Efficient synthesis of a 7-azabicyclo[2.2.1]heptane based GlyT1 uptake inhibitor

Article abstract of DOI:10.1016/j.tetlet.2010.10.079

An efficient synthetic route based on generation and subsequent electrophilic reaction of a Boc-protected azabicyclo[2.2.1]heptane anion to prepare a potent GlyT1 uptake inhibitor (1) is described.

Full text of DOI:10.1016/j.tetlet.2010.10.079

Tetrahedron Letters 51 (2010) 6741–6744
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Tetrahedron Letters
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Efficient synthesis of a 7-azabicyclo[2.2.1]heptane based GlyT1 uptake inhibitor
⇑
Hui Xiong , William Frietze, Donald W. Andisik, Glen E. Ernst, William E. Palmer, Lindsay Hinkley,
Jeffrey G. Varnes, Jeffrey S. Albert, Chris A. Veale
CNS Chemistry, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic route based on generation and subsequent electrophilic reaction of a Boc-protected
azabicyclo[2.2.1]heptane anion to prepare a potent GlyT1 uptake inhibitor (1) is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 September 2010
Revised 12 October 2010
Accepted 13 October 2010
Available online 23 October 2010
Glycine transporter type 1 (GlyT1) primarily serves to regulate
synaptic levels of glycine in the immediate vicinity of the NMDA
receptor (NMDAr). Therefore, inhibitors of GlyT1 would be
expected to raise brain glycine levels and increase NMDAr-medi-
ated neurotransmission, which should lead to improvement in
schizophrenia symptoms1 without the toxic effects of direct
NMDAr agonists. Inhibition of GlyT1 has been widely investigated,
leading to the discovery of a few advanced clinical candidates from
various pharmaceutical companies.2 Recently Roche reported
Phase II clinical study results of R1678 in schizophrenia patients
which met both its primary and secondary endpoints.3 Our own ef-
forts in this therapeutic area identified compound 1 to be a potent
inhibitor of GlyT1 (IC50 ꢀ3 nM). This Letter describes our effort to
develop an efficient, scalable, and high-yielding synthesis of 1
(Fig. 1).
phenyl lithium to imine 4 at À78 °C afforded sulfinamide 5a with
a high level of stereoselectivity. The t-butyl sulfinamide protecting
group of 5a was then selectively removed5 using HCl (3 equiv) in
methanol/1,4-dioxane, and the resulting amine was treated with
2,6-dimethyl benzoyl chloride to give amide 6. Cleavage of the
Boc group was followed by methylation using either Eschweiler–
Clarke6 or direct alkylation conditions to provide final compound
1 in 10 steps and ꢀ20% overall yield from amino acid 2.
There were several limitations associated with this synthetic
route. The lengthy synthetic sequence made structure activity rela-
tionship (SAR) exploration slow and inefficient. Large scale prepa-
ration of key intermediates and final compounds was labor
intensive and of questionable feasibility. To address these issues,
Our initial route (Scheme 1) to 1 started from known 7-azabicy-
clo[2.2.1]heptane-1-carboxylic acid 2,4 which was prepared in
eight steps (ꢀ20% overall yield) from commercially available start-
ing material.4b Carboxylic acid 2 was first esterified and then con-
verted to Boc carbamate 3 in high yield. Subsequent conversion of
3 to an aldehyde intermediate was followed by condensation with
(R)-tert-butyl sulfinamide to give chiral imine 4. The addition of
c, d, e
CO2Me
a, b
N
N
H
N
Boc
CO2H
Boc
N
O
S
t-Bu
2
3
4
f
N
N
Ph
O
Ph
O
i, j or k
g, h
N
S
Boc
N
Ph
Ph
O
N
Boc
HN
HN
O
HN
O
F
HN
O
S
F3C
O
N
CF3
t-Bu
O
N
1
6
5a
1
Roche: R1678
Scheme 1. Reagents and conditions: (a) AcCl, MeOH, 90%; (b) Boc2O, Et3N, CH2Cl2,
85%; (c) DIBAL-H, CH2Cl2, À78 °C, 97%; (d) DMSO, (COCl)2, Et3N, CH2Cl2, À78 °C,
82%; (e) (R)-2-methylpropane-2-sulfinamide, Ti(OEt)4, THF, 70%; (f) PhLi, THF,
À78 °C, 90%; (g) HCl in MeOH/dioxane (3 equiv), quant.; (h) 2,6-dimethylbenzoyl
chloride, Et3N, CH2Cl2, 87%; (i) 4 N HCl/1,4-dioxane, 97%; (j) 37% formaldehyde,
formic acid, reflux, 60%; (k) Me2SO4, NaOH, H2O/dioxane, 50%.
