Improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one, a building block for γ-secretase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2009.08.090

An improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (1), involving a selective crystallization of epimeric menthylcarbamates for the resolution step followed by simultaneous cleavage of the carbamate and the lactam protecting group is desc

Full text of DOI:10.1016/j.tetlet.2009.08.090

Tetrahedron Letters 50 (2009) 6380–6382
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one,
a building block for
c
-secretase inhibitors
b
b
c
d
Fabienne Hoffmann-Emery a, , Roland Jakob-Roetne , Alexander Flohr , Fritz Bliss , Reinhard Reents
*
a F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Process Research & Synthesis, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
b F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Discovery Chemistry, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
c F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Kilolaboratory, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
d F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Process Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2009
Revised 31 July 2009
Accepted 26 August 2009
Available online 1 September 2009
An improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (1), involving a selective crystal-
lization of epimeric menthylcarbamates for the resolution step followed by simultaneous cleavage of the
carbamate and the lactam protecting group is described. Epimerization conditions of the undesired
epimer have also been determined.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aminodibenzoazepinone
Resolution
Diastereoselective crystallization
Menthylcarbamate
Epimerization
1. Introduction
2. Synthesis of racemic amine 7
A main pathological hallmark of Alzheimer’s disease is the for-
mation of abnormal and characteristic deposits of amyloid-b (Ab)
peptides in the brain. Ab-peptides are 40–42 amino acid peptides
generated from the amyloid-b precursor protein by sequential pro-
Two main approaches have been reported for the preparation of
dibenzoazepinone 4. The first, a two-step route, comprises the
cyclization of N-biphenyl-2-yl-2-chloro-acetamide 3 via a Fri-
edel–Crafts alkylation.5 Alternatively, 2-bromoaniline was coupled
to 2-iodophenylacetonitrile and cyclization to the lactam was
achieved by saponification6 or via a five-step sequence based on
an intramolecular Staudinger-aza-Wittig reaction.7 We chose to
use the first route after improving the cyclization conditions
(Scheme 1). Commercially available 2-aminobiphenyl was acylated
with chloroacetylchloride in the presence of triethylamine at room
temperature, affording 94% crude 3. Ring closure to dibenzoazepi-
none 4 was achieved by heating 3 in the presence of 2.2 equiv of
AlCl3 in 1,3-dichlorobenzene at reflux for 9 h. After precipitation
by the addition of water, 4 was isolated in 76% yield. Attempts to
reduce the amount of AlCl3 revealed that a minimum of 2.0 equiv
was necessary for the reaction to run to completion (after 24 h,
teolysis by the b-secretase and c-secretase enzymes. The ‘amyloid
cascade hypothesis’ of Alzheimer’s disease postulates a causative
role to the accumulation of these Ab-peptides in brain tissue.1
Low molecular weight inhibitors of the
suppress the production of Ab-peptides in vivo and inhibit the
deposition of brain amyloid in mouse models. Several -secretase
c-secretase enzyme can
c
inhibitors have been described that contain (S)-7-amino-5H,7H-
dibenzo[b,d]azepin-6-one 1 as core structure (Fig. 1). The essential
properties are then conferred by the side-chain attached to the
amino group and the substituent on the nitrogen of the lactam
ring.2
The syntheses reported for 1 rely on the separation of the enan-
tiomers via chiral HPLC2a or chromatography of derived epimers.3
Resolution of the N-methylated lactam 1 has been reported by
O
H
crystallization with di-p-toluyl-D
-tartaric acid monohydrate.4 We
N
NH2
report now an improved synthesis of 1 involving crystallization
for the resolution step.
1
* Corresponding author. Tel.: +41 61 6882743; fax: +41 61 6881670.
E-mail address: fabienne.hoffmann-emery@roche.com (F. Hoffmann-Emery).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.090

F. Hoffmann-Emery et al. / Tetrahedron Letters 50 (2009) 6380–6382
6381
O
O
ClCOCH2Cl (1.1 eq.),
Et3N (1.1 eq.),
CH2Cl2, rt, 2 h
H
N
H
N
NH2
AlCl3 (2.2 eq.),
1,3-Cl2C6H4, reflux, 9
Cl
94 % (crude)
76 % (cryst.)
