A convenient method for the synthesis of (S)-N-boc-3- hydroxyadamantylglycine: A key intermediate of saxagliptin

Article abstract of DOI:10.2174/1570178611666140421231237

(S)-N-Boc-3-Hydroxyadamantylglycine is a key intermediate of saxagliptin. It was synthesized from 1- adamantanecarboxylic acid to afford 1-acetyladamantane (2), which was converted into 2-(1-adamantyl)-2-oxoacetic acid (3) through oxidation, and then into 1-adamantyl-2-hydroxyimino acetic acid (4) followed by treatment of hydroxylamine hydrochloride, then 4 was reducted and Boc-protected to give N-Boc-adamantylglycine (5), which was oxidized with KMnO4 and treated with a chiral base. Utilizing this route, (S)-N-Boc-3- Hydroxyadamantylglycine was prepared. This work is to elaborate a convenient route to synthesize (S)-N-Boc-3-Hydroxyadamantylglycine and provide a new idea for the synthesis of saxagliptin.

Full text of DOI:10.2174/1570178611666140421231237

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Letters in Organic Chemistry, 2014, 11, 627-631
627
A Convenient Method for the Synthesis of (S)-N-boc-3-hydroxyadamantyl-
glycine: A Key Intermediate of Saxagliptin
Anmin Wang, Yu Deng, Xinmei Pan, Yingjie Chen, Zhu Tao, Dinghua Liang, and Xiangnan Hu*
Department of Pharmacy, Chongqing Medical University, 400016, Chongqing. P.R. China
Received March 14, 2014: Revised April 03, 2014: Accepted April 15, 2014
Abstract: (S)-N-Boc-3-Hydroxyadamantylglycine is a key intermediate of saxagliptin. It was synthesized from 1-
adamantanecarboxylic acid to afford 1-acetyladamantane (2), which was converted into 2-(1-adamantyl)-2-oxoacetic acid
(3) through oxidation, and then into 1-adamantyl-2-hydroxyimino acetic acid (4) followed by treatment of hydroxylamine
hydrochloride, then 4 was reducted and Boc-protected to give N-Boc-adamantylglycine (5), which was oxidized with
KMnO4 and treated with a chiral base. Utilizing this route, (S)-N-Boc-3-Hydroxyadamantylglycine was prepared. This
work is to elaborate a convenient route to synthesize (S)-N-Boc-3-Hydroxyadamantylglycine and provide a new idea for
the synthesis of saxagliptin.
Keywords: Boc-protection, reduction, (S)-N-Boc-3-Hydroxyadamantylglycine, saxagliptin, synthesis, treatment.
INTRODUCTION
protecting the amino group with Boc2O to obtain the final
product. It is evident that the compound III is a necessary
intermediate to prepare (S)-N-Boc-3-hydroxyadamantyl-
glycine I, and III can be produced in accordance with four
main methods, unfortunately, these methods all carry several
imperfections. Method one [6] requires toxic reagents and
harsh conditions, the oxalyl chloride and trimethylchlorosi-
lane used in this method are hypertoxic and an extremely
low temperature(-78 °C) is required to conduct the Swern
oxidation. The expensive reagents in the method two [3],
especially the 1,1-dichloro-2,2-bis(trimethylsilyloxy) ethyl-
ene, are difficult to obtain, hindering the further study. Simi-
larly, the reagents used in method three [7], such as dimethyl
ketone peroxide and CH3Li, are also expensive; meanwhile,
the yield of this method is low (23%). Method four [8] also
only achieves a mediocre yield (36%). The respective short-
comings of the four methods mentioned above make it diffi-
cult for the large-scale preparation of compound III, thereby
hampering the preparation of Route 1. The method described
in Route 2 [9] requires the 1-adamantanecarboxylic acid
methyl ester as the starting material, followed with a set of
complicated procedures. This route uses an asymmetric rea-
Saxagliptin, co-developed by Bristol-Myers Squibb and
Astrazeneca, is a highly selective and competitive dipeptidyl
peptidase-4 (DPP-4) inhibitor with the advantages of small
doses, reduced cardiovascular risk, rare weight gain, and
restoration of the function of islet beta cell [1]. In July 2009,
saxagliptin became the third approved dipeptidyl peptidase
IV (DPP-IV) inhibitor for the treatment of type 2 diabetes
mellitus under the trade name Onglyza [2]. A complex pre-
scription of saxagliptin and metformin was approved in No-
vember 2010 and saxagliptin has entered the Chinese market
since May 2011.