Figure 1. Chemical structure of GlyT1 inhibitors: R1678 and 1.
⇑
Corresponding author. Tel.: +1 781 839 4594.
E-mail address: hui.xiong@astrazeneca.com (H. Xiong).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.079

6742
H. Xiong et al. / Tetrahedron Letters 51 (2010) 6741–6744
Table 1
a
Lithiation and electrophilic additions of azabicycle 11a
E
E +
N
Boc
N
Boc
N
Boc
s-BuLi, TMEDA
N
N
Et2O, 0 °C
7
8a
8b
E
Boc
Boc
Electrophile
11
12-18
Scheme 2. Reagents and conditions: (a) s-BuLi, TMEDA, ether, 0 °C or À78 °C,
electrophile.
Entry
Electrophile
E
Product (%yield)
1
CD3OD
DMF
CO2
MeI
c-PrCHO
D
12 (75)
13 (57)
14 (53)
15 (90)
16 (50)
we embarked on the exploration of other potential synthetic routes
to 1.
2b
3c
4
H2COH
COOH
Me
Beak et al. have reported that a-methylenes adjacent to N-Boc
5
CH(c-Pr)OH
carbamates can be functionalized via lithiation in the presence of
TMEDA or sparteine.7 In 2002, Krow et al. reported the tempera-
ture dependent regioselective lithiation and subsequent reactions
of N-Boc protected azabicyclo[2.1.1]hexane (7)8 (Scheme 2). Using
this work as a template, we investigated the lithiation and
substitution reactions of analogous azabicycle 11, noting that the
symmetry of N-Boc azabicyclo[2.2.1]heptane eliminates the regi-
oselectivity issue encountered by Krow.9
O
N
N
6
7
17 (80)
O
N O
t-Bu
Ph
N
H
N
S
t-Bu
S
O
5b (85)
O
H
Ph
19
a
Reaction condition: s-BuLi was added to the solution of 11 and TMEDA in Et2O
We prepared several hundred grams of azabicycle 11 from Boc
protected trans-4-aminocyclohexanol (9) using a two-step mesyla-
tion and base-assisted intramolecular cyclization strategy (Scheme
3).10 Mesylate intermediate 10 was used directly in the cyclization
step without further purification, and crude azabicycle 11 could be
purified by flash column chromatography or vacuum distillation
(bp 82–85 °C, 0.4 mbar). It is also noteworthy that 11 was used
next despite the presence of elimination byproduct (10–15% Boc-
3-amino cyclohexene).
With compound 11 in hand, we were now poised to investigate
deprotonation and subsequent electrophilic addition. Various reac-
tion conditions were explored: temperature (À78 °C, À30 °C, 0 °C,
rt), solvent: (THF, Et2O or MTBE), base (s-BuLi, t-BuLi, KDA, LICKOR,
LiTMP, etc.) and additive (TMEDA). As detailed in Table 1, the opti-
mal conditions for this reaction involved addition of s-BuLi to a
premixed solution of 11 and TMEDA in Et2O at 0 °C, followed by
the addition of suitable electrophiles. Thus, a deuterium quench
with CD3OD (entry 1) provided 12 in good yield with loss of a
methine proton based on NMR analysis. Alcohol 13 was obtained
upon quenching with DMF and employing a reductive workup (en-
try 2). Applying this methodology to the novel and efficient prep-
aration of 2, bubbling excess carbon dioxide through the
lithiation reaction mixture produced amino acid 14 (entry 3),
which was then converted to 2 by removal of the Boc group. Simple
alkyl halides, such as methyl iodide (entry 4), aldehydes (entry 5),
and Weinreb amides (entry 6) also reacted readily with the anion
of 11.
at 0 °C, followed by the addition of suitable electrophiles.
b
Workup includes NaBH4 reduction.
CO2 dried by passage through anhydrous CaSO4 prior to use.
c
RLi
H
Ph
O
S
N
R
N
Ph
.
.
Li
Boc
N
Boc
O
N
N
t-Bu
S
S
N
HN
O
Ph
t-Bu
5b
19
R =
t-Bu
Boc
PhLi
R
H
N
R
PhLi
Ph
.
.
Boc
Boc
O
R
S
N
N
HN
O
O
S
t-Bu
t-Bu
t-Bu
5a
4
Figure 2. Proposed transition states of anion addition to chiral imines.
