A short and efficient synthesis of 3-[2,2,2-trifluoroethyl]hexahydro-2H-1, 4-diazepin-2-one

Article abstract of DOI:10.1055/s-2007-983876

A short, high yielding, five-step synthesis of the pharmaceutically interesting fluorinated heterocycle, 3-[2,2,2-trifluoroethyl]hexahydro-2H-1,4- diazepin-2-one, has been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983876

SHORT PAPER
2779
A Short and Efficient Synthesis of 3-[2,2,2-Trifluoroethyl]hexahydro-2H-1,4-
diazepin-2-one
Synthesis
a
of 3-[2,2,2-
u
T
rifluoroeth
m
H
-1,
e
4-diazepin-2-oneBalsells,* Marjorie Waters, Karl Hansen, Gerard R. Kieczykowski, Zhiguo J. Song
Department of Process Research and Medicinal Chemistry Department, Merck Research Laboratories, P.O. Box 2000,
Rahway, NJ 07065, USA
Fax +1(732)5941499; E-mail: Jaume_Balsells@merck.com
Received 16 February 2007; revised 1 May 2007
O
Abstract: A short, high yielding, five-step synthesis of the pharma-
ceutically interesting fluorinated heterocycle, 3-[2,2,2-trifluoroeth-
yl]hexahydro-2H-1,4-diazepin-2-one, has been developed.
Boc
5 steps
N
N
BOM
H2N
COOMe
1
Key words: lactam, fluorine, alkylation, Michael addition, hydro-
genation
F3C
Boc
1) LDA, THF
–78 °C to 0 °C
O
N
2)
N
BOM
9%
I
CF3
Substituted hexahydro-1,4-diazepin-2-ones are com-
pounds of pharmaceutical interest as dipeptidyl peptidase
inhibitors for the treatment or prevention of diabetes.1
These heterocyclic compounds have been prepared by a
variety of methods including lactamizations,2 intramolec-
ular reductive amination,3 or condensations of diamines
with glyoxal derivatives.3b,4 Introduction of substituents at
C-3 by alkylation5 or aldol condensation6 has also been
demonstrated.
F3C
O
3 steps
HN
NH
2
Scheme 1 Early synthesis of 21a
Amino acid 4 was previously prepared in moderate yield
through multi-step sequences.7 An alternate, shorter ap-
proach, would involve alkylation of ethyl N-(diphenyl-
methylene)glycinate (3).8 This compound is commercially
available and would allow the preparation of 4 in an expe-
dient manner. In contrast to the alkylation of 1, the reac-
tion of 3 with 2,2,2-trifluoro-1-iodoethane afforded the
desired product 6 almost quantitatively. Hydrolysis of 6
with HCl afforded amino ester 4 in 90% overall yield after
crystallization as its hydrochloride salt (Scheme 3).
We recently required an efficient and scalable synthesis of
3-[2,2,2-trifluoroethyl]hexahydro-2H-1,4-diazepin-2-one
(2, Scheme 1), as part of an ongoing research program to
identify dipeptidyl peptidase inhibitors. Compound 2 was
first prepared1 by alkylation of the fully protected hexahy-
dro-2H-1,4-diazepin-2-one (1) with 2,2,2-trifluoro-1-io-
doethane. The synthesis involved nine steps and afforded
a very low yield of the desired heterocycle (Scheme 1). A
racemic synthesis of 2 was acceptable since the stereogen-
ic center of 2 can be easily epimerized to the desired con-
figuration after preparing an appropriate derivative.1d
Conjugate addition of amino ester 4 to acrylonitrile was
examined next. No reaction was observed in aprotic sol-
vents and reactions performed in alcoholic solvents result-
ed in preferential addition of the solvent to acrylonitrile.
The 9% yield observed in the alkylation of 1 was attribut-
ed to decomposition of CF3CH2I in the presence of the
highly basic enolate of 1. Consistent with this observation,
high yields were obtained when more stable electrophiles
such as ethyl iodide or benzyl iodide, were used in the
alkylation of 1.1a Better yields were reported for the alky-
lation of less basic enolates, such as aminomalonate deriv-
atives, with 2,2,2-trifluoroethyl triflate.7d
F3C
CF3CH2I
OR'
R2N
OR'
H2N
O
3
4
O
F3C
H2, Ra-Ni
Our strategy for the synthesis of 2 was to install the tri-
fluoroethyl side chain early in the synthesis by alkylation
of a more acidic glycine equivalent (Scheme 2). Conju-
gate addition of the resulting amino acid 4 to acrylonitrile
would afford nitrile 5. The desired heterocycle 2 could
then be accessed after nitrile reduction and lactamization.
