 5 from 11c Using EtMgCl. The procedure was the
same as described above. The reaction of 4a (0.52 g, 2.0 mmol) and
11c (1.10 g, 2.0 mmol) in the presence of TMSCl (0.22 g, 2.0 mmol),
3
.4 M EtMgCl (1.2 mL, 4.0 mmol), and 1.3 M i-PrMgCl·LiCl (2.0
0 °C for 2 h and was then poured into a saturated NH Cl solution.
4
mL, 2.6 mmol) afforded 5 (0.46 g, 42% yield) and 7 (0.099 g, 37%
yield), respectively. Another experiment using 2.0 equiv of TMSCl
The organic layer was separated, concentrated, and the obtained
residue was dissolved in ethyl acetate (6.0 vol). The solution was then
washed with water and brine, dried over Na SO , and evaporated to
(0.43 g, 4.0 mmol) was conducted in parallel, and gave 5 (0.49 g, 44%
2
4
yield) and 7 (0.097 g, 36% yield) in the same way.
give compound 10 as an oil.
5
070
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The Journal of Organic Chemistry
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Article
The oil product obtained in the first step was dissolved in CH Cl
3.0 vol) and cooled to −10 °C. Imidazole (1.8 equiv) was added,
Daibao Wei − Key Laboratory of Plant Resources and
Chemistry in Arid Regions, Xinjiang Technical Institute of
Physics and Chemistry, Chinese Academy of Sciences,
Urumqi, Xinjiang 830011, P. R. China; University of Chinese
Academy of Sciences, Beijing 100049, P. R. China
Wei Zheng − Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai 201203, P. R. China;
University of Chinese Academy of Sciences, Beijing 100049, P.
R. China
2
2
(
followed by the slow addition of TMSCl (1.2 equiv). The mixture was
stirred at −10 to −5 °C for 3−4 h. Water (3.0 vol) was added, and the
organic layer was separated. After concentration, the oil product was
dissolved in MTBE (6.0 vol), which was subsequently washed with
water and brine. The organic layer was separated, dried over Na SO ,
2
4
and evaporated to give 11c as oil, which was dissolved in extra dry
THF (3.0 vol) and held for the next step.
4a (1.0 equiv) was added in extra dry THF (10.0 vol) under a
nitrogen flow and cooled to −15 to −10 °C. TMSCl (2.0 equiv) was
slowly added, and after stirring for about 20 min, MeMgBr or
MeMgCl solution (2.0 equiv) was added slowly. About 30 min later, i-
PrMgCl·LiCl (1.4 equiv) was added. After that, the reaction mixture
was continuously stirred for about 1 h (conversion of 4a into the
Grignard reagent should be monitored). Then, the reaction
temperature increased to −5 to 0 °C, and the 11c THF solution
obtained in the second step was transferred into the reaction mixture.
The resulting mixture was stirred for 1−1.5 h at 0 °C, and 1 M
hydrochloric acid was added to adjust the pH to 1−2. After stirring
for 1 h, the organic layer was separated and concentrated. The
resulting residue was dissolved in ethyl acetate (6.0 vol) and washed
with water and brine. The organic layer was dried over Na SO and
evaporated. MTBE (4.0 vol) was then charged and evaporated,
followed by the addition of MTBE (4.0 vol) again to obtain a clear
solution. Seed crystals of 5 were added, and the mixture was cooled to
about 0 °C. After 12 h, the solid was collected by filtration and rinsed
with a 1:1 methyl tert-butyl ether/n-heptane solution. The solid was
dried to afford 5 in 65% yield with >99% purity.
Fuqiang Zhu − Topharman Shanghai Co., Ltd., Shanghai
201203, P. R. China
Guanghui Tian − Topharman Shanghai Co., Ltd., Shanghai
201203, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02986
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2
4
The authors thank the National Science & Technology Major
Project “Key New Drug Creation and Manufacturing
Program”, China (No. 2018ZX09711002), and the 2020
ANSO Collaborative Research Project (No. ANSO-CR-SP-
2
020-03).
REFERENCES
■
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02986.
■
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