Preparation of 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid: A key intermediate for saxagliptin

Article abstract of DOI:10.2174/157017812801264755

An optimized synthetic approach to prepare 2-(3-hydroxy-1-adamantyl)-2- oxoacetic acid has been reported in a good yield under mild experimental conditions. It was synthesized from 1-adamantanecarboxylic acid via successful reaction with thionyl chloride and sodium diethyl malonate to give dimethyl (1-adamantylcarbonyl) malonate, which was subjected to hydrolysis and decarboxylation by a mixture of acetic acid with water and sulfuric acid and then oxidation by potassium permanganate. The synthesized adamantane derivative was utilized to saxagliptin.

Full text of DOI:10.2174/157017812801264755

Letters in Organic Chemistry, 2012, 9, 347-350
347
Preparation of 2-(3-Hydroxy-1-Adamantyl)-2-Oxoacetic Acid: A Key
Intermediate for Saxagliptin
Jingke Li, Shurong Zhang, Hongrui Zhou, Jun Peng, Yue Feng and Xiangnan Hu*
Department of Pharmacy, Chongqing Medical University, 400016 Chongqing, P.R. China
Received January 03, 2012: Revised March 19, 2012: Accepted March 28, 2012
Abstract: An optimized synthetic approach to prepare 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid has been reported in a
good yield under mild experimental conditions. It was synthesized from 1-adamantanecarboxylic acid via successful
reaction with thionyl chloride and sodium diethyl malonate to give dimethyl (1-adamantylcarbonyl) malonate, which was
subjected to hydrolysis and decarboxylation by a mixture of acetic acid with water and sulfuric acid and then oxidation by
potassium permanganate. The synthesized adamantane derivative was utilized to saxagliptin.
Keywords: 1-Adamantanecarboxylic acid, 1-acetyladamantane, 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid, DPP-IV
inhibitor, saxagliptin.
INTRODUCTION
2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (1) has been
synthesized by several methods as described in Scheme 2. It
was previously prepared through a path as described in
Route 1 [6]. 1-bromoadamantane is condensed with tris-
Type 2 diabetes mellitus (T2DM) is common in clinic
and the prevalence is increasing. New treatment options,
such as suboptimal glycemic control, provide opportunities
to reduce the morbidity and mortality of this progressive
disease. DPP-IV (dipeptidyl peptidase IV) inhibitor has been
studied extensively as a treatment for T2DM [1]. Inhibition
of DPP-IV results in preserved levels of endogenous
insulinotropic hormone, glucagon-like peptide 1 (GLP-1),
which in turn leads to enhance insulin efficiency [2].
Saxagliptin is a highly potent and reversible DPP-IV
inhibitor [3]. It was approved for the treatment of T2DM by
the FDA in July 2009 and by the European Medicines
Evaluation Agency in October 2009 [4]. In an improved
process [5] for the preparation of saxagliptin, the
adamantylglycine fragment is prepared by an enzyme-
mediated, asymmetric reductive amination of a-keto acid 1
(
trimethylsilyloxy)-ethylene to afford adamantylglycolic
acid, which would require esterification, Swern oxidation,
and then hydroxylation by means of HNO /H SO to
provide compound 1. As shown in Route 2 [7], treatment of
-bromoadamantane with (2, 2- dichloro-1-methoxy-
3
2
4
1
vinyloxy)-trimethylsilane yields dichloro-1-adamantanyl-
acetic acid methyl ester, through hydroxylation, which is
further hydrolyzed to provide dichloro-(3-hydroxy-1-
adamantanyl)-acetic acid. Subsequent treatment of it with
sodium bicarbonate results in intermediate compound 1. Eric
et al. [8] reported a method of transforming 1-acetyl-3-
hydroxyadamantane to compound 1 by oxidation with
sodium permanganate (Route 3). The raw material 1-acetyl-
3-hydroxyadamantane was obtained by reacting 1-
adamantanecarboxylic acid with methyl lithium to produce
1-acetyladamantane [9], which then would require
hydroxylation to provide the corresponding compound 1.
Berner et al. [10] developed a method for converting 1-
acetyladamantane to compound 1 by oxidation with alkaline
potassium permanganate in the presence of a catalytic
amount of tetrabutylammonium bromide at 55-60 °C. This
route needs just one step to obtain compound 1 by oxidation
of ketone into carboxyl while the 3-H into hydroxyl, but the
yield is low (about 30 %) and the source of raw material is
not mentioned. These processes suffer from some
disadvantages such as the requirement of low temperature (-
(
Scheme 1). Therefore, compound 1 has become a widely
used key intermediate for the synthesis of saxagliptin. The
preparation of substantial quantities of 1 requires a
development of an efficient, cost-effective and scalable
synthesis.
O
HO
OH
N
HO
H N
O
2
O
CN
1
Saxagliptin
7
8 °C), the relative high cost of methyl lithium, the low yield
Scheme 1. A retrosynthetic way of Saxagliptin from 2-(3-hydroxy-
-adamantyl)-2-oxoacetic acid (1).
of oxidation and so on, they are hence considered inefficient
for large-scale work.
1
Due to the above limitations, it has become a challenge
for us to develop an alternative method for rapid access to
this intermediate in good yields. Herein we report a practical
and convenient method for the synthesis of compound 1
using readily available reagents and starting materials.
*
Address correspondence to this author at the Department of Pharmacy,
Chongqing University of Medical Sciences, 1 Yixueyuan road, Chongqing,
00016, China; Tel: +8613308360519; Fax: +8602368485161;
E-mail: huxiangnan62@163.com
4
1
875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

