Efficient preparation of ((3-chloro-2-fluorophenyl)-[7-methoxy-8-(3- morpholin-4-yl-propoxy)-10,11-dihydro-5-oxa-2,4,11-triazadibenzo(a,d) cyclohepten-1-yl]-amine) for in-vivo study

Article abstract of DOI:10.1080/00397910500377479

An improved route for the preparation of highly functionalized 5,6-dihydropyrimido[4,5-b][1,4]oxazepine 1a in multigram quantities was developed. This new methodology was highlighted by the proper methoxy disposition via a regioselective methylation of 2,4,5-trihydroxy-benzaldehyde followed by a magnesium sulfate-promoted cyclization. Copyright Taylor & Francis LLC.

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Efficient Preparation of
((3‐Chloro‐2‐fluoro‐phenyl)‐[7‐methoxy‐8‐(3‐mor
for In‐Vivo Study
Hu Liu a , Leon M. Smith II a , Yunyu Mao a , Weitao Pan a , Yong‐Jiang Xu a
Sabina Burdzovic‐Wizeman a , Matthew A. J. Duncton a & Wai C. Wong a
,
a Department of Chemistry, ImClone Systems Incorporated, Brooklyn, New
York, USA
Version of record first published: 19 Aug 2006.
To cite this article: Hu Liu, Leon M. Smith II, Yunyu Mao, Weitao Pan, Yong‐Jiang Xu, Sabina
Burdzovic‐Wizeman, Matthew A. J. Duncton & Wai C. Wong (2006): Efficient Preparation of
((3‐Chloro‐2‐fluoro‐phenyl)‐[7‐methoxy‐8‐(3‐morpholin‐4‐yl‐propoxy)‐10,11‐dihydro‐5‐oxa‐2,4,11‐triaza‐dibenzo(a,d
for In‐Vivo Study, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:3, 347-354
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Synthetic Communicationsw, 36: 347–354, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500377479
Efficient Preparation of ((3-Chloro-2-fluoro-
phenyl)-[7-methoxy-8-(3-morpholin-4-yl-
propoxy)-10,11-dihydro-5-oxa-2,4,11-triaza-
dibenzo(a,d)cyclohepten-1-yl]-amine)
for In-Vivo Study
Hu Liu, Leon M. Smith II, Yunyu Mao, Weitao Pan,
Yong-Jiang Xu, Sabina Burdzovic-Wizeman,
Matthew A. J. Duncton, and Wai C. Wong
Department of Chemistry, ImClone Systems Incorporated,
Brooklyn, New York, USA
Abstract: An improved route for the preparation of highly functionalized 5,6-dihydro-
pyrimido[4,5-b][1,4]oxazepine 1a in multigram quantities was developed. This new
methodology was highlighted by the proper methoxy disposition via a regioselective
methylation of 2,4,5-trihydroxy-benzaldehyde followed by a magnesium sulfate–
promoted cyclization.
Keywords: Oxazepine, EGFR
INTRODUCTION
Recently, the 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepines 1 were described
by us as potent EGFR inhibitors.[1] Additional attractive features of this
scaffold also include its good PK and kinase selectivity profile. Our
Received in the USA July 28, 2005
Address correspondence to Hu Liu, Department of Chemistry, ImClone Systems
Inc., 710 Parkside Avenue, Brooklyn, NY 11226, USA. Tel./Fax: 718-633-0856;
E-mail: huliu205@yahoo.com
347

348
H. Liu et al.
continued interests in this field required the preparation of multigram quan-
tities of compound 1a for preclinical studies.
Prior to our work, there was only one reported synthesis of the 5,6-dihydro-
pyrimido[4,5-b][1,4]oxazepines 5,[2] with R3 being limited to hydrogen or
halogen (Scheme 1). Although this route was suitable for our early-phase
SAR study, it soon became obvious to us that the much more complicated
substitution pattern on 1a necessitated modifications of the reported synthetic
routes and conditions. In this work, we report an improved synthesis of the
oxazepines 1 that led to the preparation of multigram quantities of 1a.
RESULTS AND DISCUSSION
A simple retrosynthetic analysis revealed that the morpholine-containing
solubilizing chain in 1a could be introduced in the later steps of the
synthesis (Scheme 2). Furthermore, the preparation of the key intermediate
6 required condensation between the readily available pyrimidine 2a and
the benzaldehyde 7 with the desired hydroxy and methoxy disposition.
The preparation of the two coupling precursors 2a and 7 were shown
in Scheme 3. Chloride substitution on 8 with the corresponding aniline
afforded 2a in a 68% yield. Although there was one report on the selective alky-
lation of 2,4-dihydroxybenzaldehyde under basic conditions,[3] the selective
methylation of 2,4,5-trihydroxy-benzaldehyde 9 was not straightforward.
Optimized methylation conditions required cesium carbonate, as base, and
DMF, as solvent, that led to 7 in a 53% yield and excellent purity after
simple workup. It is noteworthy to point out that potassium carbonate as
Scheme 1.

