Practical and Scalable Synthesis of a Glucokinase Activator via One-Pot Difluorination and Julia Olefination

Article abstract of DOI:10.1021/acs.oprd.0c00180

We describe the process research and development of a practical synthesis of glucokinase activator 1 as a potential drug for treating type 2 diabetes mellitus. The key structure, a 3,4-cis-difluorinated cyclopentane moiety, was constructed via diastereoselective epoxidation, followed by one-pot difluorination with Et3N·3HF and perfluorobutanesulfonyl fluoride (PBSF). Julia olefination of benzothiazol-2-yl sulfone with glyoxylate furnished an E/Z mixture of acrylate, followed by isomerization of the alkene to the desired E configuration during the formation of the acid chloride in the final step. This development achieved a highly practical process route to 1 (15percent overall yield, 12 steps). This process route overcomes the drawbacks of the original medicinal chemistry synthetic route, which used hazardous and costly reagents (LiAlH4, OsO4, and Deoxo-Fluor) and had low efficiency (<4percent overall yield, 20 steps).

Full text of DOI:10.1021/acs.oprd.0c00180

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Full Paper
Practical and Scalable Synthesis of a Glucokinase
Activator via One-pot Difluorination and Julia Olefination
Hideyoshi Tsuchiya, Minoru Iwamoto, hidetoshi miyamoto, Chihiro Sakumoto, Tokihiko
Tamamizu, Yasuo Inoshita, Yuzo Koyama, Yoshinori Sato, and Takuya Kumamoto
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00180 • Publication Date (Web): 16 Jun 2020
Downloaded from pubs.acs.org on June 16, 2020
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Practical and Scalable Synthesis of a Glucokinase
Activator via One-pot Difluorination and Julia
Olefination
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Hideyoshi Tsuchiya,*, †, § Minoru Iwamoto, Hidetoshi Miyamoto, Chihiro Sakumoto,
†
†
†ꢀ
†
†
†
†
Tokihiko Tamamizu, Yasuo Inoshita, Yuzo Koyama, Yoshinori Sato, Takuya
Kumamoto§
†
Active Pharmaceutical Ingredient Technology Section, Pharmaceutical Production
Technology Department, Teijin Pharma Limited, 2-1 Hinode-cho, Iwakuni-shi,
Yamaguhci 740-8511, Japan
§
Department of Synthetic Organic Chemistry, Graduate School of Biomedical &
Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi,
Hiroshima 734-8533, Japan
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TOC GRAPHIC
F
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H
H
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H
N
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N
CO H
CO Et
2
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CO Et
2
O
OH
S
O O
S
O O
O
1
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ABSTRACT: We describe the process research and development of a practical synthesis
of glucokinase activator 1 as a potential drug for treating type 2 diabetes mellitus. The
key structure, a 3,4-cis-difluorinated cyclopentane moiety, was constructed via
diastereoselective epoxidation followed by one-pot difluorination with Et N ･ 3HF and
3
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perfluorobutanesulfonyl fluoride (PBSF). Julia olefination of benzothiazol-2-yl sulfone with
glyoxylate furnished an E/Z mixture of acrylate, followed by isomerization of the alkene to
the desired E configuration during formation of the acid chloride in the final step. This
development achieved a highly practical process route to 1 (15% overall yield, 12 steps).
This process route overcomes the drawbacks of the original medicinal chemistry synthetic
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®
route, which used hazardous and costly reagents (LiAlH , OsO , and Deoxo-fluor ) and
4
4
had low efficiency (<4% overall yield, 20 steps).
