A facile synthesis of the spiroindoline-based growth hormone secretagogue, MK-677

Article abstract of DOI:10.1016/j.cclet.2012.03.032

A facile and improved route for the synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677 was described. The key step adopted the Fischer indole/reduction strategy. The preparation of the key intermediates N-protected piperidine carboxaldehyde 5 and the N-Boc-O-benzyl-d-serine (2) are also optimized.

Full text of DOI:10.1016/j.cclet.2012.03.032

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 661–664
www.elsevier.com/locate/cclet
A facile synthesis of the spiroindoline-based growth
hormone secretagogue, MK-677
*
Xian Liang Qi, Er Qun Yang, Jun Tao Zhang, Tao Wang, Xiao Ping Cao
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Received 19 January 2012
Available online 12 May 2012
Abstract
A facile and improved route for the synthesis of the orally active spiroindoline-based growth hormone secretagogue, MK-677
was described. The key step adopted the Fischer indole/reduction strategy. The preparation of the key intermediates N-protected
piperidine carboxaldehyde 5 and the N-Boc-O-benzyl-D-serine (2) are also optimized.
#
2012 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: MK-677; Synthesis; Improved route; Fischer indole/reduction
MK-677 is a medicine which acts as a potent, orally active growth hormone secretagogue, mimicking the growth
hormone stimulating action of the endogenous hormone ghrelin. It has been demonstrated to increase the release of,
and produces sustained increases in plasma levels of several hormones including growth hormone and IGF-1, however,
without affecting cortisol levels. It is currently under development as a potential treatment for reduced levels of these
hormones, such as in growth hormone deficient children or elderly adults, and human studies have shown it to increase
both muscle mass and bone mineral density, making it a promising therapy for the treatment of frailty in the elderly. It
also alters metabolism of body fat and so may have application in the treatment of obesity. A survey of the literature
revealed only two reports on the total synthesis of MK-677, which were all accomplished by Merck research
laboratories in 1997 and 1998 [1]. However, there were some drawbacks such as some toxic agents (COCl) and high
2
pressure were required in the earlier research work. Hence, the profound clinical use encouraged us to seek a facile
process and more environmentally friendly way to accomplish the total synthesis of MK-677. Here, an improved
synthesis procedure for the preparation of MK-677 was described.
Retrosynthetic analysis of the MK-677 was described in Fig. 1. MK-677 could be derived from spiroindoline 1 via
double amidations with protected amino acids 2 and 3 respectively. Spiroindoline 1 was expected from
phenylhydrazine 4 and N-protected piperidine carboxaldehyde 5 using Fischer indole type approach [2]. In turn, the
aldehyde 5 could be easily prepared from commercially available isonipecotic acid (6) via three steps.
The preparation of the aldehyde 5 was begun with isonipecotic acid (6) (Scheme 1). Thus, reduction of acid 6 with
LiAlH gave the amino alcohol 7, followed by protection of the secondary amino group with CbzCl in the presence of
4
*
Corresponding author.
E-mail address: caoxplzu@163.com (X.P. Cao).
1001-8417/$ – see front matter # 2012 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
http://dx.doi.org/10.1016/j.cclet.2012.03.032