Preparation of Functionalized 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepine
349
Scheme 2.
base gave 7 in only 20–30% yields. The observed high regioselectivity in the
methylation step might be caused by a cesium-mediated chelation effect
between the aldehyde and the 2-hydroxy moieties in 9.
With both 2a and 7 in hand, we then shift our attention to the coupling
reaction between them (Scheme 4). A brief survey of conditions indicated
that the imine formation step was crucial for the cyclization to proceed, as
magnesium sulfate as additive in the presence of catalytic amount of HCl
afforded 6 in a 88% yield, and also with acceptable purity after simple
workup, followed by filtration and wash of the solid formed. On the other
hand, when only sodium hydride was used as additive, 6 was obtained in a
70% yield and in less purity. Only decomposition occurred when the
condensation was carried out without any additives.
Scheme 3.

350
H. Liu et al.
Scheme 4.
Phenol 6 was then treated with 4-(3-chloro-propyl)-morpholine 11[4] in
the presence of sodium iodide and potassium carbonate to afford 12 in a
68% yield after chromatography (Scheme 5). Although the imine in 12 was
reduced readily with sodium borohydride to afford the crude 1a, the workup
conditions proved to be crucial to the yield of 1a because of a formed
boron complex. The optimized workup conditions used a combination of
HCl (1,4-dioxane solution) queching, NH3 (ethanol solution) neutralization,
and recrystallization, followed by column chromatography to afford 1a in
83% yield.
In summary, an improved route for the preparation of highly functiona-
lized 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepine 1a in multigram quantities
was developed. This new route was highlighted by the proper methoxy dispo-
sition via a regioselective methylation of 2,4,5-trihydroxy-benzaldehyde 9,
followed by a magnesium sulfate–promoted cyclization.
Scheme 5.

Preparation of Functionalized 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepine
351
EXPERIMENTAL
General
Unless stated otherwise, temperatures are given in degrees Celsius (8C);
procedures carried out at room or ambient temperature are carried out at a
temperature in the range of about 188C to about 258C; organic solutions
were dried over anhydrous sodium sulfate; and evaporation of solvent was
performed using a rotary evaporator under reduced pressure (600–4000
Pascals 4.5–30 mm Hg) with a bath temperature of up to 608C. The final
products were characterized using nuclear magnetic resonance (NMR)
spectra and mass spectra. Elemental analysis was performed when possible.
When present, NMR data is in the form of delta values for major diagnostic
protons, given in parts per million (ppm) relative to tetramethylsilane
(TMS) as an internal standard, determined at 300 MHz with perdeuterio
dimethyl sulfoxide (DMSO-d6) as solvent unless otherwise indicated.
Chemical symbols have their usual meanings and SI units and symbols are
used.
6-Chloro-N-4-(3-chloro-2-fluoro-phenyl)-pyrimidine-4,5-
diamine (2a)
In a 50-mL, round-bottomed flask were placed 5-amino-4, 6-dichloropyrimi-
dine (4.0 g, 0.0246 mol), 2-fluoro-3-chloroaniline (3.2 g, 0.022 mol) in a mixed
solvent of water (60 mL), ethanol (10 mL), and concentrated aq. hydrochloric
acid (1 mL). The solution was refluxed overnight and cooled to rt, and the solid
formed was filtered. The solid collected was washed with water and diethyl
ether and then stirred in a 1:1 (v/v) biphase solution of EtOAc and
saturated aq. NaHCO3 for 1 h. The layers were then separated, and the
organic layer was washed with saturated NaHCO3 aqueous solution and
brine and then dried over Na2SO4. Filtration of Na2SO4 followed by concen-
tration under vacuum afforded 2a as an orange solid (4.12 g, 68%). 1H NMR
(DMSO) d 8.65 (s, 1H), 7.81 (s, 1H), 7.59–7.54 (dt, 1H), 7.40–7.35 (dt, 1H),
7.25–7.19 (t, 1H), 5.44 (s, 2H, ArNH2). MS m/z: 274(Mþ2). Calculated for
C10H7Cl2FN4: 272.
2,5-Dihydroxy-4-methoxy-benzaldehyde (7)
Anhydrous DMF (60 mL) was slowly added to a magnetically stirred one-
necked, 250-mL flask with 2,4,5-trihydroxy-benzaldehyde (15.4 g, 0.10 mol)
and Cs2CO3 (42.36 g, 0.13 mol) at room temperature. Gas (CO2) evolved
rapidly from the reaction. After stirring at rt for half an hour, the flask
was placed in an ice bath, and CH3I (21.3 g, 0.15 mol) was added slowly.