KEYWORDS: glucokinase activator, diastereoselective epoxidation, one-pot synthesis,
isomerization of alkene
INTRODUCTION
Glucokinase (GK), also known as hexokinase (HK) type IV, is one of four HK family
members. GK plays a critical role in the maintenance of glucose homeostasis by
1
regulating glucose uptake in the liver and insulin secretion in the pancreas. Many
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pharmaceutical companies therefore developed various small-molecule glucokinase
2
activators (GKAs) that were evaluated in clinical trials. Among these, (E)-2-(4-
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(cyclopropylsulfonyl)phenyl)-3-((1r,3S,4R)-3,4-difluorocyclopentyl)-N-(5-(2-
3
hydroxyethoxy)pyrazin-2-yl)acrylamide (1) was identified as a potent GKA. Key structural
features of 1 are 1) an amide bond between aminopyrazine and 4’-sulfonylated α-
phenylacrylic acid and 2) the presence of 1,3,4-cis,cis-3,4-difluorinated cyclopentyl group,
where the β-position of the acrylic acid part is substituted in the E configuration. Late-
phase clinical trials to evaluate 1 as a potential drug for treating type 2 diabetes mellitus
require process development to prepare several tons of 1. Herein, we describe an
improved process route to 1 that enables its large-scale preparation in high yield and
purity without hazardous and costly reagents.
F
H
F
H
N
N
N
O
OH
S
O
O O
1
Figure 1. Structure of 1.
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Medicinal Chemistry Synthetic Route
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Our medicinal chemistry synthetic route to 1 is illustrated in Scheme 1. Reduction of
carboxylic acid 2 to alcohol 3 required use of LiAlH , a flammable reagent. The hydroxyl
4
group in 3 was protected by BzCl to afford benzoate 4. Dihydroxylation of 4 using toxic
OsO gave diol 5 as an approximately 6:1 mixture of diastereomers that were separated
4
by crystallization in toluene. Compound 5 was converted to cyclic sulfate 6 by treatment
4
with SOCl , followed by RuCl -catalyzed oxidation. Ring-opening fluorination of 6 with
2
3
TBAF and deoxyfluorination of the resultant cyclopentanol 7 with costly Deoxo-fluor®5
gave 1,3,4-cis,cis-3,4-difluorinated cyclopentane 8. Removal of the benzoyl group on 8
afforded alcohol 9, which was converted to phosphonium salt 11 via iodide 10. Wittig
olefination between 11 and ketoester 122a,6 provided acrylic acid ester 13 as a mixture of
E/Z isomers with phosphine oxide as a by-product. Silica-gel column chromatography
was required to isolate desired 13, but the yield was poor (35%). Oxidation of the S atom
in 13 to sulfone followed by ester hydrolysis afforded key acrylic acid 15. Amide formation
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was achieved by activation of acid 15 to the corresponding acid chloride followed by
treatment with protected aminopyrazine 16. Deprotection of the THP group in 17 provided
the final product 1. This initial route involved not only highly reactive LiAlH , toxic OsO ,
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and the costly fluorination reagent Deoxo-fluor but also numerous steps leading to low
overall yield (20 steps, <4%), which resulted in high manufacturing costs.
Scheme 1. Medicinal Chemistry Route to 1a
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CO Et
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F
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i
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j
k
CO R
2
CO Et
2
PPh3
S
O O
11
13
14: R=Et
l
15: R=H
F
H N
2
N
N
H
OTHP
F
S
O
1
6
H
N
N
1
n
m
O
OTHP
N
O
O O
2
0 steps
overall yield <4%
17
a
Reagents and conditions: (a) LiAlH , THF, reflux; (b) BzCl, pyridine, rt; (c) OsO , NMO,
4
4
acetone, t-BuOH, H O, rt, 72%; (d) SOCl , CCl , reflux, then RuCl ･nH O, NaIO , MeCN,
2
2
4
3
2
4
CCl , H O, rt, 69%; (e) TBAF, MeCN, reflux, then H SO , EtOH, reflux, 86%; (f) Deoxo-
4
2
2
4
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Fluor , THF, reflux, 71%; (g) K CO , EtOH, reflux, 98%; (h) PPh , I , imidazole, CH Cl ,
2
3
3
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rt, 36%; (i) PPh , MeCN, 93 °C, 98%; (j) LHMDS, THF, 0 °C to rt, 41%; (k) mCPBA,
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CH Cl , 0 °C to rt, 99%; (l) H SO , AcOH, H O, 98 °C, 88%; (m) SOCl , reflux, then 16,
2
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pyridine, THF, rt; (n) HCl, H O, THF, rt
2
Practical Synthesis: Overview
Our strategy for the large-scale synthesis of 1 is described in Scheme 2. Alcohol 9 was
the key intermediate common to our medicinal chemistry and process routes and needed
to be prepared economically because the first half of the initial process (prior to Wittig
olefination) had the biggest impact on manufacturing cost. Therefore, we decided to
extensively investigate a more efficient and shorter synthetic route from 2 to 9. Acrylic
7
acid 15 would be constructed using Julia olefination between ketone 12 and
benzothiazole (BT) sulfone 19. Direct amide bond formation between 15 and unprotected
aminopyrazine 18 was also explored.