COOR'
CN
CN
HN
5
F3C
HN
F3C
O
lactamization
COOR'
NH
HN
NH2
2
7
Scheme 2 Proposed synthesis of 2 (compounds 2–5 and 7 are depic-
ted with general structures; specific structures are shown in Schemes
3–5)
SYNTHESIS 2007, No. 18, pp 2779–2781
Advanced online publication: 29.08.2007
DOI: 10.1055/s-2007-983876; Art ID: M01107SS
x
x.
x
x
.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

2780
J. Balsells et al.
SHORT PAPER
selectively through the primary amine without the need to
introduce a protecting group on the secondary amine. Di-
azepinone 2 was isolated by crystallization of its hydro-
chloride salt in 86% yield from 7.
CF3
OEt
1) t-BuOK, DMF,
–5 °C
2) CF3CH2I
Ph
Ph
OEt
Ph
N
Ph
N
O
O
6
3
In summary, we have developed a high yielding five step
synthetic process that does not involve the use of protect-
ing groups or chromatographic purifications to prepare
the desired 3-[2,2,2-trifluoroethyl]hexahydro-2H-1,4-di-
azepin-2-one.
F3C
HCl, i-PrOAc
OEt
H2N
⋅HCl
O
4, 90%
Scheme 3 Alkylation of ethyl N-(diphenylmethylene)glycinate (3)
All reactions were performed using reagent grade solvents and they
were used as received. All reagents were used without prior purifi-
cation. All manipulations were carried out under an inert atmo-
sphere of nitrogen. 1H NMR and 13C NMR spectra were recorded in
CD3OD, DMSO-d6 or D2O on either a Bruker DPX400 (400.13
MHz and 100.62 MHz) or a Bruker DRX500 (500.13 MHz and
125.77 MHz) spectrometer. The chemical shifts (d) are reported in
ppm relative to residual CHD2OD (d = 3.31), DMSO-d5 (d = 2.50)
or HDO (d = 4.79) for proton and CD3OD (δ = 49.0) or DMSO-d6
(d = 39.5) for carbon. Melting points were determined on a Büchi
B-545 apparatus and are uncorrected. Combustion analysis was per-
formed by Quantitative Technologies Inc., Whitehouse, NJ (USA).
Next, we decided to study the reactivity of a carboxylic
salt of 4. To this end, ester 4 was hydrolyzed at room tem-
perature in aqueous KOH. In contrast to the poor reactiv-
ity of ethyl ester 4, the corresponding potassium
carboxylate reacted very efficiently with acrylonitrile
(Scheme 4). This two-step sequence can be carried out as
a one-pot operation. During the optimization of the reac-
tion, we found that it was important to adjust the pH of the
reaction with potassium monophosphate prior to the addi-
tion of acrylonitrile in order to suppress basic hydrolysis
of the nitrile moiety. After completion of the conjugate
addition, HCl was added to the reaction and amino acid 5
crystallized from the reaction mixture. Under our opti-
mized conditions, 91% isolated yield of analytically pure
5 was obtained.
Ethyl 2-Amino-4,4,4-trifluorobutanoate Hydrochloride (4)
To DMF (2.0 L) was added t-BuOK (176.3 g, 1.57 mol, 1.05 equiv)
at 0 °C and the mixture was stirred for 10 min to dissolve the base.
Ethyl N-(diphenylmethylene)glycinate (3; 399.5, 1.49 mol) was
added at 0 °C in portions over 10 min. After aging 30 min, 2,2,2-tri-
fluoro-1-iodoethane (362.6 g, 1.73 mmol, 1.16 equiv) was added
over 10 min maintaining the temperature at –5 °C to 5 °C. The re-
action was aged at this temperature for 6 h and then allowed to
warm to r.t. The mixture was partitioned between 5% aq NH4Cl (2
L) and i-PrOAc (4 L). The layers were separated and the organic
was washed with aq 2% NaCl (3 × 2 L). Concd HCl (154 mL, 1.9
mol) was added to the organic layer. The resulting solution was con-
centrated in vacuo and flushed with of fresh i-PrOAc (8 L) to azeo-
tropically dry the solution resulting in the precipitation of the HCl
salt. The final slurry was concentrated to 2 L. The solid was isolated
by filtration, washed with i-PrOAc (3 × 500 mL) and dried on the
filter under N2. Ethyl 2-amino-4,4,4-trifluorobutanoate hydrochlo-
ride (4) was obtained as an off-white solid; yield: 297.4 g (90%); mp
154 °C.
F3C
OH
O
1) 2.1 equiv KOH, H2O,
1 h, 25 °C
F3C
H2N
HN
OEt
⋅HCl
2) KH2PO4,
12 h, 25 °C
CN
O
CN
4
5, 91%
Scheme 4 Conjugate addition of 4 to acrylonitrile
Hydrogenation of nitrile 5 was accomplished using Ra-Ni
in methanol (Scheme 5). Sodium methoxide was used as
a co-catalyst for the nitrile reduction. Under these condi-
tions, 2-[(3-aminopropyl)amino]-4,4,4-trifluorobutanoic
acid (7) was obtained in 95% assay yield and carried to the
next step without isolation.
