(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date (10) International Publication Number

9 A u g u s t 2001 (09.08.2001) PCT W O 01/56992 A2
(51) International Patent Classification7 : C 0 7 D 223/22 CH-4104 Oberwil (CH). ZAUGG, Werner [CH/CH];
Waltersgrabenweg 15, CH-4125 Riehen (CH).
(21) International Application Number: PCT/EP01/01330
(74) Agent: BECKER, Konrad; Novartis AG, Corporate
(22) International Filing Date: 7 February 2001 (07.02.2001) Intellectual Property, Patent & Trademark Department,
CH-4002 Basel (CH).

(25) Filing Language: English

(81) Designated States (national)·. AE, AG, AL, AM, AT, AU,
AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
(26) Publication Language: English DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR,
HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
(30) Priority Data: LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
0002740.9 7 February 2000 (07.02.2000) GB NO, NZ, PL, PT, RO, RU, SD, SE, SG, Si, SK, SL, TJ, TM,
TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
(71) Applicant (for all designated States except AT, US): NO-
VARTIS A G [CH/CH]; Schwarzwaldallee 215, CH-4058 (84) Designated States (regional)·. ARIPO patent (GH, GM,
Basel (CH). KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
(71) Applicant (for AT only)·. NOVARTIS-ERFINDUNGEN patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
VERWALTUNGSGESELLSCHAFT M.B.H [AT/AT]; ΓΤ, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
Brunner Strasse 59, A-1230 Vienna (AT). CG, Cl, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).

(72) Inventors; and Published:

(75) Inventors/Applicants (for US only)·. FLFNF- — without international search report and to be republished
SCHILLING, Peter [CH/CH]; Ochsengasse 62, CH-4123 upon receipt of that report
Allschwil (CH). KAUFMANN, Daniel [CH/CH];
Im Wilacker 21, CH-4106 Therwil (CH). LOHSE, For two-letter codes and other abbreviations, refer to the "Guid­
Olivier [FR/FR]; 28, rue des Sapins, F-68170 Rixheim ance Notes on Codes and Abbreviations " appearing at the begin­
(FR). BEUTLER, Ulrich [CH/CH]; Im Lohgraben 42, ning of each regular issue of the PCT Gazette.

r *

ON

in

(54) Title: DIBENZO [B,F]AZEPINE DERIVATIVES AND THEIR PREPARATION

(57) Abstract: The invention relates to new processes for the preparation of the pharmaceutical oxcarbazepine, as well as novel
intermediates prepared by or used for said processes, and the preparation of said intermediates.
 W O 01/56992 PCT/EP01/01330
1

Dibenzo ib.flazepine derivatives and their prepararion

The present invention relates to novel dibenzo [b,f]azepine derivatives and their preparation.
The compounds of the invention are useful as intermediates for the preparation of
pharmaceuticals.

More particularly the invention provides the compounds of formula I

O-R1

wherein Ri is (Ci. 4)alkyl and R2 is (Ci_4)alkyl or phenyl.

The compounds of formula I are useful starting materials for the pharmaceutical oxcarbazepine
(Trileptal®) of formula IV (see below), useful as anticonvulsant, e.g. in the treatment of epilepsy.

Oxcarbazepine can be prepared f r o m the compounds of formula I for example according t o the
following reaction scheme:

carbamoylation
I

a b
H

I I
O-R O
hydrolysis
i
C

-k NH2
O
III IV

Reactions a, b a n d c may be carried o u t according t o known procedures, for example as

described in the Example, steps f t o h .
 W O 01/56992 PCT/EP01/01330
2

In a further aspect the invention provides a process for the production of the compounds of
formula I, whereby a compound of formula V

wherein R2 is as defined above, is reacted with a compound of formula R 1 O H or (R1 O^CH, Ri

being as defined above.

The reaction may be effected in known manner, e.g. as described in the Example, steps d, d' and
d".

The compounds of formula V have never been described in the literature and are also part of
the present invention, as well as a process f o r their production.

According to the invention, the compounds of formula V can be prepared b y ring closure of a
compound of formula VI or VII

HO.

COOR.

CH.
O' O

VI VII

wherein R2 is as defined above and R3 and R 4 , independently, are (Q.^alkyl.