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Scheme 2. Synthetic Strategy for 1 via Key Intermediate 9
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Direct amide formation
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OH
CO H
2
O
O
OH
S
O
S
O O
1
O O
15
18
More efficient and
shorter synthetic route
F
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Julia olefination
O
CO Et
2
+
CO H
2
S
R
9
: R = OH
19: R = BT sulfone
12
2
New Approach to Key Intermediate 9
The improved synthetic route to key intermediate 9 is shown in Scheme 3. The process
starts with the esterification of 2 using SOCl in ethanol to afford cycloalkene 20.
2
Subsequent stereocontrolled introduction of vicinal difluorides into 20 is challenging. A
combination of HF salts and in situ generated iodoarene difluroride were previously
8
reported to be effective for the difluorination of acyclic alkenes but a large excess of the
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fluorine source was required and the yield of the cycloalkane was low. As expected, the
yield of desired difluoride 23 from 20 was less than 5 area% in GC analysis, despite the
use of more than 60 equivalents of the fluorine source (Scheme 4). We therefore turned
our efforts to a stepwise process involving stereoselective epoxidation followed by a one-
pot difluorination of the epoxide using relatively inexpensive fluorination reagents.
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Small-scale screening of epoxidation conditions for 20 was performed as shown in Table
1. Magnesium monoperoxyphthalate (MMPP), a mild and safer oxidant for large-scale
reactions compared with commonly used peroxycarboxylic acid, was used in a mixture of
9
H O/ethyl acetate in the presence of n-Bu NHSO as a phase transfer catalyst (PTC).
2
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The desired trans isomer 21 was obtained as the major isomer (3.5:1 = trans:cis) in almost
quantitative yield (entry 1). On the other hand, epoxide formation from 20 via
10
bromohydrin generated undesired cis isomer 22 as the major product (0.3:1 = trans:cis,
entry 2). We examined hydrogen peroxide as an alternative and clean oxidant because
the only by-product is H O. Epoxidation of 20 using dioxirane generated from
2
trifluoroacetophenone and hydrogen peroxide provided lower diastereoselectivity than
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the use of MMPP, although 20 was completely consumed (2.6: 1 = trans:cis, entry 3).11
Greater diastereoselectivity was achieved using Na WO ･2H O as a catalyst instead of
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17 3
4
entry 4 improved the diastereoselectivity and gave excellent yield (91.8 area%, 11:1 =
13
trans:cis, entry 5). The alkyl groups on the PTC contribute to reactivity. In particular, the
epoxidation of 1-octene with n-Bu NHSO was reported to be slow, although n-Bu NHSO
4
4
4
4
is a less expensive and less lipophilic PTC than [Me(n-C H ) N]HSO . We found that the
8
17 3
4
use of n-Bu NHSO decreased the yield at room temperature (27.7 area%) but improved
4
4
the diastereoselectivity to 15:1 (entry 6). Raising the reaction temperature to 50 °C
resulted in the reaction proceeding completely and diastereoselectivity was further
14
improved to approximately 17:1 (entry 7). Under the developed conditions, the reaction
proceeded without any difficulty even for a large scale of 20 (generated from 275 g of 2)
to afford a 15:115,16 mixture of 21 and 22 in 81% yield from 2 (Scheme 3). It was known
that a small amount of undesired isomer 22 could be removed later by crystallization,17
therefore, subsequent steps were conducted using 21 without further purification.