With this methodology validated, we sought to apply it to the
large scale synthesis of compound 1. We were initially concerned
about an exotherm associated with deprotonation of 11 and subse-
quent addition to imine 19 because of the low flash point of ether
(À45 °C). Therefore, 1.3 equiv of s-BuLi was added over 25 min to a
pre-cooled mixture of N-Boc protected azabicycloheptane 11 and
TMEDA in Et2O at À25 °C. The internal temperature was kept under
À25 °C during the addition process. After an additional 20 min at
À25 °C, the anion solution was cooled to À50 °C, and the pre-
cooled solution of imine 19 in Et2O was added.12 Neutralization
with aqueous NH4Cl afforded a crude mixture of diastereomers
in a 12:1 (R,R):(S,R) ratio. The major isomer 5b (R,R) was directly
isolated in 50% yield upon recrystallization of the crude mixture
from hot hexanes.
We were also gratified to determine that condensation of chiral
imine 19 with the anion of 11 resulted in formation of key interme-
diate 5b in 85% yield with high diastereoselectivity (>10:1
(R,R):(S,R)) in the newly formed stereogenic center. It should be
noted that the stereochemistry of chiral sulfinamide 19 used in this
transformation is opposite that used in initial synthetic route
(imine 4). The rationale for the stereoselectivity can be predicted
from the proposed transition states which are shown in Figure 2.11
OMs
OH
a
b
N
Upon scale up, we made several modifications in the following
steps leading to compound 1. A solution of major isomer 5b in
methanol was treated with 1.1 equiv of 4 N HCl in 1,4-dioxane to
give the primary amine 20 in quantitative yield.13 A CH2Cl2 solu-
tion of 20 and 2 equiv DIPEA was then treated with 2,6-dim-
ethylbenzoyl chloride at 0 °C to afford the crude amide, which
Boc
NHBoc
10
NHBoc
9
11
Scheme 3. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, quant.; (b) t-BuOK, THF,
80%.

H. Xiong et al. / Tetrahedron Letters 51 (2010) 6741–6744
6743
6. (a) Eschweiler, W. Ber. 1905, 38, 880; (b) Clarke, H. T.; Gillespie, H. B.;
Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571; (c) Moore, M. L. Org. React.
1949, 5, 301.
7. Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res.
1996, 29, 552.
8. Krow, G. R.; Herzon, S. B.; Lin, G.; Qiu, F.; Sonnet, P. E. Org. Lett. 2002, 4, 3151.
9. For a review on 7-azabicyclo[2.2.1]heptanes, see: Chen, Z.; Trudell, M. L. Chem.
Rev. 1996, 96, 1179.
10. (a) Cheng, J.; Trudell, M. L. Org. Lett. 2001, 3, 1371; (b) Hassner, A.; Belostotskii,
A. M. Tetrahedron Lett. 1995, 36, 1709; (c) Davis, C. R.; Johnson, R. A.; Cialdella, J.
I.; Liggett, W. F.; Mizsak, S. A.; Marshall, V. P. J. Org. Chem. 1997, 62, 2244–2251.
11. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
12. Preparation of tert-butyl 1-((R)-((S)-1,1-dimethylethyl-sulfinamido)(phenyl)
methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (5b): A solution of tert-butyl
7-azabicyclo[2.2.1]heptane-7-carboxylate (11) (192 g, 975 mmol) and TMEDA
(0.164 L, 1100 mmol) in 1.7 L of anhydrous diethyl ether was stirred with an
N
Ph
S
N
Boc
a
b
Ph
NH2
N
Boc
HN
O
Boc
t-Bu
11
5b
20
c, d
N
N
Ph
Ph
H
e
HN
HN
O
O
overhead mechanical stirrer and kept under
a nitrogen atmosphere. The
stirring solution was cooled to an internal temperature between À30 °C and
À25 °C, and 1.4 M s-BuLi in cyclohexane (0.754 L, 1050 mmol) was added over
a 25 min period while maintaining the internal temperature in the same range.
