Synthesis of...

Details Synthesis of... Synthesis of...

2002-03-08

2003-12-09

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06660856

ABSTRACT:

BACKGROUND OF THE INVENTION
1) Field of the Invention
This invention relates to a novel process for synthesis of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) analogues in a high yield. Specifically, this invention relates to a process for preparing PBD analogues starting from a substituted 2-amino benzoic acid, which enables a practical and large scale (e.g., ca. 10 g) synthesis of PBD analogues.
2) Description of the Related Art
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of potent, naturally occurring anti-tumor antibiotics produced by Streptomyces species (M. D. Tendler et. al.,
Nature
(1963), 199, 501; L. H. Hurley,
J. Antibiot
. (1977), 30, 349). The cytotoxic and antitumor effects of PBD compounds are believed to arise from their interaction with DNA molecules, which leads to inhibition of nucleic acid synthesis and production of excision-dependent single- and double-strand breaks in cellular DNA (K. W. Kohn, Anthramycin. In
Antibiotics III Mechanism of Action of Antimicrobial and Antitumor Agents
; ed. by J. W. Corcoran et. al. (Springer-Verlag, New York), pp. 3-11. (1975); R. L. Petrusek, et. al.
J. Biol. Chem
. 1982, 257, 6207). These antibiotics have been proposed to covalently bond to N2 of guanine to form a neutral minor groove adduct (L. H. Hurley et al.,
Nature
(1979), 282, 529; S Cheatham et al.,
Med. Chem
. (1988), 31, 583; J. J. Wang et al.,
Med. Chem
. (1992), 35, 2995; J. A. Mountzouris et al.,
J. Med. Chem
. (1994), 37, 3132).
Tomaymycin, cross-linker DSB-120 (J. A. Mountzouris et al.,
J. Med. Chem
. (1994), 37, 3132; D. E. Thurston et al.,
J. Org. Chem
. (1996), 61, 8141) and DC-81 (W. P. Hu et. al.
J. Org. Chem
. 2001, 66, 2881), the structure of which are shown below, are the best known examples of PBD analogues.
Synthetic approaches of these PBD analogues have been reported (D. E. Thurston et. al.
Chem. Rev
. (1994), 94, 433 and references cited therein; A. Kamal et. al.
Tetrahedron Lett
. (2000), 41, 8631; T. Wang et. al.
Org. Lett
. (1999), 1, 1835.); however, most of them are tedious. For instance, the following scheme shows a widely used method which involves the cyclization of an amino dithioacetal (9) using mercuric chloride to yield an imine product.
It is noted that it takes six steps to synthesize the starting material, i.e. (2S)-pyrrolidine-2-carboxaldehyde diethyl thioacetal, from L-proline. The overall yield of this 10-step synthesis process of DC-81 is about 15-20% (Thurston, D. E., et al.,
J. Org. Chem
. (1996), 61, 8141. Thurston, D. E., et al.,
Synthesis
(1990), 81). More recently, Wang et al. reported the total synthesis of DC-81 over 13 steps in 4% yield (Wang, T. et al.,
Org. Lett
. (1999), 1, 1835).
Accordingly, there still exists a need to develop an efficient and practical process for the production of PBD analogues in a high yield.
SUMMARY OF THE INVENTION
Accordingly, in the first aspect, the present invention provides a process for preparing a compound of formula (I):
wherein
R
1
and R
2
independently represent: hydrogen; halogen; amino; cyano; hydroxy; nitro; phenoxy; C
1
-C
12
alkyl or C
1-C
12
alkoxy or C
2
-C
1
2 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C
1
-C
3
alkoxy;
R
3
represents: hydrogen, or alkyl or alkenyl or alkenylidene, or R form or S form of hydroxyl or alkoxy; and
R
4
and R
5
independently represent: hydrogen, halogen, cyano, hydroxy, phenoxy, C
1
-C
6
alkyl or C
1
-C
6
alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C
1
-C
3
alkoxy;
 the process comprising the steps of:
(a) reacting a substituted 2-amino benzoic acid compound of formula (II) with triphosgen to form an isatoic anhydride compound of formula (III):
wherein
R
1
and R
2
independently represent: hydrogen; halogen; amino; cyano; nitro; phenoxy; C
1
-C
12
alkyl or C
1
-C
12