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Next, we examined the ring-opening fluorination of 21 to difluoride 23. In preliminary trials,
we used pure trans-epoxide 21, obtained by SiO column chromatography purification of
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a mixture of 21 and 22. We first examined the reaction under basic conditions because
18
acidic conditions may generate dangerous HF but found that using KF in triethylene
glycol gave no desired fluorohydrin 24. Fortunately, ring-opening of 21 under acidic
19
conditions proceeded cleanly using triethylamine trihydrofluoride (Et N･3HF) at 115 °C
3
to afford 24 in 86% yield (Scheme 5). Subsequent deoxyfluorination20 of 24 with
perfluorobutanesulfonyl fluoride (PBSF),19,21 a relatively inexpensive and thermally stable
reagent, in combination with Et N･3HF and Et N gave crude 23 in almost quantitative
3
3
yield.
We next focused on developing a one-pot method for the conversion of 21 to 23.
Compound 21 was treated with 1.9 equivalents of Et N･3HF at 115 °C, followed by the
3
addition of 1.4 equivalents of PBSF to minimize use of the fluorine source. After
completion of the reaction, aqueous KHCO and toluene were added, and a triphasic
3
mixture of organic, aqueous, and fluorous layers was formed. The aqueous layer was
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
discarded and the separated fluorous layer was further extracted with toluene. The
original organic layer and toluene layer were combined and concentrated to give difluoro
compound 23 in 96% yield (69% assay yield). Application of these optimized conditions
to the reaction using 21 containing a small amount of 22 provided desired 23 in 82% yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 3).
Ester 23 was reduced using NaBH422 instead of highly reactive LiAlH . MeOH was slowly
4
added over a 5 h period to a mixture of 23 and NaBH in THF to suppress the rapid
4
evolution of H . After aqueous workup, the crude product was purified by simple distillation
2
to give alcohol 9 in 45% yield from 2 (Scheme 3).
Scheme 3. Optimized Synthesis of 9
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9
O
O
3
0% aq. H O , Na WO ・2H O
2 2 2 4 2
EtOH
SOCl2
PhP(O)(OH) , n-Bu NHSO
4
2
4
+
CO H
CO Et
o
2
rt
2
5
3 C
CO Et
CO Et
2
2
8
1% from 2
2
20
21
22
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
F
F
F
o
o
1) NaBH , MeOH, THF, 53 C
1
) Et N・3HF, 115 C
4
3
o
2) purify by distillation
2
) PBSF, Et N, THF, 25 C
3
CO Et
2
68%
OH
82%
23
9
Scheme 4. Trials for the Direct Difluorination of 20
p-iodotoluene, Selectfluor R
Et N・3HF (30 equiv HF)
F
F
3
Pyr(HF) (30 equiv HF), CH Cl , rt
n
2
2
CO Et
2
or
p-iodotoluene, mCPBA
Pyr(HF) (100 equiv HF), CH Cl , rt
CO Et
2
2
3
20
n
2
2
<5 area% (GC)
Table 1. Screening of Reaction Conditions for the Epoxidation of 20
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
O
+
CO Et
2
CO Et
CO Et
2
2
20
21
22
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
GC area%a
ratioa
21/22
3.5
entry
1
reagents and solvents
conditions
rt, 25 h
20
21
22
MMPP, n-Bu NHSO ,
nd
77.9
22.1
4
4
EtOAc, H O
2
2
3
1) NBS, acetone, H O
1) rt, 22 h
2) rt, 21 h
rt, 19 h
nd
nd
22.4
72.0
75.4
28.0
0.3
2.6
2
2
) DBU, CH Cl
2
2
aq. H O , buffer
2
2
2
,2,2-trifluoroacetophenone
MeCN, t-BuOH
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4
5
aq. H O , Na WO ･2H O,
rt, 19 h; 60
°C, 5 h
24.7
nd
63.1
91.8
10.2
8.3
6.2
2
2
2
4
2
MeOH
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aq. H O , Na WO ･2H O,
rt, 17 h
11.1
2
2
2
4
2
[
Me(n-C H ) N]HSO ,
8
17 3
4
PhP(O)(OH)2
6
7
aq. H O , Na WO ･2H O,
rt, 20 h
69.5
27.7
94.4
1.8
5.6
15.4
16.9
2
2
2
4
2
n-Bu NHSO , PhP(O)(OH) ,
4
4
2
Na SO
2
4
aq. H O , Na WO ･2H O,
50 °C, 2 h
nd
2
2
2
4
2
n-Bu NHSO , PhP(O)(OH) ,
4
4
2
Na SO
2
4
aMeasured using GC condition A (see Experimental Section). nd = not detected.