The turbid, pale amber reaction mixture was stirred at À25 °C for an additional
20 min. During this time, in a separate flask was prepared a solution containing
(S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (170 g, 812 mmol) in
300 mL of diethyl ether cooled in a À78 °C dry ice/acetone bath. After the
anion solution had stirred for the required amount of time, it was cooled to an
internal temperature of À50 °C and the cooled imine solution was cannulated
into the anion solution over 45 min (internal temp maintained between À55 °C
and À45 °C during addition). The reaction mixture was then allowed to slowly
warm up to 5 °C over the course of 4.5 h before being quenched by slow
addition of satd aq NH4Cl solution (300 mL over 10 min—gas evolution
observed). The quenched mixture was stirred for 15 min, and the layers were
separated. The aqueous layer was washed with diethyl ether, and the
combined organic extracts were washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. 1H NMR of the crude product showed
approx. 12:1 diastereoselectivity. The semi-solid residue was recrystallized
from hot hexanes to give the desired product 5b (170 g, 51% yield), and the
mother liquor was collected to give 209 g of an amber semi-solid. 1H NMR
(300 MHz, DMSO-d6) d 7.49 (d, J = 7.17 Hz, 2H), 7.20–7.34 (m, 3H), 5.46 (s, 2H),
4.15 (t, J = 4.64 Hz, 1H), 1.94–2.09 (m, 1H), 1.60 (d, J = 10.12 Hz, 3H), 1.41 (s,
9H), 1.29–1.38 (m, 3H), 1.16–1.23 (m, 1H), 1.12 (s, 9H). MS (+ESI): m/z: 407.3
(M+H)+.
1
21
Scheme 4. Reagents and conditions: (a) s-BuLi, TMEDA, Et2O, À25 °C to À50 °C, (S)-
19, 50%; (b) 1.1 equiv HCl in MeOH/1,4-dioxane, quant.; (c) 2,6-dimethylbenzoyl
chloride, DIPEA, CH2Cl2, 90%; (d) 4 N HCl in 1,4-dioxane, 97%; (e) 37% formaldehyde,
formic acid, reflux, 61%.
was sufficiently pure after acid/base workup to be used in the next
step without further purification. The Boc group was easily re-
moved14 when exposed to HCl in 1,4-dioxane and CH2Cl2. The sec-
ondary amine 21 was then subjected to Eschweiler–Clarke reaction
conditions to install the N-methyl group. The crude product was
first filtered through a pad of basic alumina and then directly
recrystallized from hexanes to give compound 1 (28 g, 61% yield)
in >99% purity (Scheme 4).15
In conclusion, we have demonstrated that the anion of N-Boc
protected azabicyclo[2.2.1]heptane can be generated via lithiation
and subsequently reacted with a wide variety of electrophiles to
prepare substituted azabicycloheptanes. Based on this methodol-
ogy, an efficient and scalable synthesis of GlyT1 uptake inhibitor
1 from N-Boc azabicyclo[2,2,1]heptane was achieved in five steps
and 26% overall yield. This route was also sufficiently flexible to al-
low the synthesis of a number of potential GlyT1 inhibitors to ex-
plore the SAR in this series.
13. Preparation of (R)-tert-butyl 1-(amino(phenyl)methyl)-7-azabicyclo[2.2.1]
heptane-7-carboxylate (20): To a cooled (ice bath) solution of tert-butyl 1-
((R)-((S)-1,1-dimethylethylsulfinamido)(phenyl)
methyl)-7-azabicyclo-
[2.2.1]heptane-7-carboxylate 5b (185 g, 455 mmol) in MeOH (500 mL) was
added 4 M HCl in dioxane (125 mL, 500 mmol) dropwise over 1 h. The reaction
mixture was stirred at 0 °C for an additional 2.5 h, then the solvent was
removed in vacuo. The residue was treated with concd NaHCO3 and extracted
with CH2Cl2 (2Â). The organic extracts were combined, dried over Na2SO4,
filtered, and the product (quantitative yield—of suitable purity) was kept as a
solution in CH2Cl2 for subsequent use. MS (+ESI): m/z: 303.2 (M+H)+.
14. Preparation
dimethylbenzamide (21): To
solution of (R)-tert-butyl 1-(amino(phenyl)methyl)-7-azabicyclo[2.2.1]-
of
(R)-N-(7-azabicyclo[2.2.1]heptan-1-yl(phenyl)methyl)-2,6-
a
cooled (ice bath) reaction flask containing
a
Acknowledgments
heptane-7-carboxylate (64 g, 212 mmol) and DIPEA (73.9 mL, 423 mmol) in
CH2Cl2 (440 mL), stirring under a nitrogen atmosphere, was added a solution of
2,6-dimethylbenzoyl chloride (35.7 g, 212 mmol) in CH2Cl2 (150 mL) dropwise
over 45 min. The reaction mixture was stirred at room temperature for 16 h
and then partitioned between CH2Cl2 and water. The layers were separated and
the aqueous layer was washed with CH2Cl2. The organic extracts were
combined and washed successively with 0.5 N aq HCl and 0.5 N aq NaOH
before being dried over MgSO4, filtered and reduced in volume in vacuo to
give (R)-tert-butyl 1-((2,6-dimethylbenzamido)(phenyl)methyl)-7-azabicyclo
The authors are grateful to Jennifer Van Anda, James Hall, and
physical chemistry group for analytical chemistry support; to
Drs. James Muir, Chad Elmore, Thomas R. Simpson, and Profs. Barry
Lygo, Timothy J. Donohoe for helpful discussion.