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X.L. Qi et al. / Chinese Chemical Letters 23 (2012) 661–664
Fig. 1. Retrosynthetic analysis of MK-677.
Scheme 1. The preparation of N-protected piperidine carboxaldehyde 5.
K CO provided alcohol 8 in 80% yield for two steps [3]. Then, oxidation of 8 using PCC in CH Cl provided
2
3
2
2
aldehyde 5 in 85% yield. All reactions were carried out at room temperature and ordinary pressure, which avoided the
using of (COCl) and high pressure reported previously [1], and guaranteed a totally convenient process for the
2
preparation of the key intermediate 5 by directly reduction of the acid.
The preparation of another key intermediate, N-Boc-O-benzyl-D-serine (2) was started from known D-serine 9
(Scheme 2). Thus, protection of the amine group in 9 by tert-butyl dicarbonate [(Boc) O] in the presence of Na CO in
saturated NaHCO aqueous afforded the amino acid 10 in 95% yield [4]. However, the consecutive selective protection
2 2 3
3
of the primary alcohol in 10 without esterification was a challenge to us. To enhance the reactive efficiency of the
amidation step between compounds 13 and 2, the acid 10 must be converted completely. Initially, common conditions
(
NaH, BnBr, DMF) was adopted for the protection of the primary alcohol in 10, however, there was nearly a half of
starting material converted with the low yield of 2 (Table 1, entry 1) [5,6]. Then, the same reaction was carried out at
8C and extended the reaction time to 48 h, the yield of the desired product had a slightly increase (entry 2). But the
0
conversion of the compound 10 decreased when the temperature enhanced to 40 8C (entry 3). Further screening of the
reaction conditions using the catalysts (n-C H ) NI or KI [6] did not enhance the yield of the compound 2 (entry 4).
Changing the reaction solvent or treatment with Ag O, only the ester 11 was obtained (entry 5 and 6) [7,8]. According
4
9 4
2
to literature precedent, Wang tried the same reaction and achieved similar results at room temperature [9]. When the
reaction ran with NaOt-Am as base at À10 8C, the yield was improved to 74% [1], and 45% with Na/NH (l) at À50 8C
3
to À30 8C [10]. So in our case, the reaction was carried out in DMF at À40 8C for 5 h to provide the desired amino acid
2
temperature, which made the S 2 process occurred in the hydrooxyl group.
in 75% yield (entry 7). It is due to the intramolecular hydrogen bond between the NH and CO H stabilized at low
2
N
With the key intermediates 5 and 2 in hand, we first investigated the formation of spiroindoline unit using Fischer
indole/reduction strategy (Scheme 3). Hence, treatment of an equivmolar mixture of aldehyde 5 and phenylhydrazine
4
with 2.5 equiv of TFA in CH C1 at 35 8C for 16 h gave a nearly quantitative yield of imine with no evidence of the
2
2
Scheme 2. The preparation of 2.

X.L. Qi et al. / Chinese Chemical Letters 23 (2012) 661–664
663
Table 1
The optimization of selective protection of primary alcohol in 10.
Entry
Conditions
Time (h)
Products
Yield (%)
1
2
3
4
5
6
7
NaH, BnBr, DMF, rt
24
24–48
24
2, 10 (1:1)
2, 10 (3:2)
2, 10 (1:3)
2, 10 (1:3)
11
37 for 2
46 for 2
18 for 2
18 for 2
65
NaH, BnBr, DMF, 0 8C
NaH, BnBr, DMF, 40 8C
NaH, BnBr, (n-C
NaH, BnBr, DMF/THF, rt
Ag O, BnBr, THF, rt
NaH, BnBr, DMF, À40 8C
4
H
9
)
4
NI or KI, DMF, 40 8C
24
24
2
24
11
65
5
2
75
Scheme 3. Synthesis of MK-677.
Wagner-Meerwein ring expansion product [11]. In situ reduction of the imine with NaBH in MeOH gave
4
spiroindoline 1. Subsequently, sulfonamidation of 1 with MsCl and DIEA in THF provided the sulfonamide 12 in 65%
yield for three steps from aldehyde 5. Soon afterward catalytic hydrogenolysis of 12 using 10% Pd/C in EtOH under
normal pressure of H atmosphere afforded the deprotected piperidine 13 in 93% yield (high pressure was used in the
2
literature [1]). Spiroindoline 13 was amidated with N-Boc-O-benzyl-D-serine (2) in the presence of DCC and 1-
hydroxybenzotriazole (HOBt) in 2:1 isopropyl acetate (IPAC)-water to give the N-Boc-monopeptide 14, followed by
deprotection with MsOH in EtOH to provide compound 15. Then the second amidation with N-Boc-amino-isobutyric
acid (3), followed by Boc-deprotection of the resulting compound 16 gave MK-677 in 75% yield from 13 without
isolation of any intermediates. Crystallization of crude MK-677 as the MsOH salt from EtOAc-EtOH gave the pure
drug substance. The NMR data of synthesized MK-677 were identical with the reported data [12].
In conclusion, an improved synthesis of N-protected piperidine carboxaldehyde 5 and an optimization of
preparation conditions for N-Boc-O-benzyl-D-serine (2) were explored. Thus a facile process for the synthesis of the
Growth Hormone MK-677 from commercially available starting material had also been accomplished.
Acknowledgments
Project supported by the National Basic Research Program of China (973 Program, No. 2010CB833203) and the
National Natural Science Foundation of China (Nos. 20972060 and 21061160494).