Scheme 5. Difluorination of 21 under Acidic Conditions
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
o
HO
F
F
OH
Et N・3HF (1.1 eq.), 115 C;
3
then column chromatography
+
86%
CO Et
CO Et
CO Et
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
21
24a
24b
(
pure diastereoisomer)
mixture
PBSF (1.5 eq.)
Et N・3HF (1.5 eq.)
3
Et N (3.0 eq.)
3
THF, rt
4% (assay yield)
9
o
1) Et N・3HF (1.9 eq.), 115 C
3
o
F
F
2
) PBSF (1.4 eq.), Et N (2.7 eq.), THF, 25 C
3
6
9% (assay yield)
CO Et
2
2
3
Practical Synthesis of 1 from 9
7
We next examined Julia olefination between sulfone 19 derived from alcohol 9 and
2
3
ketoester 12 (Scheme 6). To prepare sulfide 27, mesylation of 9 in toluene was followed
by the introduction of thiobenzothiazole (SBT) in a one-pot process. The latter process to
introduce SBT was carried out in a two-phase system of toluene and H O. However,
2
precipitated salt hampered agitation when toluene was used without H O, resulting in
2
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incompletion reaction. Impurities, including the derivative from cis-epoxide 22, were
removed effectively by recrystallization using toluene/i-PrOH/n-heptane as solvents to
afford 27 with excellent purity (>99%). For the oxidation of sulfide 27 into sulfone 19, similar
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reagent system for the epoxidation of 20 was successfully applied. A mixture of EtOH and H O
2
efficiently purified 19 by recrystallization, and therefore EtOH was used (selected) as the reaction
solvent.
We next examined Julia olefination. Using LHMDS, the reaction proceeded at -13 °C with
excellent yield but low E/Z selectivity (E:Z = 57:43) and thus we explored the following
steps using 13 as a mixture of diastereomers, expecting separation or isomerization at a
®
®
later step. We first tried OXONE for the oxidation of sulfide 13 to sulfone 15 but OXONE
generated a large amount of waste due to its high molecular weight. We therefore used
hydrogen peroxide instead, in a mixture of acetic acid, sulfuric acid and H O. The reaction
2
proceeded smoothly; after quenching the reaction with aqueous NaHSO , the reaction
3
mixture was directly used for the acidic hydrolysis of ester in 14 in the presence of
additional sulfuric acid, acetic acid and H O. A mixture of carboxylic acid E/Z-15 in 77%
2
yield was obtained from 19 and the purity of 15 was estimated as >99%.
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2
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2
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4
4
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4
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5
5
5
5
5
5
5
5
5
6
Relatively inexpensive 2-amino-5-bromopyrazine (28) was selected as the starting
material for the synthesis of aminopyrazine 18. The amino group of 28 was protected as
an imine using anisaldehyde, followed by addition of ethylene glycol to give 29, since 28
did not react with ethylene glycol directly to furnish 18. The use of benzaldehyde instead
of anisaldehyde to protect the amine decreased the yield due to the lower stability of the
corresponding imine. Imine 29 was hydrolyzed to aminopyrazine 18 in acidic conditions.
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
24
Our first attempt at amide formation involved treating the E diastereomer of carboxylic
acid 15 with SOCl in THF to afford the corresponding acid chloride, which was directly
2
reacted with aminopyrazine 18 to afford crude 1 in 92% yield. However, sulfite 25 was
formed as a by-product, was difficult to remove by recrystallization of the crude product,
and was predicted to be genotoxic by an in silico quantitative structure–activity
relationship study. We thus used oxalyl chloride in MeCN instead of SOCl and THF.