352
H. Liu et al.
The reaction was then stirred at rt for overnight. Concentrated HCl was then
added dropwise until pH ¼ 1. Then EtOAc (50 mL) was added, and the
mixture was stirred for 0.5 h. Pure 7 (8.83 g, 53%) was obtained as a brown
solid by filtration of the precipitation, followed by washing with water
(50 mL ꢀ 3) and methanol (30 mL ꢀ 3). Mp: 193.2–195.1 8C; 1H NMR
(DMSO) d 10.50 (s, 1H), 9.95 (s, 1H), 8.88 (s, 1H), 6.99 (s, 1H), 6.50
(s, 1H), 3.82 (s, 3H); 13C NMR (DMSO) d 190.92, 156.47, 155.62, 139.89,
114.41, 113.94, 100.11, 55.76. Anal. calcd. for C8H8O4: C, 57.14; H, 4.80;
found: C, 56.85; H, 4.73.
1-(3-Chloro-2-fluoro-phenylamino)-7-methoxy-5-oxa-2,4,11-triaza
dibenzo[a,d]cyclohepten-8-ol (6)
2a (2.73 g, 0.01 mol), 7 (1.68 g, 0.01 mol), MgSO4 (3.6 g) were pleaced in a
50-mL tube in anhydrous DMF (20 mL). Concentrated HCl (aq., 3 drops)
was added, and the tube was then sealed. The suspension was heated to
95 8C overnight and poured into water. The solid formed was filtered and
washed with methanol (5 mL ꢀ 3) to give 6 (3.41 g, 88%) as a brown solid.
1H NMR (DMSO) d 9.46 (s, 1H), 9.10 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H),
7.73 (m, 1H), 7.39 (m, 1H), 7.23 (m, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 3.86
(s, 3H); MS m/z: 386.97(Mþ1), 388.86; calculated for C18H12ClFN4O3:
386.06
4-(3-Chloro-propyl)-morpholine (11)
1-Bromo-3-chloro-propane (20 g, 0.127 mol) to a magnetically stirred one-
necked, 250-mL flask with toluene (100 mL) at 75 8C were added and
morpholine (24.4 g, 0.28 mol). The solution was stirred at 758C for 4 h. The
reaction was then filtered to remove the precipitation, and the filtrate was
concentrated under vacuum to afford crude 11. Column chromatography
(CH2Cl2:CH3OH5520 : 1) afforded pure 11 as a colorless liquid (15.56 g,
1
75%). H NMR (CDCl3) d 3.77–3.74 (m, 4H), 3.66 (t, J ¼ 6.6 Hz, 2H),
2.55–2.47 (m, 6H), 2.04–1.95 (m, 2H).
(3-Chloro-2-fluoro-phenyl)-[7-methoxy-8-(3-morpholin-4-yl-
propoxy)-5-oxa-2,4,11-triaza-dibenzo[a,d]cyclohepten-1-yl]-
amine (12)
6 (10.5 g, 0.027 mol), 11 (6.2 g, 0.038 mol), NaI (0.21 g, 0.0014 mol), K2CO3
(11.2 g, 0.081 mol) in anhydrous DMF (125 mL) were placed in a 250 mL
flask. The mixture was heated to 78C overnight. The mixture was then
filtered and the filtrate was poured into ethyl acetate (150 mL). The organic