4
3
2
Cl
MeO
(1.1eq.)
quant.
(crude)
KOH (1.1 eq.),
Bu4NBr (0.1 eq.),
THF, rt, 3 h
H2 (10 bar),
O
O
O
N
iAmONO (2.0 eq.),
tBuOK (1.5 eq.),
tol., 0 °C, 2 h
Pd/C (0.034 eq.),
HCl 2N (2.0 eq.),
MeOH, 50 °C, 19 h
OH
O
O
O
N
NH2
.HCl
N
N
90% (crude)
85% (cryst.)
7.HCl
5
6
1. (-)- MenthOCOCl (1.1 eq.)
K2CO3 aq. (2.5 eq.),
THF, rt, 70 min.
2. heptane
O
O
H
CF3CO2H (10 eq.),
CF3SO3H (3 eq.),
CH2Cl2, reflux, 2 h
O
H
N
N
N
NH2
O
O
cryst. (42%)
d.r. = 99.9:0.1
94% (cryst.)
8
1
mother liquors
(51%)
O
N
1. LDA (3.0 eq.), THF,
-15 - 0 °C, 3 h
2. EtOH, 0 - 10 °C, 30 min.
O
H
38% (cryst.)
d.r. = 99.9:0.1
N
O
O
9
Scheme 1. Synthesis of 1 with resolution via crystallization.
only 0.3% starting material 3 remaining vs 28% with 1.5 equiv
AlCl3). Two approaches have been described for the N-alkylation
of the lactam and the introduction of the amino group in the alpha
position of the carbonyl group.4 One route applied a sequence of
iodination, substitution by azide, reduction, then lactam alkylation
whereas the other commenced with alkylation of the lactam fol-
lowed by nitrosation at C(7), and reduction. We applied the latter,
safer option and optimized the reaction conditions. The use of
aqueous KOH and a catalytic amount of Bu4NBr in THF was pre-
ferred to NaH in DMF for the protection of the lactam function of
4, because of easier handling of the base and lower toxicity of
the solvent. Crude p-methoxybenzyllactam 5 was obtained quanti-
tatively. On a kg-scale, 5 was filtered through a pad of silica gel
with the aid of CH2Cl2 then crystallized from CH2Cl2/TBME afford-
ing 70% of pure 5. The usually reported base, KHMDS employed
with isoamylnitrite for the nitrosylation of 5 was replaced by
cheaper and easier to handle tBuOK providing 90% crude oxime
6. Crystallization of the crude product from EtOAc/n-hexane affor-
ded 63% of 6. However, this purification was not mandatory and
the crude oxime was smoothly hydrogenated at 10 bar H2 in the
presence of 2 N HCl/MeOH and Pd/C at 50 °C. Racemic amine 7
was crystallized as the HCl salt to be isolated in 85% yield from
MeCN or in 73% yield from EtOAc. Despite the lower yield, the lat-
ter solvent was preferred for larger scale work for economical, eco-
logical, and toxicity reasons.
contrast, the corresponding epimeric menthylcarbamates 8 and 9
displayed differing crystallization behavior. Thus, the crude mix-
ture of 8 and 9 obtained after the treatment of 7 with (ꢀ)-menthyl-
chloroformate and pyridine in CH2Cl2 afforded 8 in 44% yield and
with a dr = 97.5:2.5 after crystallization from n-heptane. Further-
more, when the menthylcarbamates were generated in the pres-
ence of aqueous K2CO3 in THF, 8 precipitated directly from the
reaction mixture upon addition of n-heptane and was isolated in
42% yield with a dr = 99.9:0.1.9,10 Concentration of the mother li-
quors furnished 51% 9 with a dr = 4.4:95.6. When the reaction
was performed with hydrochloride salt of 7, 2.5 equiv of aqueous
K2CO3 was required, whereas 2.0 equiv was sufficient when the
free amine of 7 was used. The menthylcarbamate and p-methoxy-
benzyl group were cleaved simultaneously by stirring 8 in CH2Cl2
in the presence of an excess of CF3CO2H and CF3SO3H in CH2Cl2
at reflux for 2 h. After crystallization from TBME/n-heptane, 1
was isolated in 94% yield.11 Thus, 1 could be synthesized in a se-
ven-step sequence, involving four crystallizations as purification
operations, and with 22% overall yield on a laboratory scale. In a
3 kg campaign, an overall yield of 13% was attained.