2
Treatment of an E/Z mixture of 15 with oxalyl chloride in MeCN, followed by the addition
of aminopyrazine 18, afforded crude 1 in 76% yield, although amide ester 26 was also
generated. To our delight, the E/Z ratio in crude 1 was estimated to be E/Z = 99.8/0.2,
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despite using an E/Z mixture of 15 as the starting material, indicating effective
isomerization of the alkene during the formation of the acid chloride of 15 or the
subsequent reaction step. Extensive examination showed that the isomerization occurred
during preparation of the acid chloride from 15. Screening additives for the formation and
isomerization of acid chloride and amide identified 1,1,3,3-tetramethylurea (TMU) as a
suitable replacement for DMF or DMA.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
F
F
H
F
H
H
F
S
F
S
F
S
H
H
H
H
F
S
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
S
O
O
O
O
O
O
O
O
O
O
26
O O
25
Figure 2. By-products generated in the amide formation step.
We established that the optimized procedure for amide formation involved adding a
stoichiometric amount of TMU and oxalyl chloride at 25 °C to a solution of E/Z-15 in MeCN
to generate the corresponding acid chloride 30 with E configuration. Following addition of
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
aminopyrazine 18 to the acid chloride solution, 2,6-lutidine was added dropwise at -30 to
-25 °C to minimize formation of by-product 26. Upon completion of the reaction, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reaction was quenched by adding DMSO and H O, and crude 1 was isolated by filtration.
2
Finally, successive recrystallizations from MeCN/anisole to reduce less-polar impurities
and EtOH/H O to decrease polar impurities and residual anisole were applied to provide
2
efficiently purified 1 in 73% yield from 15 with >99.5% purity.25
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Scheme 6. Scale-up Route to 1
1
) MsCl, Et N, toluene, 15 o
C
3
2)
O
N
3
0% aq. H O
2 2
F
F
CO2Et
F
F
NaS
S
F
F
Na WO ・2H O
2
4
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H O, 80 o
S
C
2
PhP(O)(OH) , EtOH
2
12
N
N
3) recrystallization with
toluene / i-PrOH / n-heptane
4%
0 o
5
C
S
S
OH
S
S
LHMDS, THF
O
2
93%
-
13 o
C
6
9
27
19
1
) 30% aq. H O2
2
F
F
F
aq. H SO , AcOH
2
4
53 oC;
H
H
H
F
S
F
(COCl) , TMU
F
S
2
then aq. NaHSO3
MeCN
CO H
COCl
2
CO Et
2
2) conc. H SO4
5 o
2
2
C
AcOH, H O
S
O O
2
01 o
O O
1
7
C
E/Z-13
E/Z-15
30
7% from 19
(
E:Z=57:43)
1
) o-anisaldehyde,
OMe
N
toluene, 113 o
C
HCl / EtOAc
H N
2
N
H N
N
N
azeotropic
H O, THF
2
2
HCl
N
OH
N
Br
25 o
C
O
2
) ethylene glycol,
t-BuOK, 98 o
0%
C
OH
98%
N
O
28
18
8
2
9
F
H
1) recrystallization
with MeCN / anisole
F
2
,6-lutidine,
DMA
H
N
N
crude 1
2) recrystallization
-
28 o
C
O
OH
with EtOH / H O
S
O O
N
O
2
73% from E/Z-15
1
CONCLUSION
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We developed a robust and scalable synthetic route to glucokinase activator 1 in 12 steps
and 15% overall yield. Key intermediate alcohol 9 was synthesized via diastereoselective
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epoxidation of cyclopentene 20 with tungsten catalyst, stepwise difluorination using Et N･
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HF and PBSF, and subsequent NaBH reduction of ester 23. Our approach avoids the
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®
use of highly reactive LiAlH , toxic OsO , and the costly fluorination reagent Deoxo-fluor
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4
used in the medicinal chemistry synthetic route. Acylate 13 was obtained by Julia
olefination between sulfone 19 derived from alcohol 9 and ketone 12, avoiding use of the
Wittig reaction which provided a low yield and required silica-gel column chromatography
to remove the phosphine oxide. Despite low diastereoselectivity in the olefination step,
isomerization to the desired E configuration during formation of the acid chloride from
E/Z-15 afforded acid chloride 30. Careful treatment of 30 with aminopyrazine 18 afforded
1 with greater than 99.5% purity after purification.