The ring closure of the compound of formula VI is suitably carried out under acidic conditions,
e.g. as described in the Example, step c2. If the resulting compound of formula V is prepared
for the preparation of a compound of formula I, it is preferably not isolated but reactedin situ
into a compound of formula I, e.g. as described in the Example, step e.
 W O 01/56992 PCT/EP01/01330
3

It has surprisingly been found that this cyclisation leads to compounds of formula V and not to
the 5-membered lactam of formula VHI

VIII

with cleavage of the -COOR2, as would be expected from J.W. Schulenberg et al., J. Amer.
Chem. Soc. 82, 2 0 3 5 (1960) in view of the electron withdrawing character of the -COOR 2
group.

The ring closure of the compound of formula VII is suitably carried out under strongly alkaline
conditions, e.g. as described in the Example, step c l .

The compounds of formula VI, as well as the compounds of formula VII wherein R2 is not tert.-
butyl when R3 and R 4 are both isopropyl, are also novel and part of the present invention, as
well as processes f o r their production.

According to the invention, the compounds of formula VI can be prepared by reaction of the
compound of formula VQI under strong basic conditions with a compound of formula X-
COOR 2 , R 2 being as defined above and X being chlorine or methoxy. The reaction may be
effected in conventional manner, e.g. as described in the Example, step a2.

Also according to the invention, the compounds of formula VH can be prepared by reaction of
a compound of formula I X

R.
N

IX
 W O 01/56992 PCT/EP01/01330
4

wherein R 3 and R 4 are as defined above, with a compound of formula Cl-COOR2 , R 2 being as
defined above but not tert.-buty! when R 3 and R 4 are both isopropyl. The reaction may be
effected in conventional manner, e.g. as described in the Example, step b.

The compounds of formula IX are also novel and part of the present invention. They may be
prepared b y reacting the compound of formula X

OH

with a compound of formula R 3 -NH-R 4 , R 3 and R 4 being as defined above, in conventional

manner, e.g. as described in the Example, step a l .

The starting materials of formulae VHI and X are known.

In still a further aspect the invention provides an improved process for the production of the
compounds of formula ΓΠ by carbamoylation of a compound of formula Π. Carbamoylation of
the compound of formula Π wherein R is methyl is described in W O 96/21649. According to
this disclosure, metal cyanates in the presence of mineral acids or relatively strong carboxylic
acids and a solvent are used.

It has now surprisingly been found that this carbamoylation can also be achieved under mild
conditions, using acetic acid. Presence of a strong acid and an additional solvent is not required.
In view of the relatively low stability of the compounds of formula Π, the absence of a strong
acid is particularly advantageous. As a consequence the yield is significantly improved.

Accordingly the invention provides a process f o r the production of a compound of formula ΙΠ

by carbamoylation of a compound of formula Π with a metal cyanate, whereby the reaction is
effected using acetic acid, in the presence of a substantial excess of metal cyanate and in the
absence of a further solvent.
 W O 01/56992 PCT/EP01/01330
5

The metal cyanate is preferably sodium or potassium cyanate. "Substantial excess" of metal
cyanate means at least 0.2 equivalents, preferably 0.2 to 0.5 equivalents. Such excess is an
essential condition for the reaction to take place with the improved yield as compared to the
known carbamoylation process. The reaction may be effected for example as described in the
Example, step g.

The following example illustrates the invention.

Example

a l ) N,N-Dimethv 1-2-o-tolylamino-benzamide

2-o-Tolylamino-benzoic acid (101 g, 0.444 mol) is suspended in toluene (800 mL) and heated
to 58°C. A solution of thionyl chloride (57.6 g, 0.484 mol, 1,1 eq.) in toluene (100 mL) is
added within 2 0 min. T h e mixture is slowly heated to 82°C (1 hour) and concentrated in
vacuum. Toluene (800 mL) is added t o the evaporation residue and the solution is concentrated
in vacuum. The crude acid chloride is dissolved in toluene (500 mL) a n d the solution is cooled
down t o 3°C. A solution of dimethylamine (61.3 mL of an aqueous 4 0 % solution, 1.1 eq.),
sodium hydroxide (77 g of a 3 0 % aqueous solution, 1.3 eq.) and water (240 mL) is added in
4 5 min. The obtained suspension is stirred for 30 min. at 3°C and then warmed t o 30°C. The
phases are separated and the aqueous phase is extracted with toluene (100 mL). The combined
organic phases are washed twice with water (200 mL), evaporated t o dryness and degassed in
vacuum for 1 h o u r (30 mbar, 60°C). T h e product is obtained as an oil that solidifies on
standing (104.7 g, 93.5 % yield). Eventually, the so obtained title compound can be
recrystallized f r o m cyclohexane.