4. Epimerization of 9
In order to improve the overall yield of 8, we examined the race-
mization at C-7 of the epimer 9. Treatment of 9 with 3 equiv LDA at
ꢀ75 °C for 2.5 h followed by quenching with MeOH did not lead to
any epimerization. However, treatment of 9 (dr 10.1:89.9) with
3 equiv LDA at ꢀ15 to 0 °C for 3 h followed by quenching with EtOH
at 0–10 °C, afforded 8 in 38% yield with a dr = >99.9:0.1 after
3. Resolution of racemic amine 7
Attempts to crystallize the free amine of 7 selectively with chi-
ral acids failed to afford any useful enantiomeric enrichment.8 In

6382
F. Hoffmann-Emery et al. / Tetrahedron Letters 50 (2009) 6380–6382
7. Fuwa, H.; Okamura, Y.; Morohashi, Y.; Tomita, T.; Iwatsubo, T.; Kan, T.;
Fukuyama, T.; Natsugari, H. Tetrahedron Lett. 2004, 45, 2323–2326.
8. Optically active acids used were:
-(+)-tartaric acid, (ꢀ)-dibenzoyl-
acid, (+)-dipivaloyl-
-tartaric acid, (S)-(+)-mandelic acid, (S)-(ꢀ)-pyroglutamic
acid,
-(ꢀ)-quinic acid, (S)-(ꢀ)-N-(1-phenylethyl)phthalamic acid, (+)-mono-
(1S)-(+)-menthyl phthalate, (ꢀ)-N-acetyl- -glutamic acid, (1R,3S)-(+)-
camphoric acid, (1S)-(+)-camphorsulfonic acid, (R)-(+)-2-(4-hydroxyphenoxy)
propionic acid, and (S)-(+)-4-isobutyl- -methylphenylacetic acid.
O
L
L-tartaric
D
D
O
H
N
H
L
N
N
N
a
O
O
9. Hoffmann-Emery, F.; Jakob-Roetne, R. WO2008/145525.
10. Representative procedure to 8: 14.4 kg of 7.HCl (37.8 mol) were suspended in
54 L THF at room temperature and a solution of 13.1 kg (93.7 mol, 2.5 equiv)
K2CO3 in 72 L water was added over 15 min. After stirring for 20 min, 9.36 kg
(ꢀ)-menthylchloroformate (41.9 mol, 1.1 equiv) were added over 15 min so
that the temperature did not exceed 40 °C. The feeding vessel was rinsed with
5 L THF. The reaction mixture was stirred for 70 min at room temperature,
warmed to 65 °C and 200 L n-heptane were added over 2 h. After the addition
of 60 L n-heptane, crystallization commenced. The suspension was cooled to
room temperature over 6 h and stirred for a further 12 h. The precipitate was
filtered, washed with 18 L water followed by 70 L n-heptane, then dried at
10
O
O
O
H
H
O
N
N
N
45 °C under 20 m bar yielding 8.43 kg (42.4%)
8
as white crystals of
N
dr = 99.9:0.1. Mp = 203–209 °C; ½a D20
ꢁ
ꢀ158.4 (c = 1.45, CHCl3); IR (Nujol) m
O
3402, 2923, 2854, 1709, 1655, 1499, 1452, 1396, 1377, 1244, 1193, 1049,
756 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.53–7.27 (m, 8H), 6.71 (d, 2H), 6.60 (d,
;
2H), 6.41 (d, 1H), 5.25–5.17 (m, 2H), 4.76 (d, 1H), 4.51 (m, 1H), 3.70 (s, 3H),
2.07–1.97 (m, 2H), 1.66 (d, 2H), 1.50–1.37 (m, 2H), 1.08–1.02 (m, 2H), 0.90 (d,
6H), 0.75 (d, 3H); ISP-MS (m/z) 549 (M+Na+, 9), 527 (M+H+, 100).