EXPERIMENTAL SECTION
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General. Starting materials, reagents, and solvents were obtained from commercial
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suppliers and used without further purification. H and C NMR spectra were acquired
with a Bruker AV400M spectrometer using the solvents indicated. Data are reported as
follows: chemical shift in ppm (δ) relative to tetramethylsilane, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, quint. = quintet, dd = doublet of doublets, dt = doublet of
triplets, td = triplet of doublets, br = broad signal, m = multiplet), coupling constant (Hz)
and integration. Infrared spectra were acquired using attenuated total reflectance (ATR)
measured with a Bruker ALPHA spectrometer. High-resolution mass spectrometry
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(HRMS) with electrospray ionization (ESI) was performed using a Shimadzu LCMS-
ITTOF mass spectrometer. Gas chromatography (GC) analysis was performed using an
Agilent 7890A or 7890B system. High-performance chromatography (HPLC) analysis
was performed using a Waters Alliance system or Agilent 1100 series.
GC conditions. (A) Column, Agilent HP-5 30.0 m × 0.25 mm × 0.25 µm; flow rate, 1.0
mL/min; oven temperature gradient, 40 °C held for 2 min and then ramped at 20 °C/min
to 280 °C; retention times, 20 6.5 min, 21 7.8 min, 22 8.1 min. (B) Column, Agilent DB624
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0.0 m × 0.32 mm × 1.80 µm; flow rate, 2.0 mL/min; oven temperature gradient, 80 °C
held for 2 min and then ramped at 15 °C/min to 170 °C; retention times, 2 8.6 min, 20 8.1
min, 21 11.5 min, 22 12.7 min, 23 12.1 min, 9 10.6 min.
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HPLC conditions. (A) Column, Phenomenex Kinetex F5 150 mm × 3.0 mm, 5 µm; elution
A, 0.1% acetic acid aqueous solution; elution B, 0.1% acetic acid in MeOH; gradient,
linear ramp from 40% B to 90% B over 15 min, held at 90% B for 3 min, linear ramp from
90% B to 40% B over 0.1 min, then 6.9 min post time at 40% B; flow rate, 0.6 mL/min; at
35 °C; wavelength, 226 nm; retention times, 27 11.6 min, 19 8.4 min, 12 11.9 min, E-13
12.9 min, Z-13 14.0 min, E-15 6.2 min, Z-15 6.7 min, 1 7.8 min. (B) Column, Develosil
ODS-MG-3 250 mm × 4.6 mm, 3 µm; elution A, 0.01mol/L ammonium acetate solution;
elution B, MeOH; gradient, linear ramp from 5% B to 40% B over 10 min, linear ramp from
40% B to 80% B over 65 min, linear ramp from 80% B to 5% B over 0.1 min then 14.9
min post time at 5% B; flow rate, 0.5 mL/min; at 40 °C; wavelength, 230 nm; retention
times, 19 49.2 min, E-15 21.3 min, Z-15 23.1 min, 1 44.5 min. (C) Column, Daicel
CHIRALPAK AS-H 250 mm × 4.6 mm, 5 µm; elution A, n-hexane; elution B, 0.2%
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diethylamine in EtOH; isocratic, 20% B; flow rate, 1.0 mL/min; at 40 °C; wavelength, 271
nm; retention times, 19 18.5 min, diastereomer of 19 derived from 22 28.0 min. (D)
Column, Daicel CHIRALCEL OJ-3 250 mm × 4.6 mm, 3 µm; elution A, n-hexane; elution
B, 0.2% diethylamine in EtOH; gradient, linear ramp from 30% B to 35% B over 45 min,
held at 35% B for 10 min, linear ramp from 35% B to 40% B over 40 min, linear ramp from
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40% B to 30% B over 10 min; flow rate, 1.0 mL/min; at 40 °C; wavelength, 316 nm;
retention times, 1 59.7 min, diastereomer of 1 derived from 22 87.2 min.