b) (2-Dimethvlcarbamovl-phenvl)-o-tolvl-carbamic acid methyl ester

N,N-Dimethyl-2-o-tolylamino-benzamide (104.7 g, 0.412 mol, 1 eq.) is dissolved in toluene

(800 mL) and cooled down t o - 8 ° C . A solution of n-Butyllithium in hexane (257 mL of a 1.6
M solution, 1 eq.) is added slowly in order t o keep the temperature below 0°C (1 hour). The
orange suspension thus obtained is stirred for 3 0 min at - 8 ° C and methylchloroformiate (42.8
g, 1.1 eq.) is added in 3 0 min. T h e suspension is stirred for 1 hour a t 5°C before quenching
with sodium bicarbonate (500 mL of a saturated aqueous solution). T h e phases are separated
and the aqueous phase is extracted with toluene (200 mL). The combined organic phases are
 W O 01/56992 PCT/EP01/01330
6

washed twice with water (200 mL), evaporated to dryness and degassed in vacuum for 1 hour
(30 mbar, 60°C). T h e crude compound (133.8 g) is dissolved in ethylacetate (240 mL) a t 50°C
and hexane (990 mL) is added. T h e solution is allowed t o cool d o w n t o 25° C (30 min) whereby
crystallization begins. T h e suspension is stirred for 1 hour a t 25°C, cooled t o 3°C and stirred
another 4 hours a t this temperature. After filtration, the solid is washed with cold hexane and
dried in vacuum f o r 16 hours (50°C, 5 0 mbar). The title compound is obtained as a slightly
yellow solid (98.0 g, 7 0 . 5 % global yield f r o m 2-o-Tolylamino-benzoic acid).

c l ) 10-Qxo-10.11-dihvdro-dibenzo[b,flazepine-5-carboxvlic acid methyl ester

Diisopropylamine (11.66 g, 0.115 mol, 1.2 eq.) is dissolved in T H F (150 mL) and the solution
is cooled d o w n t o - 1 0 ° C . A solution of n-Butyllithium in hexane (72 mL of a 1.6 M solution,
1.2 eq.) is added slowly in order t o keep the temperature below 0°C (40 min). A solution of (2-
dimethylcarbamoyl-phenyl)-o-tolyl-carbamic acid methyl ester (30.2 g, 0.096 mol, 1 eq.) in
T H F (80 mL) is added in 4 5 min. t o the obtained solution. T h e reaction mixture is stirred for 1
hour a t - 5 ° C before quenching by addition of water (30 mL). The mixture is concentrated in
vacuum and water (220 mL) a n d ethylacetate (220 mL) are added t o the oily residue. The
phases are stirred rapidly before letting them separate. The organic phase is washed with
aqueous sulfuric acid (300 mL of I - M solution) and twice with water (300 mL). The organic
phase is evaporated t o dryness a n d delivers 23.0 g (89.5 % yield) of the title compound as an
orange oil that solidifies o n standing.

a2) i2-(Methoxvcarbonvl-phenvl-amino)-phenvl1-acetic acid

A mixture of l-phenyl-l,3-dihydro-indol-2-one (80g, 382 mmol), sodium hydroxide (16.06g,

4 0 2 mmol) a n d tetrahydrofuran (113 ml) is heated t o reflux (67°C) for 5 hours. T h e solution is
diluted with another portion of tetrahydrofuran (169 ml) a n d cooled t o -10°C. A 2 0 % solution
of butyllithium in cyclohexane (122.3g, 382 mmol) is added a t this temperature followed by
dimethylcarbonate (51.7g, 5 7 3 mmol). Afterwards, the solution is stirred a t - 1 0 ° C for 2 hours.
Concentrated hydrochloric acid (38 ml) and water (125 ml) are added and the organic solvents
are distilled off a t reduced pressure. After addition of toluene (345 ml) t o the suspension, the
p H of the water phase is adjusted t o 1.5 using hydrochloric acid (34 ml). After phase separation
a t 75°C, the organic phase is washed with another portion of water (120 ml), concentrated a t
reduced pressure a n d allowed t o crystallize at 0°C t o yield 81.2 g of pure title compound
(75%).
 W O 01/56992 PCT/EP01/01330
7