Retrosynthetic analysis of saxagliptin reveals that (S)-N-
Boc-3-hydroxyadamantylglycine is one of the pivotal
intermediates [3] (Scheme 1). (S)-N-Boc-3-hydroxyadam-
antylglycine has been synthesized by four methods reported
in present literatures (Scheme 2), as depicted in Route 1 [4,
5], it was originally prepared through an expensive and
sophisticated enzyme-catalyzed reaction reductively amina-
ting the 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (III)
with phenylalanine dehydrogenase as the catalyst, and then
OH
OH
O
O
O
O
N
N
II
+
OH
NHBoc
CN
NH2
CN
Saxagliptin
I
Scheme 1. Retrosynthesis analysis of saxagliptin.
gent method to obtain the product I, and because it needs
expensive and hypertoxic reagents which cause great harm to
humans and the environment, it is not suitable for industrial
*Address correspondence to this author at the Department of Pharmacy,
Chongqing Medical University, 400016, Chongqing. P.R. China;
Tel: +8615123328166; Fax: +8602368485161;
E-mail:huxiangnan62@163.com
1875-6255/14 $58.00+.00
© 2014 Bentham Science Publishers

628 Letters in Organic Chemistry, 2014, Vol. 11, No. 8
Wang et al.
Route 1
OH
OH
OH
(Boc)2O
phenylalanine dehydrogenase
CO2H
NHBoc
CO2H
NH2
CO2H
NADH
NAD
O
III
I
CO2
ammonium
formate
Route 2
1. LiAlH4, THF
HO
CN
2. (COCl)2, DMSO, -78 °C
HCl,HOAc, 80 °C,16h,78%
OMe
HN
OH
NH2
, KCN
3.
O
OH
O
HO
Pd(OH)2, H2
NaOH
CO2H
O
KMnO4, 2% KOH
NH
CO2H
NHBoc
HN
(Boc)2O
HO2C
I
Route 3
HCOONH4, [Cp*RhCl2]2
MeOH
KMnO4, Pyridine
KOH, H2O
CO2H
CO2H
O
O
NH2
OH
OH
OH
H2SO4,HNO3
4.5 h, rt
(Boc)2O
CO2H
NHBoc
CO2H
CO2H
NH2
NHBoc
I
Route 4
OH
SOCl2
N,N-Dibromohydantoin
H2SO4/HNO3
CO2H
CO2H
CO2H
Br
Br
OH
OH
OH
NH4OH/EtOH
(Boc)2O
CO2H
Resolution
CO2H
NHBoc
CO2H
NH2
NHBoc
I (70-80% ee)
Scheme 2. The existing synthetic routes of intermediate I.

A Convenient Method for the Synthesis of (S)-N-boc-3-hydroxyadamantylglycine
Letters in Organic Chemistry, 2014, Vol. 11, No. 8 629
1. SOCl2 reflux
O
O
2. Na/CH2(COOC2H5)2
rt
10% NaOH/HONH3Cl
OH
KMnO4/t-BuOH 40~45 °C
3.H2SO4/AcOH reflux
H2O rt
CO2H
O
3
2
1
OH
OH
NOH
O
NHBoc
OH
NHBoc
O
resolution
1. Ni-Al/EtOH 50 °C
KMnO4
OH
OH
2. Boc2O/NaOH
OH
O
O
NHBoc
4
6
5
I
Scheme 3. A convenient route for synthesis of intermediate I.
production. As shown in Route 3, 1-acetyladamantane was
oxidated into 1-adamantylglyoxylic acid, and then the 1-
adamantylglycinic acid was directly obtained from 1-
adamantylglyoxylic acid by reductive amination using a
metal catalyst. With hydroxylation and Boc-protection to
obtain racemic N-Boc-3-hydroxyadamantylglycine, [10] the
target product was obtained in a further study. However, this
method is uneconomical due to the application of the expen-
sive metal catalyst [Cp*RhCl2]2 in the process of reductive
amination. As depicted in Route 4, this synthesis used 1-
adamantaneacetic acid as starting material through compli-
cated procedures to acquire I, but the enantiomeric excess
value% of I only reached 70-80% [4].
for preparing compound I (S)-N-Boc-3-hydroxyadamantyl-
glycine. Meanwhile, the related reagents used in this route
are relatively common and environmentally friendly than
those used in the aforementioned routes (scheme 2), thereby
mitigating the difficulty and cost of preparation of I, and the
compound I obtained by this method reached 99% ee.