Ethyl (1R,3s,5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (21).
A reactor was charged with EtOH (550 mL) and 2 (275.0 g, 2.45 mol), and cooled to 0−5
°
C. SOCl (291.8 g, 2.45 mol) was added to the mixture dropwise below 10 °C. After
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addition, the mixture was warmed to 25−35 °C and stirred for 5 h. The resulting mixture
was quenched with H O (1375 mL), and then extracted twice with i-PrOAc (550 mL, 275
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mL). The combined organic layer was washed with NaHCO solution (220.0 g in 2750 mL
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of H O) followed by NaCl solution (137.5 g in 1375 mL of H O) to give a solution of 20.
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Na WO ･2H O (8.09 g, 0.0245 mol), PhP(O)(OH) (1.94 g, 0.0122 mol) and n-Bu NHSO
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(8.31 g, 0.0245 mol) were added to the above solution of 20 and the mixture was heated
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to 50−55 °C. 30% aqueous H O (361.4 g, 3.19 mol) was added below 55 °C over a
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period of 5−6 h, and then the mixture was stirred at 50−55 °C for 20 h. After cooling to
25−35 °C, i-PrOAc (275 mL) was added to the mixture, and the organic layer was
separated. The organic layer was cooled to 0−10 °C, and sodium thiosulfate pentahydrate
solution (174.4 g in 1100 mL of H O) was added slowly to the organic layer at 0−10 °C.
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The mixture was warmed to 25−35 °C and washed with NaCl solution (68.8 g in 688 mL
of H O). The organic layer was concentrated under reduced pressure below 40 °C to give
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21 (308.5 g, 81% yield based on 2) as a pale yellow oil. GC purity 21 90.2 area%, 22 6.0
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area% (GC condition B); 21: H-NMR (400 MHz, CDCl ) δ 4.13 (q, J = 7.2 Hz, 2H), 3.52
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(s, 2H), 2.59−2.68 (m, 1H), 2.32−2.38 (dd, J = 14.0, 8.0 Hz, 2H), 1.86−1.92 (m, 2H), 1.25
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t, J = 7.2 Hz, 3H). 22: H-NMR (400 MHz, CDCl ) δ 4.13 (q, J = 7.2 Hz, 2H), 3.47 (s, 2H),
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2.68−2.73 (m, 3H), 1.82−1.88 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H); C-NMR (100 MHz,
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CDCl ) δ 174.8, 60.7, 56.2, 38.1, 30.4, 14.2; FTIR (ATR, cm ) 2981, 2932, 1723, 1213,
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1178, 1061, 836.
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Ethyl (1r,3R,4S)-3,4-difluorocyclopentane-1-carboxylate (23).
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Caution! PBSF and Et N·3HF generate volatile and corrosive HF. All contact with skin
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must be avoided. The experiment must be handled in a well-ventilated hood.
A reactor was charged with Et N･3HF (600.0 g, 3.72 mol) and 21 (300.0 g, 1.92 mol) and
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the mixture was heated to 110−120 °C and stirred for 10 h. After cooling to below 30°C,
THF (2100 mL) was charged to the mixture. The mixture was cooled to 0−5 °C, and Et N
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(525.0 g, 5.19 mol) was added dropwise at 0−10 °C. PBSF (90% assay, 786.6 g, 2.34
mol) was added to the mixture at 0−10 °C and the reaction mixture was stirred for 5 h at
25−30 °C. The reaction mixture was cooled to 0−10 °C, and KHCO solution (288.5 g, in
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442 mL of H O) was added dropwise at 0−30 °C to give a pH of 7. Toluene (3000 mL)
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and H O (600 mL) were charged to the mixture at 20−30 °C, and the resulting organic
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layer (organic layer I), aqueous layer and fluorous layer were separated. The aqueous
layer was extracted with toluene (1500 mL) to give organic layer II. The fluorous layer
was extracted with organic layer II to give organic layer III. The resulting fluorous layer
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