11
A sample of the mother-liquor was purified by flash chromatography (eluent:
Figure 2.
CH2Cl2/EtOAc 98:2) to afford
a
pure sample of
9
as
a
white foam of
3413, 3326, 2921,
1H NMR
dr = >99.9:0.1. ½a D20
ꢁ
+74.66 (c = 0.999, CHCl3); IR (Nujol) m
2855, 1720, 1666, 1513, 1486, 1456, 1377, 1246, 1177, 1049 cmꢀ1
;
(300 MHz, CDCl3) d 7.51–7.35 (m, 8H), 6.72 (d, 2H), 6.60 (d, 2H), 6.40 (d, 1H),
5.25–5.16 (m, 2H), 4.67 (d, 1H), 4.53 (m, 1H), 3.70 (s, 3H), 2.11–1.94 (m, 2H),
1.70–1.63 (m, 2H), 1.46–1.37 (m, 2H), 1.07–0.97 (m, 2H), 0.96 (d, 3H), 0.88 (d,
3H), 0.81 (d, 3H); ISP-MS (m/z) 549 (M+Na+, 20), 527 (M+H+, 100), 389 (34), 345
(49).
work-up and crystallization from THF/n-heptane.12 Including this
epimerization loop, the overall yield of 1 from 2 was improved to
30%.
Other epimerization attempts failed. Stirring 9 in neat DBU at
room temperature, in toluene in the presence of tBuOK, in o-xylene
with DABCO or phosphazen-base P1-t-Bu at reflux did not lead to
changes in the diastereoisomeric ratio of the reaction mixture. Fi-
nally, heating 9 at 135 °C in neat DBU for 24 h afforded 23% urea
11. Representative procedure to 1: 8.43 kg of 8 (16.0 mol) were dissolved in 134 L
CH2Cl2 and cooled to 0 °C. 18.6 kg trifluoroacetic acid (160 mol) were added,
the feeding vessel rinsed with 10 L CH2Cl2, 7.4 kg trifluoromethanesulfonic acid
(48.3 mol) were added slowly, so that the temperature never exceeded 5 °C
(caution: exothermic) and the feeding vessel was rinsed with 10 L CH2Cl2. The
reaction mixture was stirred for 10 min at 0 °C and 2 h at reflux. After cooling
to room temperature, 140 L water and 22 L acetic acid were added. The
biphasic mixture was stirred for 15 min at room temperature and the phases
were separated. The organic phase was diluted with 6.7 L acetic acid and
extracted with 45 L water then further diluted with 3.4 L acetic acid and
extracted with 45 L water. Eighty-four litres of CH2Cl2 were added to the
combined aqueous phases which were adjusted to ca. pH 11 by the addition
over 1 h of 80 L 28% aqueous NaOH with stirring. After separation of the
phases, the aqueous layer was further extracted with two portions of 45 L
CH2Cl2. The combined organic layers were concentrated under reduced
pressure at 50 °C to a volume of 17 L and the solvent was exchanged at
constant volume with 70 L tert-butyl-methyl-ether, inducing crystallization.
The suspension was cooled to 0 °C and 42 L n-heptane were added within
20 min. After 1 h at 0 °C, the suspension was filtered, the crystallization vessel
rinsed with 10 L n-heptane precooled to 0 °C and the precipitate washed with
20 L n-heptane precooled to 0 °C affording, after drying at 45 °C under 1 mbar,
10 resulting from reaction with N-(3-aminopropyl)-e-caprolactam,
the precursor of DBU and 28% of urea 11 (Fig. 2).