In this study, 1-acetyladamantane (2) was prepared with a
one-pot method previously reported by our team [11b], and
this method was optimized by us with the advantages of high
yield (94%), good reproducibility, simple operation, and
accessible raw materials. In the process of potassium per-
manganate oxidation, a screening on phase transfer catalysts
was conducted and the reaction catalyzed by TEBAC
achieved the highest yield after comparing the three catalysts
of tetrabutyl ammonium bromide (TBAB), benzyltriethy-
laminium chloride (TEBAC) and polyethylene glycol 400
(PEG-400) (Table 1). Therefore a catalytic amount of ben-
zyltriethylammonium chloride (TEBAC) was added as phase
transfer catalyst to improve the yield and promote the reac-
tion progress smoothly. This method directly prepared oxime
4 and successfully obviated the existing difficulties in the
synthesis of III. In the choice of reducing agents for the fol-
lowing reduction reaction, we selected the Ni-Al alloy sys-
tem as reductive agent after comparing the merits of
Zn/AcOH, Pd/H2, Raney-Ni/H2 and Ni-Al systems. In this
system, aluminum was reacted with NaOH to provide the
reductant H2, thereby avoiding additional provision of H2
during this reaction. More importantly, the pH value of the
reaction solution was found to be alkaline after completion
of the reaction, and thus the amino group can be directly
treated with Boc2O without isolation of 1-adamantyl glycine
to give the desired N-Boc-1-adamantyl glycine (5), this two-
step reaction gave a high yield (71%). Although the interme-
diate I of saxagliptin can be efficiently and selectively ob-
tained from keto acid III through the currently industry-
adopted method by enzyme catalyst, the expensive and inac-
cessible enzyme used in this approach significantly hinders
the synthesis in developing countries. By using this chiral
resolution method instead of the enzyme catalyst method, we
ameliorated the cost and difficulty in producing I. On basis
of patented approach [4], we had optimized the operations
of chiral resolution and improved the ee value of the product
(from 70-80%ee to 99%ee). Compared with method of pat-
Due to the aforementioned liminations in each route, it is
necessary for us to develop a new approach to synthesize
(S)-N-Boc-3-hydroxyadamantylglycine I. Herein, we devel-
oped a convenient route (Scheme 3) based on the above
route 3 and route 4 in (Scheme 2). This synthesis used 1-
adamantanecarboxylic acid (1) as the starting material to
synthesize (S)-N-Boc-3-hydroxyadamantylglycine in six
linear steps and the total yield of (S)-N-Boc-3-hydroxy-
adamantylglycine was about 20%.
RESULTS AND DISCUSSION
The synthesis commenced from 1-adamantanecarboxylic
acid (1), through acylation, substitution and decarboxylation
to afford 1-acetyladamantane (2) [11a, 11b], which was then
converted into 2-(1-adamantyl)-2-oxoacetic acid (3) [12] via
oxidation with potassium permanganate. Compound 3 was
treated with hydroxylamine hydrochloride to give 1-ada-
mantly-2-hydroxyimino acetic acid (4), which was then re-
duced by Ni-Al alloy and protected by Boc to afford N-Boc-
adamantylglycine (5). Sequent hydroxylation of the adaman-
tyl moiety with KMnO4 afforded N-Boc-3-hydroxyada-
mantylglycine (6) [9]. Finally, the key intermediate (S)-N-
Boc-3-hydroxyadamantylglycine I was obtained by chiral
resolution of 6. In a further embodiment of this work, the
(S)-N-Boc-3-Hydroxyadamantylglycine was used for pre-
paration of saxagliptin. This route not only brilliantly
avoided the difficult synthesis of compound III, but also cir-
cumvented the intellectual property issues of the application
of phenylalanine dehydrogenase in current industrial method

630 Letters in Organic Chemistry, 2014, Vol. 11, No. 8
Wang et al.
ent WO 2004/052850 A2, our reaction conditions are differ-
ent and the optimized operations focus on changing the reac-
tion temperature and the times of recrystallization. We used
‘reflux condition’ instead of the condition of 50 °C reported
in the patent and recrystallized the product twice, sometimes
more than twice. On one hand, heating under reflux can ac-
celerate and complete the reaction sufficiently. At the same
time we extended the reaction time from 1.5 h to 2 h. On the
other hand, this chiral resolution was based on the differ-
ent solubility of the salts formed from the racemic amino
acid and chiral base in the solvent. Increasing the times of
recrystallization led to purer product and higher ee value.
washed with water, and dried to give 1-acetyladamantane (2)
(Yield 18.60 g, 94%); mp 53-54 °C (53-55 °C [13]); IR
(KBr, cm-1): 2930, 2913, 2851, 1698, 1451, 1345; ESI-MS,
1
(m/z): 177 [M-H]-; H NMR (300 MHz, CDCl3): ꢀ: 2.09 (s,
3H), 2.07-1.56 (m, 15H).