References and notes
[2.2.1]-heptane-7-carboxylate of suitable purity as
a solution in CH2Cl2
(300 mL). To this was added 4 M HCl in 1,4-dioxane (130 mL, 520 mmol),
and the reaction mixture was stirred for 16 h before being concentrated in
vacuo. The residue was partitioned between Et2O and 0.5 N aq HCl, and the
layers were separated. The aqueous layer was made basic (to pH 8–9) by
cautious addition of 5 N aq NaOH. The mixture was then extracted with CH2Cl2
(3Â) and the combined organic extracts were dried over MgSO4, filtered and
concentrated in vacuo to give crude (R)-N-(7-azabicyclo[2.2.1]heptan-1-
yl(phenyl) methyl)-2,6-dimethylbenzamide (21) of suitable purity to be used
directly in the next step (57 g, 81% yield). 1H NMR (500 MHz, CDCl3) d 1.20–
1.31 (m, 1H), 1.38–1.51 (m, 5H), 1.62–1.72 (m, 1H), 1.75–1.85 (m, 1H), 2.25 (s,
6H), 3.52–3.57 (m, 1H), 5.42 (d, J = 7.9 Hz, 1H), 6.84 (br s, 1H), 7.00 (d,
J = 7.3 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.27–7.31 (m, 1H), 7.32–7.40 (m, 4H). MS
(+ESI): m/z: 335.2 (M+H)+.
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15. Preparation
of
(R)-2,6-dimethyl-N-((7-methyl-7-azabicyclo-[2.2.1]heptan-1-
yl)(phenyl)methyl)benzamide (1): To a solution of (R)-N-(7-azabicyclo[2.2.1]-
heptan-1-yl(phenyl)methyl)-2,6-dimethyl benzamide (21; 44 g, 132 mmol) in
formic acid (100 mL, 2600 mmol) was added 37% aqueous formaldehyde
(50 mL, 635 mmol) The solution was heated in a 100 °C oil bath for 18 h. An
additional amount of both formic acid (50 mL) and 37% aqueous formaldehyde
solution (25 mL) was added and heating was continued for 18 h. The reaction
mixture was reduced in volume in vacuo and then cautiously treated with 5%
aq NaHCO3 (gas evolution). The resulting basic mixture was extracted with
5. (a) Jiang, W.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C. W.; Arellano, L. M.;
White, N. S.; Tucci, F. C. J. Org. Chem. 2005, 70, 8924; (b) Rajapakse, H. A.; Young,
M. B.; Zhu, H.; Charlton, S.; Tsou, N. N. Tetrahedron Lett. 2005, 46, 8909.

6744
H. Xiong et al. / Tetrahedron Letters 51 (2010) 6741–6744
CH2Cl2 (3Â), and the combined organic extracts were dried over Na2SO4,
azabicyclo[2.2.1]-heptan-1-yl)(phenyl)methyl)benzamide (1; 28.07 g, 61%
yield) with >99% purity. 1H NMR (500 MHz, CDCl3) d 1.02–1.22 (m, 3H),
1.32–1.40 (m, 1H), 1.62 (br s, 1H), 1.67–1.81 (m, 2H), 1.93–2.03 (m, 1H), 2.27
(s, 3H), 2.34 (s, 6H), 3.21 (t, J = 4.7 Hz, 1H), 5.10 (d, J = 4.0 Hz, 1H), 6.60 (br s,
1H), 7.01 (d, J = 7.6 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 7.26–7.28 (m, 1H), 7.32 (t,
J = 7.5 Hz, 2H), 7.36–7.40 (m, 2H). MS (+ESI): m/z: 349.3 (M+H)+.
filtered and concentrated in vacuo. The resulting residue was filtered through
basic alumina (CH2Cl2 and EtOAc wash) and the filtrate was concentrated in
vacuo to give a slightly off-white foam. This was dissolved in hot hexane and
needlelike crystals formed upon cooling. The cooled mixture was allowed to
stand for 18 h, and the crystals were collected by vacuum filtration before
being dried under high vacuum to afford (R)-2,6-dimethyl-N-((7-methyl-7-