In conclusion, we have described an improved synthesis of 1,
using only crystallizations for purification or separation of enanti-
omers. 1 was obtained in 7 steps and 22% overall yield. Including
epimerization of the undesired isomer the overall yield was further
increased to 30%.
Acknowledgments
The authors thank Jean-Pierre Gaertner, Joseph Wuhrlin, Gino
Semadeni, and Kathrin Schneider for skillful experimental work,
Marcel Althaus, Brigitte Horisberger, and Jean-Claude Jordan for
analytical support, and the Analytical Services of F. Hoffmann-La
Roche Ltd for providing and interpreting the physical data of all
compounds described. We thank S. Wang for performing the
hydrogenation. The careful reading of the Letter by Pius Waldmeier
and Paul Spurr is gratefully acknowledged.
3.4 kg (94%) 1 as white crystals of dr = 99.85:0.15. Mp = 164.5–168 °C; ½a D20
ꢁ
ꢀ216.6 (c = 0.991, CH3OH); IR (Nujol)
m 3368, 3206, 2926, 2855, 1674, 1584,
1466, 756, 730 cmꢀ1 1H NMR (400 MHz, CDCl3) d 8.30 (sbr, 1H), 7.70–7.63 (m,
;
2H), 7.52–7.31 (m, 5H), 7.14 (dd, 1H), 4.38 (s, 1H), 2.03 (sbr, 2H); ISP-MS (m/z)
449 (2M+H+, 11), 225 (M+H+, 100).
12. Representative procedure of the racemization of 9 and isolation of 8: A solution of
32.3 g mother liquor concentrate (61 mmol, dr = 10.1:89.9) in 130 mL THF was
cooled to ꢀ15 °C and 92 mL LDA (2 M solution in THF/heptane/methylbenzene,
184 mmol, 3 equiv) were added over 30 min so that the temperature did not
exceed ꢀ10 °C. The dropping funnel was rinsed with 7 mL THF and the reaction
mixture was stirred at 0 °C for 3 h. Fourteen millilitres of EtOH were added
dropwise at 0–10 °C and stirring was continued for 30 min. 44 mL EtOAc were
added to the clear solution and after cooling to ꢀ15 °C, 50 mL aq 25% HCl
(385 mmol, 6.3 equiv) were added bringing the aqueous phase to pH 1–2. After
separating the phases, the organic layer was washed with 44 mL aq 3 N HCl
and twice with 105 mL water. The organic phase was concentrated under
reduced pressure and the residue was taken up in 65 mL THF. To this orange
suspension, 224 mL n-heptane were added dropwise at 30–40 °C and the
suspension was further stirred at room temperature for 1 h. The precipitate
was filtered, washed with three portions of 44 mL n-heptane, and dried under
reduced pressure at 50 °C affording 12.2 g (38%) 8 as yellow-white crystals of
dr = >99.9:0.1.
References and notes
1. Beher, D.; Graham, S. L. Exp. Opin. Investig. Drugs 2005, 14, 1385.
2. (a) Flohr, A.; Galley, G.; Jakob-Roetne, R.; Kitas, E.; Peters, J.-W.; Wostl, W.
WO2005/023772.; (b) Audia, J. E.; Dressman, B. A.; Shi, Q. US6528505.
3. Fauq, A. H.; Simpson, K.; Maharvi, G. M.; Giolde, T.; Das, P. Bioorg. Med. Chem.
Lett. 2007, 17, 6392–6395.
4. Audia, J. E.; Porter, W. J.; Scott, W. L.; Stack, D. R.; Thompson, R. C. WO01/34571.
5. (a) Wiesner, K.; Valenta, Z.; Manson, A. J.; Stonner, F. W. J. Am. Chem. Soc. 1955,
675–682; (b) Brown, R. F. C.; Butcher, M. Tetrahedron Lett. 1971, 12, 667–670.
6. Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. J. Org. Chem. 2002, 67, 1199–
1207.