1H NMR (CD3OD): d = 1.33 (t, J = 7.1 Hz, 3 H), 2.90–3.10 (m, 2
H), 4.34 (q, J = 7.1 Hz, 2 H), 4.48 (dd, J = 6.7, 5.2 Hz, 1 H), 4.86
(br s, 3 H).
13C NMR (CD3OD): d = 12.7, 33.5 (q, J = 30 Hz), 47.3, 63.0, 125.1
(q, J = 280 Hz), 166.9.
Lactamization was accomplished using EDC. Adding cat-
alytic amounts of HOBt and collidine to the reaction mix-
ture increased the reaction rate. The reaction occurred
Anal. Calcd for C6H11ClF3NO2: C, 32.52; H, 5.00; N, 6.32. Found:
C, 32.28; H, 4.83; N, 6.43.
F3C
OH
O
2-[(2-Cyanoethyl)amino]-4,4,4-trifluorobutanoic Acid (5)
2-Amino-4,4,4-trifluorobutanoate hydrochloride (4; 20.06 g, 90.5
mmol) was dissolved in aq 1.9 N KOH solution (100 mL) and the
mixture aged at r.t. for 4 h giving complete hydrolysis. The pH was
adjusted to 9.9 by addition of 1 M KH2PO4 solution (11 mL). Acry-
lonitrile (9.0 mL, 136.7 mmol) was added and the solution aged
overnight. Concd HCl (8.4 mL, 101.4 mmol) was added dropwise
to the reaction giving a thick, white slurry. The solid was isolated
by filtration, washed with H2O (3 × 35 mL) and MeCN (100 mL),
and dried on the filter under N2. The product 5 was obtained as a
white solid; yield: 17.4 g (91%); mp 226 °C (dec.).
F3C
OH
O
1) NaOMe
HN
HN
2) Ra-Ni (20 wt%),
MeOH, H2, 6 atm
NH2
7, 95%
CN
5
1) 1 equiv EDC,
F3C
HN
0.2 equiv HOBt,
0.2 equiv collidine
O
NH
2) HCl–i-PrOAc
⋅HCl
1H NMR (DMSO-d6): d = 2.50–2.70 (m, 5 H), 2.80–2.85 (m, 1 H),
3.45 (t, J = 6.5 Hz, 1 H), 4.10 (br s, 1 H), 7.90 (br s, 1 H).
2, 86%
Scheme 5 Hydrogenation and EDC cyclization
Synthesis 2007, No. 18, 2779–2781 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of 3-[2,2,2-Trifluoroethyl]hexahydro-2H-1,4-diazepin-2-one
2781
13C NMR (DMSO-d6): d = 18.4, 36.3 (q, J = 25 Hz), 43.1, 55.4,
120.2, 126.8 (q, J = 275 Hz), 173.9.
Anal. Calcd for C7H13F3N2O2: C, 39.25; H, 6.12; N, 13.08. Found:
C, 38.99; H, 6.21; N, 13.10.
Anal. Calcd for C7H9F3N2O2: C, 40.01; H, 4.32; N, 13.33. Found:
C, 40.04; H, 4.09; N, 13.26.
References
3-[2,2,2-Trifluoroethyl]hexahydro-2H-1,4-diazepin-2-one
Hydrochloride (2)
(1) (a) Biftu, T.; Liang, G.-B.; Qian, X.; Weber, A. E.; Feng, D.
D. PCT Int. Appl. WO 2004037169, 2004; Chem. Abstr.
2004, 140, 391494. (b) Biftu, T.; Feng, D. D.; Liang, G.-B.;
Qian, X. PCT Int. Appl. WO 2004103276, 2004; Chem.
Abstr. 2005, 142, 23098. (c) Biftu, T.; Feng, D. D.; Gao, Y.-
D.; Singh, S.; Weber, A. E. PCT Int. Appl. WO 2006009886,
2006; Chem. Abstr. 2006, 144, 171018. (d) Biftu, T.; Song,
Z. J.; Zhang, F.; Rosner, T.; Hansen, K.; Armstrong, J. D. III
PCT Int. Appl. WO 2006065826, 2006; Chem. Abstr. 2006,
145, 63148.