d) 10-Methoxv-dibeiizofb,flazepine-5-carboxvlic acid methyl ester

Crude 10-Oxo-10,ll-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (22.3 g, 0.083

mol, 1 eq.) is dissolved in methanol (112 mL) at 50°C . A catalytic amount of p-toluenesulfonic
acid (0.445 mg) is added, followed by trimethyl orthoformate (11.5 mL, 1.25 eq.). The mixture
is allowed t o react for 5 hours before methanol is allowed t o distill off. Fresh methanol is added
continuously t o replace the distillate. When 100 mL of methanol have been distilled, the
mixture is allowed t o cool down t o 25°C in 1 hour. T h e suspension is further cooled down t o
3°C in 2 0 minutes, stirred a t this temperature for 1 hour and filtered. T h e solid is washed with
cold methanol a n d dried in vacuum for 15 hours (50°C, 5 0 mbar). Pure title compound is
obtained as a light yellow powder (18.02 g, 80.8 % yield).

c2) 10-Oxo-10,ll-dihvdro-dibenzofb,flazepine-5-carboxvlic acid methyl ester

A mixture of [2-(methoxycarbonyl-phenyl-amino)-phenyl]-acetic acid (16g, 55.5 mmol) and

polyphosphoric acid (29g, 167mmol in terms of P2O5) is heated t o IOO0C for 4 hours. T o the
reaction mixture, water (41ml) is added dropwise a t 85-100°C with stirring and cooling. At
65°C toluene (41ml) is added and the mixture is stirred for 3 0 min. The t w o phases are
separated and washed. T h e organic phases are concentrated and allowed t o crystallize a t 0°C t o
yield 12 g of pure title compound (80%).

d') 10-Methoxv-dibenzoib,flazepine-5-carboxvlic acid methyl ester

A suspension of 10-oxo-10,ll-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (15g,

5 6 mmol) in methanol (75 ml) is heated t o 60°C a n d a catalytic amount of p-toluene sulfonic
acid (0.213g, 1.1 mmol) is added. After addition of trimethyl ortho-formate (6.25g, 58.9 mmol)
the solution is stirred a t 60-70°C for 4 hours. During this reaction the product precipitates as
white crystals. T h e mixture is cooled t o r o o m temperature, filtered and dried t o yield 15.5g of
pure title compound (98%).

d") 10-Ethoxv-dibenzoib.flazepine-5-carboxvlic acid methyl ester

A suspension of 10-oxo-10,ll-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (15g,

5 6 mmol) in ethanol (75 ml) is heated t o 60°C and a catalytic amount of p-toluene sulfonic acid
 W O 01/56992 PCT/EP01/01330
8

(0.213g, 1.1 mmol) is added. Af:er addition of triethyl ortho-formate (8.73g, 58.9 mmol) the
solution is stirred at 60-70°C for 4 hours. During this reaction the product precipitates as white
crystals. The mixture is cooled t o r o o m temperature, filtered and dried t o yield 16.Og of pure
title compound (97%).

e) 10-Methoxv-dibenzofb.flazepine-5-carboxvlic acid methyl ester

A mixture of [2-(methoxycarbonyl-phenyl-amino)-phenyl]-acetic acid (16g, 55.5 mmol) and

polyphosphoric acid (29g, 167mmol i n terms of P2O5) is heated t o 100°C f o r 4 hours. T o the
reaction mixture, methanol (50 ml) is added dropwise at 65°C with stirring. The resulting
suspension is cooled t o r o o m temperature, filtered a n d washed with methanol (40 ml). The
white crystals are dried t o yield 12.2g of pure title compound (80%).

f) 10-Methox v-5 H-dibenzo lb.fl azepine

A mixture of 10-methoxy-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (19g, 67.5 mmol),

poly (ethylene glycol) 2 0 0 (20 ml) and sodium hydroxide solution 5 0 % (13 ml, 2 4 6 mmol) is
heated t o 100°C f o r 4hours. Water (30 ml) is added and the suspension is cooled t o 20°C and
filtered. The filter cake is washed with water and dried a t 60°C/30 mbar t o yield 14.7g of pure
title compound (98%).