Preparation of 2-(1-adamantyl)-2-oxoacetic acid (3):
NaOH (2.0 g, 0.05 mol), t-butanol (30 mL) and TEBAC (0.5
g) were added at room temperature to a suspension of 2 (8.9
g, 0.05 mol) in 100 mL H2O, and the mixture was heated to
40-45°C. Then potassium permanganate (15.8 g, 0.1 mol)
was added within one hour, and the reaction was stirred for
an additional two hours at 40°C. The mixture was quenched
with 10% Na2SO3 (10 mL) and filtered off while hot, and the
filter cake and reaction flask were rinsed with 20 mL hot
water. The filtrate was adjusted to pH=1 by concentrated
hydrochloric acid and a large amount of white solid formed
immediately. The white solid was filtered off and dried to
afford 3. (Yield 9.90 g, 95%); mp 98-101°C (102-104 °C
[14]); IR (KBr, cm-1): 2906, 2887, 2848, 2675, 2557, 1717;
Table 1. The impact of phase transfer catalyst on the reaction.
Types of Phase Transfer Catalyst
Yield (%)
None
83
90
95
87
1
ESI-MS, (m/z): 207[M-H]-; H NMR (300 MHz, MeOH-d4),
Tetrabutyl ammonium bromide (TBAB)
Benzyltriethylaminium chloride (TEBAC)
Polyethylene glycol 400 (PEG-400)
ꢀ: 2.05 (s, 3H), 1.92-1.74 (m, 12H).
Preparation of 1-Adamantyl-2-hydroxyimino acetic
acid (4): Hydroxylamine hydrochloride (3.34 g, 0.048 mol)
was added to a 100 mL water solution of 3 (8.32 g, 0.04 mol)
and sodium hydroxide (1.6 g, 0.04 mol). The mixture was
stirred in an ice-water bath for 2 h, and the white precipitate
was filtered off, washed with water, and dried to afford 4
(Yield 7.93 g, 89%); mp 135-137 °C IR (KBr, cm-1): 3280,
2905, 2850, 1651, 1702, 2527; ESI-MS (m/z): 222 [M-H]-;
1H NMR (400 MHz, DMSO-d6) ꢀ 1.93 (s, 3H), 1.79 – 1.56
(m, 12H).
EXPERIMENTAL
All the compounds synthesized were characterized by
1
melt point, IR, H NMR and MS. Melting points were de-
termined by X-4 digital melting point apparatus and are un-
corrected. Infrared spectra were recorded on a Nicolet FTIR
1
5700 spectrophotometer with KBr pellets. H NMR spectra
were measured in MeOH-d4 and CDCl3 on a Bruker Avance
300 spectrometer (300 MHz) and on a Varian Mercury-Plus
400 NMR–nuclear magnetic resonance instrument in
DMSO-d6 and CDCl3 solution with TMS as internal stan-
dard. Low-resolution electrospray ionization mass spectra
(ESI–MS) were determined with a Finnigan LCQ Advantage
Max spectrometer.