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48 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Li et al.
TMSO
TMSO
OTMS
COOH MeOH/AcCl
Route 1:
COOMe
ZnCl ,DCM
Br
2
OH
OH
COCl , DMSO,
2
Et N, DCM, -
3
78 ˚C
OH
OH
HNO /H SO
O
NaOH/THF
3
2
4
COOMe
COOMe
OH
O
O
O
1
OH
OH C
Cl
Cl
3
HNO /H SO
4
Route 2:
OTMS
COOMe
Cl Cl
3
2
COOMe
Cl Cl
Br ZnCl
, CH Cl
2 2
2
(
1). NaOH, H O,
2
MeOH
2). HCl
(
OH
OH
O
NaOH/THF
COOH
Cl Cl
OH
O
1
(
1). NaMnO , H O,
4 2
OH
t-BuOH,NaOH
(2). HCl
O
O
O
MeLi
Route 3:
OH
COOH
HO
COCH3
COCH
3
O
Scheme 2. Reported methods for the synthesis of compound 1.
RESULTS AND DISCUSSION
malonate. However, the preliminary results were not
satisfactory. The reaction failed by the applicability of
sodium hydroxide and sodium ethoxide because of possible
hydrolysis of the initial acyl chloride. A low yield (56%) of 5
was obtained by using the lower activity of magnesium.
Therefore, the sodium was chosen due to its high reactivity.
In addition, the intermediate dimethyl (1-adamantylcarbonyl)
malonate (4) was hydrolyzed by a mixture of acetic acid with
In this letter, we generated a safe and economically
competitive synthesis of compound 1 (Scheme 3), which was
obtained from 1-adamantanecarboxylic acid (2) in four steps
using inexpensive and commercially available raw materials
and reagents. To the best of our knowledge, we synthesized
1
-acetyladamantane using a simple method and improved the
yield of compound 1 by optimized oxidation conditions.
3 2 2 4
water and sulfuric acid (CH COOH: H O: H SO ratio 7: 5:
Many methods [11-13] have been reported for the
synthesis of 1-acetyladamantane (5). We developed an
optimized route to prepare compound 5, in which the
expected yield is 82%. It was achieved by the action of
diethyl malonate and sodium on 1-adamantanecarbonyl
chloride (3) in anhydrous ether at 5-10 °C and subsequent
hydrolysis by a mixture of acetic acid with water and sulfuric
acid. In this procedure, the key factor affected the yield was
the activity of the metal. We had used sodium hydroxide,
sodium ethoxide and magnesium instead of sodium for the
synthesis of compound 5 from compound 3 and diethyl
1.5) to afford compound 5.
In the last step, compound 5 was converted into
compound 1 by oxidation with potassium permanganate
,
referring to Berner s method. By optimizing the reaction
conditions, particularly changing the catalyst, this reaction
was performed under a basic condition (1.5% NaOH),
followed by oxidation for 14 h at 75-80 °C using benzyl
triethylammonium chloride (TEBAC) as the phase transfer
catalyst. The product 1 was purified by recrystallization from
ethyl acetate and heptane (1: 2) to obtain colorless crystals in
4
7 % yield. Through a four-step reaction, compound 2 was