g) 10-Methoxv-dibenzonb.flazepine-5-carboxvlic acid amide

Acetic acid (150mL) is added dropwise t o a stirred mixture of 10-methoxy-5H-

dibenzo[b,f]azepine (25.Og, 112mmol) a n d N a O C N (9.25g, 142mmol) under a nitrogen
atmosphere at r o o m temperature. After stirring for 7 hours the resulting yellow suspension of
the title compound (>95% area of the compound by HPLC) is used for synthesis of 10-oxo-
10,ll-dihydro-dibenzo[b,f]azepine-5-carboxylic acid amide. The title compound can be isolated
by adding I N N a O H t o a p H of >8 followed by extraction with toluene. Drying of the
combined organic layers a n d concentration in vacuo yields the title compound as a light yellow
solid (yield > 7 5 % ) .

h) lO-Oxo-lO.ll-dihvdro-dibenzorb.flazepine-5-carboxvlic acid amide

T o the acetic acid mixture obtained under g) is added water (12.5mL, 694mmol) and 100%
H 2 SO 4 (ca. 7.5mL, 140mmol) until a p H of < 1 is achieved. After stirring f o r 17 hours water is
 W O 01/56992 PCT/EP01/01330
9

added (275mL). The precipitated title compound is filtered and dried in vacuo (overall yield
startingfrom 10-methoxy-5H-dibenzo[b,f]azepine >78%).
 W O 01/56992 PCT/EP01/01330
10

Claims

1. A process f o r the production of a compound of formula IH

O-R

NH,
III

wherein Ri is (Ci_4)alkyl, by carbamoylation of a compound of formula Π

O-R.

Il

wherein Ri is as defined above, with a metal cyanate, whereby the reaction is effected
using acetic acid, in the presence of a substantial excess of metal cyanate and in the
absence of a further solvent.

2. A process for the production of a compound of formula V

wherein R 2 is (Ci_4)alkyl or phenyl, which comprises the ring closure of a compound of

formula V I

Ao
 W O 01/56992 PCT/EP01/01330
11

HO

O 0

VI

wherein R 2 is as defined above.

3. A process f o r the production of a compound of formula V according to claim 2, which

comprises the ring closure of a compound of formula ΥΠ

C00R.

VII

wherein R 2 is as defined in claim 2 and R 3 and R 4 , independently, are (C1 . 4 )alkyl.

4. A compound of formula V as defined in claim 2 .

5. AcompoundofformulaI

O-R

wherein Ri is as defined in claim 1 and R 2 is as defined in claim 2 .

 W O 01/56992 PCT/EP01/01330
12

A process f o r the production of a compound of formula I as defined in claim 5, which

comprises reacting a compound of formula V as defined in claim 2 with a compound of
formula R i O H or (RiO^CH, wherein R 1 is as defined in claim 1.

A compound of formula VI

HO

VI

wherein R 2 is as defined in claim 2 .

8. A process f o r the production of a compound of formula VI as defined in claim 7, which

comprises reacting the compound of formula VlII

under strong basic conditions with a compound of formula X-COOR 2 , wherein R 2 is as

defined in claim 2 and X is chlorine or methoxy.

9. A compound of formula V E
 W O 01/56992 PCT/EP01/01330
13

COOR.

CH.

VII

wherein R 2 is as defined in claim 2 and R3 and R 4 are as defined in claim 3, provided that
R 2
is not tert.-butyl when R 3 and R 4 are both isopropyl.

10. A process for the production of a compound of formula VII as defined in claim 9, which
comprises reacting a compound of formula IX

wherein R 3 and R 4 are as defined in claim 9, with a compound of formula ClCOOR2 ,

wherein R 2 is as defined in claim 2 but not tert.-butyl when R3 and R 4 are both isopropyl.

11. A compound of formula IX

wherein R 3 and R 4 are a s defined in claim 9.

W O 01/56992 PCT/EP01/01330
14

12. A process f o r the production of a compound of formula I X as defined in claim 11,

w h i c h comprises reacting the compound of formula X

with a compound of formula R3-NH-R4, R3 and R 4 being as defined in claim 9.