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X.L. Qi et al. / Chinese Chemical Letters 23 (2012) 661–664
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[
[
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1
7] Data of compound 2 [5b]: H NMR (400 MHz, CDCl
3
): d 10.1 (s, 1H, COOH), 7.31–7.27 (m, 5H, 5 Â ArH), 5.52 (d, 1H, J = 7.6 Hz, NH),
13
3 3
4
.51–4.48 (m, 3H, ArCH
2
and H-2), 3.92–3.89 (m, 1H, H-3a), 3.72–3.69 (m, 1H, H-3b), 1.44 (s, 9H, 3 Â CH
); C NMR (100 MHz, CDCl
): d
1
74.7 (CO), 155.6 (CO, C-1), 137.3 (C), 128.3 (CH), 127.7 (CH), 127.5 (CH), 80.2 (C), 73.2 (CH
2
), 69.7 (CH
2
, C-3), 53.7 (CH, C-2), 28.2
À
1
À
1
+
); IR (KBr, nmax/cm ): 3438, 2979, 2624, 1719, 1505, 1367, 1164, 738 cm ; EIMS (m/z, %): 295 (M , < 1), 239 (2), 194 (3), 148
(
3 Â CH
13), 132 (6), 133 (5), 91 (100), 57 (49).
3
(
1
[
8] Data of compound 11 [6]: H NMR (400 MHz, CDCl
ArCH
3
): d 7.32 (m, 5H, 5 Â ArH), 5.73 (d, 1H, J = 8.0 Hz, NH), 5.17 (d, 2H, J = 1.6 Hz,
13
3
2
), 4.39 (s, 1H, CH, H-2), 3.98–3.94 (m, 1H, H-3a), 3.86–3.83 (m, 1H, H-3b), 3.45 (s, 1H, OH), 1.42 (s, 9H, 3 Â CH
100 MHz, CDCl ): d 170.8 (CO), 155.7 (CO, C-1), 135.2 (C), 128.4 (CH), 128.2 (CH), 127.9 (CH), 80.0 (C), 67.0 (CH ), 62.9 (CH
CH, C-2), 28.1 (3 Â CH
94 (8), 148 (30), 132 (13), 133 (11), 91 (100), 57 (49).
9] S.T. Chen, K.T. Wang, Synthesis (1989) 36.
); C NMR
, C-3), 55.7
); IR (KBr, nmax/cm ): 3365, 2979, 1693, 1520, 1369, 1165, 1062, 783 cm ; EIMS (m/z, %): 295 (M , <1), 239 (3),
(
(
3
2
2
À1
À1
+
3
1
[
[
[
10] V.J. Hruby, K.W. Ehler, J. Org. Chem. 35 (1970) 1690.
11] (a) Y. Nomura, T. Bando, Y. Takeuchi, et al. Bull. Chem. Soc. Jpn. 56 (1983) 3199;
(
b) A.H. Jackson, P. Smith, Tetrahedron 24 (1968) 2227.
1
12] Data of synthesized MK-677: in the literature, some of H NMR and C NMR signals appeared as pairs of peaks due to the presence of amide
13
[
1
13
1
rotamers. Here, the H and C NMR data of the two rotamers were also described. H NMR (400 MHz, CD
3
OD): d 7.38–7.22 (m, 12H), 7.22–
.18 (m, 3H), 7.06 (t, 1H, J = 7.2 Hz), 6.99 (t, 1H, J = 7.6 Hz), 6.80 (d, 1H, J = 7.6 Hz), 5.27–5.13 (m, 2H), 4.58–4.46 (m, 6H), 4.09–3.98 (m,
H), 3.93 (s, 4H), 3.87–3.74 (m, 4H), 3.26–3.17 (m, 2H), 2.97 (s, 3H), 2.95 (s, 3H), 2.89–2.80 (m, 2H), 2.73 (s, 6H), 1.98–1.92 (m, 1H), 1.87–
7
2
1
13
3
.65 (m, 5H), 1.65 (s, 5H), 1.62 (s, 9H); C NMR (100 MHz, CD OD): d 173.1 (173.0, CO), 170.2 (170.0, CO), 142.7 (142.6, C), 139.6 (139.4,
C), 139.3 (C), 129.9 (129.8, CH), 129.7 (129.6, CH), 129.2 (CH), 129.13 (129.07, CH), 125.0 (CH), 124.6 (CH), 114.5 (114.4, CH), 74.5 (74.3,
CH ), 71.0 (70.2, CH ), 60.3 (60.0, CH ), 58.5 (C), 58.4 (CH ), 51.6 (50.9, CH), 44.5 (44.4, CH ), 44.2 (C), 41.1 (40.8, CH ), 39.7 (CH ), 37.6
36.9, CH ), 34.7 (CH ), 24.4 (24.3, CH ), 24.2 (24.1, CH ).
2
2
2
2
2
2
3
(
2
3
3
3