alkoxy or C
2
-C
12
alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C
1
-C
3
alkoxy; and
R
4
and R
5
independently represent: hydrogen, halogen, cyano, hydroxy, phenoxy, C
1
-C
6
alkyl or C
1
-C
6
alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C
1
-C
3
alkoxy;
(b) coupling the isatoic anhydride compound of formula (III) from step (a) with an L-proline compound of formula (IV) to form a compound of formula (V):
wherein R
3
is hydrogen, hydroxyl, alkyl, alkenyl or alkenylidene or alkoxy;
(c) converting the compound of formula (V) from step (b) to a compound of formula (VI) by reacting the compound of formula (V) with NaH, followed by reaction with methoxymethyl chloride (MOMCl):
 and
(d) converting the compound of formula (VI) from step (c) to the compound of formula (I) by a reduction reaction in the presence of lithium borohydride (LiBH
4
); and
(e) when any one of R
1
, R
2
, R
4
and R
5
of the compound of formula (I) from step (d) is phenoxy or C
1
-C
12
alkoxy substituted with phenyl, an optional step of converting said any one of R
1
, R
2
, R
4
and R
5
of formula (I) to a hydroxy group.
In a preferred embodiment, prior to step (a), the present process further includes an additional step of subjecting a substituted 2-nitrobenzoic acid of formula (IIA) to a reduction reaction to form the amine compound of formula (II):
wherein R
1
, R
2
, R
4
and R
5
are the same as those defined for formula (II).
The reduction reaction of the additional step may be carried out: (1) by hydrogenation in the presence of a palladium-on-carbon system, (2) in the presence of an In/NH
4
Cl aqueous ethanol system, or (3) in the presence of a metal reducing agent selected from ferric chloride (FeCl
3
) and stannous chloride (SnCl
2
). In a more preferred embodiment, the reduction reaction of the additional step prior to step (a) of the present process is carried out in the presence of SnCl
2
.
In a further preferred embodiment, the optional step (e) of the present process is carried out in the presence of 1,4-cyclohexadiene.
In a preferred embodiment, the present process produces a compound of formula (I) wherein both R
4
and R
5
are hydrogen.
In a further preferred embodiment, the present process produces a compound of formula (I), wherein R
1
and R
2
independently represent halogen, cyano, phenoxy, hydroxy, or C
1
-C
12
alkyl or C
1
-C
12
alkoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, C
1
-C
3
alkoxy or phenyl. Preferably, R
1
and R
2
independently represent hydroxy, or C
1
-C
12
alkyl or C
1
-C
12
alkoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, C
1
-C
3
alkoxy or phenyl.
In a more preferred embodiment, the present process produces a compound of formula (I), wherein one of R
1
, R
2
, R
4
and R
5
is halo(en, cyano, phenoxy, hydroxy or C
1
-C
12
alkyl or C
1
-C
12
alkoxy or C
2
-C
12
alkenoxy optionally substituted with halogen, amino, cyano, hydroxy, C
1
-C
3
alkoxy or phenyl, and the others are hydrogen.
In a more preferred embodiment, the present process produces a compound of formula (I), wherein both R
4
and R
5
s are hydrogen, and R
1
and R
2
independently represent halogen, cyano, phenoxy, hydroxy, or C
1
-C
12
alkyl or C
1
-C
12
alkoxy or C
2
-C
12
alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, C
1
-C
3
alkoxy or phenyl. Preferably, R
1
is benzyloxy and R
2
is methoxy. In a further preferred embodiment, R
1
is hydroxy and R
2
is methoxy.
In a preferred embodiment, the present process produces a compound of formula (I), wherein R
3
is hydrogen, ethylidene, or R
3
is R form or S form of hydroxyl or alkoxy.
In a more preferred embodiment, the present invention provides a process for preparing 8-hydroxy-7-methoxy-pyrrolo[2,1-c][1,4] benzodiazepin-5-one, comprising the steps of:
(a)subjecting 4-benzyloxy-5-methoxy 2-nitrobenzoic acid to a reduction reaction to form 2-amino-4-benzyloxy-5-methoxybenzoic acid;
(b)re

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