Preparation of N-Boc-adamantylglycine (5): A solu-
tion of 20 mL of 10% NaOH and 4 (4.46 g, 0.02 mol) dis-
solved in ethanol (40 mL) was stirred and heated to 50 °C,
then 2.96 g of Ni-Al alloy (50-50) was added in an hour, and
the reaction was stirred at 50 °C under ordinary pressure for
7 h. After the undissolved substance had been removed by
filtration, the solvent of the filtrate was removed under re-
duced pressure. 30mL distilled water was added to the resi-
due and pH10 was adjusted by adding concentrated HCl,
then the mixture was treated with Boc2O (5.23 g, 0.024 mol)
in tetrahydrofuran (THF, 30 mL), and the reaction was
stirred at room temperature overnight. After phase separa-
tion, the pH of the water phase was set to 2 by adding 65%
HCl, and extracted with 10 mL ethyl acetate three times. The
combined organic phases were washed with 30 mL saturated
NaCl solution, dried over anhydrous sodium sulfate. After-
wards, the organic solvent was removed by rotary
evaporation instrument, and the residue was recrystallized to
afford N-Boc-adamantylglycine (5) (Yield: 4.39 g, 71%); mp
194-195 °C; IR (KBr, cm-1): 3326, 2976, 2904,2618,
Preparation of 1-acetyladamantane (2): A mixture of
20 g (0.11 mol) of 1-adamantanecarboxylic acid and 40 mL
of SOCl2 was stirred and refluxed for 4 hours in the first
reactor, and the excess SOCl2 was distilled off under reduced
pressure. The residue was cooled to give 1-adamantane-
carbonyl-chloride, and then 50 mL of petroleum ether was
added to the residue for the preparation for the next step. In
the second reactor, a solution of 30 mL (0.17 mol) of diethyl
malonate and 50 mL of petroleum ether was added drop wise
to 3.83 g (0.20 mol) of metallic sodium in 100 mL of petro-
leum ether at room temperature, and the mixture was then
stirred until the metallic sodium was consumed completely.
Afterwards, the 1-adamantanecarbonyl-chloride solution in
the first reactor was added slowly to the resulting suspension
of sodium diethylmalonate, and the mixture was stirred at
room temperature overnight. 200 mL distilled water was
added to the resulting white suspension, and then the organic
layer and water layer were separated. The organic solvent
was distilled off under reduced pressure, a mixture of acetic
acid (80 mL), distilled water (24 mL) and concentrated sul-
furic acid (8 mL) was added to the residue, and refluxed for
6 hours. The reaction mixture was allowed to cool to room
temperature, and poured into 600 mL cold water for crystal-
lisation, and the needle crystals formed were collected,
1
1708,1653; ESI –MS (m/z): 308 [M-H]-; H NMR (400
MHz, DMSO-d6) ꢀ 6.75 (d, J = 9.0 Hz, 1H), 3.66 (t, J = 34.6
Hz, 1H), 1.90 (s, 3H), 1.66–1.46 (m, 12H), 1.36 (s, 9H).
Preparation of N-Boc-3-hydroxyadamantylglycine (6):
N-Boc-adamantylglycine (1.54 g, 0.005mol) was added por-
tion wise to a warm solution of potassium permanganate (0.8
g, 0.005 mol) and potassium hydroxide solution (16 mL,
2%). After all of the amino acid had been added, the mixture
was stirred at 90 °C for 2.0 hours, and then cooled to 0 °C in
ice bath. The solution was adjusted to pH2~3 by adding
concentrated HCl, and extracted with three 30 mL portions

A Convenient Method for the Synthesis of (S)-N-boc-3-hydroxyadamantylglycine
Letters in Organic Chemistry, 2014, Vol. 11, No. 8 631
centrated HCl, and extracted with three 30 mL portions of
ethyl acetate, the combined organic phases were washed with
saturated NaCl solution and dried with anhydrous sodium
sulfate. The solvent was then removed by rotary evaporation
instrument, and the residue was recrystallized to afford N-
Boc-3-hydroxyadamantylglycine 6 (Yield: 0.97 g, 60%) mp
177-179 °C; IR (KBr, cm-1): 3407, 3288, 2977, 2926, 2595,
1718, 1696; ESI-MS(m/z): 324 [M-H]-; 1H NMR (400 MHz,
CDCl3) ꢁ 6.48 (s, 1H), 5.18 (d, J = 8.8 Hz, 2H), 4.08 (d, J =
8.6 Hz, 1H), 2.25 (s, 2H), 1.59 (dd, J = 44.4, 22.8 Hz, 12H),
1.44 (s, 9H).
ACKNOWLEDGEMENTS
This work was supported by Natural Science Foundation
of Chongqing (CSTC, 2006BB5286). We also thank
Chongqing Medical University for partial financial support
of this work.
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CONCLUSION
[10]
[11]
In conclusion, we explored a convenient and practical
synthesizing method for saxagliptin intermediate (S)-N-Boc-
3-hydroxyadamantylglycine I. The highlights and advantages
of this route are the using of common and cheap raw materi-
als, mild reaction conditions, avoiding the existing shortcom-
ings in the current industrial preparation methods and pro-
viding a new idea for synthesis of saxagliptin. To the best of
our knowledge, this route has not been reported before. It is
of significance both for practical application or academic
study.
[12]
[13]
[14]
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.