(2) (a) Han, Y.; Mierke, D. F.; Chorev, M. Biopolymers 2002,
64, 1. (b) Breslin, H. J.; Kukla, M. J.; Kromis, T.; Cullis, H.;
De Knaep, F.; Pauwels, R.; Andries, K.; De Clerq, E.;
Janssen, M. A. C.; Paul, A. J. Bioorg. Med. Chem. 1999, 7,
2427. (c) Weitz, I. S.; Pellegrini, M.; Mierke, D. F.; Chorev,
M. J. Org. Chem. 1997, 62, 2527.
A solution of NaOMe in MeOH (417 g, 25% w/w, 1.93 mol) was
added to a suspension of nitrile 5 (270 g, 1.28 mol) in MeOH (1.2
L). After all solids had dissolved, Ra-Ni 2800® (62.5 g) was added
and the vessel was pressurized with H2 at 6 atm (90 psi) for 12 h.
The catalyst was filtered off, washed with MeOH (600 mL), and the
resulting mixture assayed at 1.21 mol of 7 (95% yield). The solution
was diluted with MeOH to a final volume of 3.5 L. To this solution
was charged concd HCl (182 g, 37% w/w in H2O, 1.85 mol), HOBt
(32.6 g, 0.24 mol), collidine (28.4 g, 0.24 mol), and EDC-HCl (249
g, 1.3 mol). After aging the resulting mixture for 5 h, the batch was
concentrated at reduced pressure, diluted with aq 10% NaCl solu-
tion (3 L) and extracted with MTBE (4 × 1 L). The organic cuts were
combined, dried and concentrated at reduced pressure. Assay
showed 1.1 mol of lactam 2 (90% yield). The residue was dissolved
in i-PrOAc (1.0 L) and HCl (305 mL, 5 N in i-PrOAc) was added
until pH 2. The resulting slurry was filtered and the solid washed
with cold i-PrOAc. The hydrochloride of lactam 2 was obtained as
a white solid; yield: 242 g (86%); mp 228 °C (dec.).
(3) (a) Nakajima, N.; Isobe, T.; Irisa, S.; Ubukata, M.
Heterocycles 2003, 59, 107. (b) Knapp, S.; Moriello, G. J.;
Nandan, S. R.; Emge, T. J.; Doss, G. A.; Mosley, R. T.;
Chen, L. J. Org. Chem. 2001, 66, 5822.
(4) Chassonery, D.; Chastrette, F.; Chastrette, M.; Blanc, A.;
1H NMR (CD3OD): d = 1.90–2.20 (m, 2 H), 2.70–2.90 (m, 1 H),
3.30–3.70 (m, 5 H), 4.53 (dd, J = 3.9, 7.8 Hz, 1 H), 4.90 (br s, 3 H).
13C NMR (CD3OD): d = 23.9, 32.9 (q, J = 30 Hz), 38.6, 48.5, 52.8,
125.3 (q, J = 270 Hz), 167.0.
Mattioda, G. Bull. Soc. Chim. Fr. 1994, 131, 188.
(5) Pohlmann, A.; Guillaume, D.; Quirion, J.-C.; Husson, H.-P.
Tetrahedron Lett. 1997, 38, 5809.
(6) Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett 2004, 1443.
(7) (a) Walborsky, H. M.; Baum, M. E. J. Org. Chem. 1956, 21,
538. (b) Steglich, W.; Heininger, H. U.; Dworschak, H.;
Weygand, F. Angew. Chem., Int. Ed. Engl. 1967, 6, 807.
(c) Maki, Y.; Inukai, K. Yuki Gosei Kagaku Kyokaishi 1976,
34, 722; Chem. Abstr. 1977, 87, 68600. (d) Tsushima, T.;
Kawada, K.; Shoichi, I.; Uchida, N.; Shiratori, O.; Higaki, J.;
Hirata, M. Tetrahedron 1988, 44, 5375. (e) Schedel, H.;
Dmowski, W.; Burger, K. Synthesis 2000, 1681.
Anal. Calcd for C7H12ClF3N2O: C, 36.14; H, 5.20; N, 12.04. Found:
C, 35.93; H, 5.01; N, 11.83.
Intermediate Amine 7
An analytical sample of the intermediate 7 was obtained after con-
centration of the crude hydrogenation mixture and two recrystalli-
zations from MeOH; mp 196 °C (dec.).
1H NMR (D2O): d = 1.70–1.80 (m, 2 H), 2.35–2.65 (m, 4 H), 2.99
(t, J = 7.2 Hz, 2 H), 3.26 (t, J = 6.9 Hz, 1 H), 4.70 (br s, 4 H).
13C NMR (D2O): d = 26.2, 36.4 (q, J = 30 Hz), 38.3, 44.6, 58.0,
126.2 (q, J = 275 Hz), 179.5.
(8) (a) O’Donnell, M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron
Lett. 1978, 19, 2641. (b) Stork, G.; Leong, A. Y. W.;
Touzin, A. M. J. Org. Chem. 1976, 41, 3491.
(c) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506.
Synthesis 2007, No. 18, 2779–2781 © Thieme Stuttgart · New York