Preparation of 2-(3-Hydroxy-1-Adamantyl)-2-Oxoacetic Acid
Letters in Organic Chemistry, 2012, Vol. 9, No. 5
349
b
c
a
COOH
COCl
COCH(COOEt)2
2
3
4
OH
d
O
COCH3
OH
O
5
1
Scheme 3. Reagents and conditions: (a) SOCl
2
, 80 °C, 4 h, 97 %; (b) Na, CH
ratio 7 : 5 : 1.5, 100 °C, overnight, 83 %; (d) KMnO
2 h, 25-30 °C, overnight, 47 %.
2
2 5 2 2 5 2 5 3
(COOC H ) , C H OC H , 5-10 °C, overnight; (c) CH COOH
:
H
2
O : H
2
SO
4
4
, 1.5 % NaOH, benzyl triethylammonium chloride (TEBAC), 75-80 °C,
1
successfully transformed into product 1 with a total yield of
7 %.
2 4
were dried over anhydrous Na SO , concentrated under
vacuum, and recrystallized with 75% ethanol to afford a buff
3
compound 5 (Yield 14.7 g, 83 %). mp. 52-53 °C. {lit. [15]
-
1
mp: 53-55 °C}. IR (KBr, cm ): 2930, 2913, 2851, 1698,
1
EXPERIMENTAL SECTION
1
3
451, 1345; H NMR (CDCl , 300 MHz): δ 2.09 (s, 3H,
CH ), 2.07-1.56 (m 15H, CH , CH).
3
2
The compounds synthesized were characterized by IR,
HNMR and MS. The IR spectra were recorded on a Perkin-
Elmer 257 spectrometer using KBr discs. H NMR spectra
1
Preparation of 2-(3-hydroxy-1-adamantyl)-2-oxoacetic
Acid (1)
were measured in DMSO-d
6 3
and CDCl on a Bruker Avance
3
00 spectrometer (300 MHz). The mass analysis was
To a suspension of 5 (8.9 g, 0.05 mol) in 10 % NaOH
performed on Shimadzu 2010A LC-MS mass spectrometer.
o
(
125 mL) at 60 C was added benzyltriethylammonium
o
chloride (0.20 g). To this mixture, heated to 75 C in an oil
bath, was added potassium permanganate (25.2 g, 0.16 mol)
during 2.5 h. After the reaction mixture was stirred at 75-80
Preparation of 1-Adamantanecarbonyl Chloride (3)
To 1-adamantanecarboxylic acid (2) (27.0 g, 0.15 mol)
was added slowly to thionyl chloride (32 mL, 0.45 mol) at
room temperature, and the resulting suspension was stirred at
o
C for 12 h, removed the oil bath (ambiguous sentence,
please contact author). The reaction mixture was then cooled
to room temperature and stirred for additional 15 hrs. The
mixture was quenched with 20 % Na SO (40 mL) and was
2 3
8
0 °C for 4 h. Then the mixture was cooled to room
temperature and the excess SOCl was removed under
2
filtered through celite. The filtrate was adjusted to pH 1 by 6
N HCl (10 mL). The resulting mixture was extracted with
ethyl acetate (70 mL×3). The organic fractions were
reduced pressure. The pale yellow solid was dried at room
temperature to afford the crude 3 (Yield 29.2 g, 97%). mp.
4
8-51 °C {lit. [14] mp: 48-52 °C}.
2 4
combined, dried over anhydrous Na SO , and concentrated
under vacuum to give the crude product 1. Recrystallization
from ethyl acetate and heptane (1: 1) gave 1 as colorless
solid (Yield 5.29 g, 47 %). mp. 162-164 °C. {lit. [7] mp:
Preparation of 1-Acetyladamantane (5)
To a mixture of sodium (2.5 g, 0.11 mol) and anhydrous
ethyl ether (20 mL) was added slowly a suspension of
diethyl malonate (22.6 mL, 0.15 mol) in anhydrous ethyl
ether (80 mL) at 5-10 °C (duration 1 h), and the mixture was
stirred until sodium was consumed completely. A solution of
compound 3 (19.87 g, 0.1 mol) in absolute ethyl ether (50
mL) was added slowly (duration 1.5 h) to the resulting
suspension. The mixture was stirred for 3 h at room
temperature. Then a solution of sulfuric acid (10 %, 40 mL)
was added and the organic layer was separated. The aqueous
layer was re-extracted with ethyl ether (50 mL×2). The
combined organic extracts were concentrated under vacuum
to afford the crude product of dimethyl (1-
adamantylcarbonyl) malonate (4) as a yellow oil residue.
This material was used directly in the next step.
-
1
1
1
64-165 °C}. IR (KBr, cm ): 3401, 2932, 2861, 2482, 1713,
689; ESI-MS m/z 223.0 [M-H] ; H NMR (DMSO-d6, 300
- 1
MHz): δ 3.32 (br s, 1H, OH), 2.16 (s, 2H, CH), 1.74-1.42 (m
2H, CH ).
1
2
CONCLUSION
In conclusion, this is a practical and convenient synthesis
of 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid. Cheap and
efficient reagents as well as the high yields of products are
the main the advantages, which make the route reportedly
useful for large-scale production.
CONFLICT OF INTEREST
To a suspension of crude 4 was added acetic acid (70
mL), water (50 mL) and concentrated sulfuric acid (15 mL).
The reaction mixture was refluxed for 10 h until carbon
dioxide was not produced. It was cooled to the room
temperature, poured into ice water, and extracted with
dichloromethane (70 mL×2). The combined organic extracts
None declared.
ACKNOWLEDGEMENTS
This work was supported by Natural Science Foundation
of Chongqing (CSTC, 2006BB5286). We also thank

3
50 Letters in Organic Chemistry, 2012, Vol. 9, No. 5
Li et al.
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