Preparation of Functionalized 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepine
353
phase was washed with brine (100 mL ꢀ 3) and dried over MgSO4. Filtration
followed by concentration of the filtrate under vacuum provided crude 12.
Further purification by column chromatography (silica gel, EtOAc–
hexane–CH3OH ¼ 5 : 5 : 1) provided pure 12 as a yellow solid (9.51 g,
1
68%). Mp: 126.1–128.28C; H NMR (DMSO) d 9.15 (s, 1H), 8.55 (s, 1H),
8.23 (s, 1H), 7.71 (m, 1H), 7.38 (m, 1H), 7.25 (m, 2H), 6.88 (s, 1H),
4.03(t, J ¼ 6.4 Hz, 2H), 3.86 (s, 3H), 3.57(m, 4H), 2.43–2.35 (m, 6H), 1.89
(m, 2H); 13C NMR (DMSO) d 161.83, 160.28, 158.31, 156.57, 154.53,
151.26, 150.97 (d, JC–F ¼ 246.8 Hz), 145.64, 128.25 (d, JC–F ¼ 11.3 Hz),
125.85, 124.71(d, JC–F ¼ 4.5 Hz), 124.48, 119.75 (d, JC–F ¼ 16.6 Hz),
118.12, 116.41, 114.41, 105.32, 67.40, 66.19, 56.25, 54.74, 53.34, 25.89;
MS m/z: 514.18, 516.13 (Mþ1); calculated for C25H25ClFN5O4: 513.16;
anal. calcd for C25H25ClFN5O4: C, 58.42; H, 4.90; N, 13.63; found: C,
58.41; H, 4.83; N, 13.57.
(3-Chloro-2-fluoro-phenyl)-[7-methoxy-8-(3-morpholin-4-yl-
propoxy)-10,11-dihydro-5-oxa-2,4,11-triaza-dibenzo[a,d]
cyclohepten-1-yl]-amine (1a)
12 (11.32 g, 0.022 mol) was placed in a 250-mL flask in a mixed solvent of
THF (50 mL) and EtOH (15 mL). Sodium borohydride (3.67 g, 0.097 mol)
was then added, and the reaction was heated to 60 8C for 3 h. The flask was
then placed in an ice bath and MeOH (30 mL) was added slowly, followed
by HCl (4M in 1,4-dixane, 40 mL). The mixture was stirred at room tempera-
ture for 1.5 h and then vacuum filtrated to remove inorganic salts. The filtrate
was rotatory evaporated to remove most of the solvent, and the residue was
kept at 2208C overnight. The yellow solid formed was collected by
vacuum filtration, followed by washing with water and diethyl ether. The
yellow solid was then suspended in NH3 ethanol solution (2M, 300 mL),
and the suspension was stirred at rt for 1 h. The yellow solid was then
collected by vacuum filtration, decolorized by active carbon in methanol
(300 mL), and recrystallized from methanol to afford the first batch of 1a as
a light yellow solid. The mother liquor and the filtrate from the previous
NH3 neutralization step were combined and extracted with ethyl acetate.
The combined organic phases were washed with brine and dried over
MgSO4. Filtration followed by concentration under vacuum gave a brown
solid, which was purified by column chromatography (silica gel, EtOAc–
Hexane–Methanol ¼ 5 : 5 : 1) to provide a second batch of 1a as a light
yellow solid. Both batches of 1a were combined and recrystallized from
methanol (250 mL) to provide 1a as a light yellow crystal. (9.37 g, 83%).
1
Mp: 86.0–88.0 8C; H NMR (DMSO) d 8.27 (s, 1H), 7.83 (s, 1H), 7.63
(m, 1H), 7.31 (m, 1H), 7.18 (m, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 5.40
(t, J ¼ 4.8 Hz, 1H), 4.37 (d, J ¼ 4.8 Hz, 2H), 3.99 (t, J ¼ 6.3 Hz, 2H), 3.76
(s, 3H), 3.58–3.55(m, 4H), 2.43–2.35 (m, 6H), 1.89–1.84 (m, 2H);

354
H. Liu et al.
13C NMR (DMSO) d 154.95, 153.44, 150.50 (d, JC–F ¼ 246.8 Hz), 149.40,
149.29, 146.71, 144.75, 129.33(d, JC-F ¼ 11.3 Hz), 124.85, 124.65(d,
JC–F ¼ 4.5 Hz), 123.84, 123.58, 119.78 (d, Jc–F ¼ 16.6 Hz), 117.11,
113.78, 105.62, 67.54, 66.21, 56.00, 54.82, 53.35, 45.18, 26.09; MS m/z:
516.07, 518.09 (Mþ1); calculated for C25H25ClFN5O4: 515.17; anal. calcd.
for C25H27ClFN5O4: C, 58.20; H, 5.27; N, 13.57; found: C, 57.81; H, 5.10;
N, 13.51.
REFERENCES
1. Smith, L. M., II; Hadari, Y. Chem. Abstr. Patent WO 2005009384, 2005, 142,
172179.
2. Levkovskaya, L. G.; Sazonov, N. V.; Grineva, N. A.; Mamaeva, I. E.;
Serochkina, L. A.; Safonova, T. S. Khim. Geterotsiklicheskikh Soedine. 1985, 1,
122.
3. Mendelson, W. L.; Holmes, M.; Dougherty, J. Synth. Commun. 1996, 26, 593.
4. Gilday, J. P.; Moody, D. Chem. Abstr. Patent WO 2004024703, 2005, 2003140,
287403.