Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues
First Claim
Patent Images
1. A process for preparing a compound of formula (I):
-
whereinR1 and R2 independently represent;
hydrogen;
halogen;
amino;
cyano;
hydroxy;
nitro;
phenoxy;
C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C1-C3 alkoxy;
R3 represents;
hydrogen, or alkyl or alkenyl or alkenylidene, or R form or S form of hydroxyl or alkoxy; and
R4 and R5 independently represent;
hydrogen, halogen, cyano, hydroxy, phenoxy, C1-C6 alkyl or C1-C6 alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C1-C3 alkoxy;
the process comprising the steps of;
(a) reacting a substituted 2-amino benzoic acid of formula (II) with triphosgen to form an isatoic anhydride compound of formula (III);
whereinR1 and R2 independently represent;
hydrogen;
halogen;
amino;
cyano;
nitro;
phenoxy;
C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C1-C3 alkoxy; and
R4 and R5 independently represent;
hydrogen, halogen, cyano, hydroxy, phenoxy, C1-C6 alkyl or C1-C6 alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C1-C3 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 R3 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 (LiBH4); and
(e) when any one of R1, R2, R4 and R5 of formula (I) from step (d) is phenoxy or C1-C12 alkoxy substituted with phenyl, an optional step of converting said any one of R1, R2, R4 and R5 of formula (I) to a hydroxy group.
1 Assignment
0 Petitions
Accused Products
Abstract
The present invention provides an efficient process for the preparation of pyrrolo [2,1-c][1,4]benzodiazepines (PBDs) represented by the formula (I):
which starts from a subsituted 2-amino benzoic acid compound, and involves a step of an intermediate MOM-protected dilactam compound in the presence of LiBH4. The process enables a practital and large scale (e.g. ca. 10 g) synthesis of PBD analogue.
96 Citations
35 Claims
-
1. A process for preparing a compound of formula (I):
-
wherein R1 and R2 independently represent;
hydrogen;
halogen;
amino;
cyano;
hydroxy;
nitro;
phenoxy;
C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C1-C3 alkoxy;
R3 represents;
hydrogen, or alkyl or alkenyl or alkenylidene, or R form or S form of hydroxyl or alkoxy; and
R4 and R5 independently represent;
hydrogen, halogen, cyano, hydroxy, phenoxy, C1-C6 alkyl or C1-C6 alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C1-C3 alkoxy;
the process comprising the steps of;
(a) reacting a substituted 2-amino benzoic acid of formula (II) with triphosgen to form an isatoic anhydride compound of formula (III);
wherein R1 and R2 independently represent;
hydrogen;
halogen;
amino;
cyano;
nitro;
phenoxy;
C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C1-C3 alkoxy; and
R4 and R5 independently represent;
hydrogen, halogen, cyano, hydroxy, phenoxy, C1-C6 alkyl or C1-C6 alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C1-C3 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 R3 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 (LiBH4); and
(e) when any one of R1, R2, R4 and R5 of formula (I) from step (d) is phenoxy or C1-C12 alkoxy substituted with phenyl, an optional step of converting said any one of R1, R2, R4 and R5 of formula (I) to a hydroxy group. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
wherein R1, R2, R4 and R5 are the same as those defined for formula (II).
-
-
3. A process according to claim 2, wherein the reduction reaction of the additional step is carried out by hydrogenation in the presence of a palladium-on-carbon system.
-
4. A process according to claim 2, wherein the reduction reaction of the additional step is carried out in the presence of an In/NH4Cl aqueous ethanol system.
-
5. A process according to claim 2, wherein the reduction reaction of the additional step is carried out in the presence of a metal reducing agent selected from ferric chloride (FeCl3) and stannous chloride (SnCl2).
-
6. A process according to claim 5, wherein the reduction reaction of the additional step is carried out in the presence of SnCl2.
-
7. A process according to claim 1, wherein, in the compound of formula (I), both R4 and R5 are hydrogen or halogen.
-
8. A process according to claim 1, wherein, in the compound of formula (I), R1 and R2 independently represent halogen, cyano, phenoxy, hydroxy, or C1-C12 alkyl or C1-C12 alkoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, C1-C3 alkoxy or phenyl.
-
9. A process according to claim 1, wherein, in the compound of formula (I), one of R1, R2, R4 and R5 is halogen, cyano, phenoxy, hydroxy or C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally substituted with halogen, amino, cyano, hydroxy, C1-C3 alkoxy or phenyl, and the others are hydrogen.
-
10. A process according to claim 1, wherein, in the compound of formula (I), both R4 and R5 are hydrogen, and R1 and R2 independently represent halogen, cyano, phenoxy, hydroxy, or C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, C1-C3 alkoxy or phenyl.
-
11. A process according to claim 10, wherein, in the compound of formula (I), R1 is hydroxy and R2 methoxy.
-
12. A process according to claim 10, wherein, in the compound of formula (I), R1 is benzyloxy and R2 methoxy.
-
13. A process according to claim 1, wherein, in the compound of formula (I), R1 and R2 independently represent hydroxy or methoxy.
-
14. A process according to claim 1, wherein, in the compound of formula (I), both R4 and R5 are hydrogen, and R1 and R2 independently represent hydroxy or methoxy.
-
15. A process according to claim 1, wherein, in the compound of formula (I), R3 is hydrogen.
-
16. A process according to claim 1, wherein, in the compound of formula (I), R3 is ethylidene.
-
17. A process according to claim 1, wherein, in the compound of formula (I), R1 is R form or S form of hydroxyl or alkoxy.
-
18. A process according to claim 1, wherein the optional step (e) is carried out in the presence of 1,4-cyclohexadiene.
-
19. 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) reacting the 2-amino-4-benzyloxy-5-methoxybenzoic acid from step (a) with triphosgen to form 7-benzyloxy-6-methoxy-isatoic anhydride, (c) coupling the 7-benzyloxy-6-methoxy-isatoic anhydride from step (b) with L-proline to form 8-benzyloxy-7-methoxypyrrolo [2,1-c][1,4]benzodiazepine-5,11-dione;
(d) forming N-(10-methoxymethyl)-8-benzyloxy-7-methoxypyrrolo [2,1-c][1,4]benzodiazepine-5,1-dione by reacting the 8-benzyloxy-7-methoxypyrrolo[2,1-c][1,4]benzo-diazepine-5,11-dione from step (c) with NaH, followed by reaction with methoxymethyl chloride (MOMCl);
(e) converting the N-(10-methoxymethyl)-8-benzyloxy-7-methoxypyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione from step (d) to 8-benzyloxy-7-methoxy-pyrrolo[2,1-c][1,4]benzodiazepin-5-one via a reduction reaction in the presence of LiBH4; and
(f) reacting the 8-Benzyloxy-7-methoxy-pyrrolo[2,1-c][1,4]benzodiazepin-5-one from step (e) with 1,4-cyclohexadiene. - View Dependent Claims (20, 21, 22)
-
-
23. A process for producing a compound of formula (I):
-
wherein R1 and R2 independently represent;
hydrogen;
halogen;
amino;
cyano;
hydroxy;
nitro;
phenoxy;
C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C1-C3 alkoxy;
R3 represents;
hydrogen, or alkyl or alkenyl or alkenylidene, or R form or S form of hydroxyl or alkoxy; and
R4 and R5 independently represent;
hydrogen, halogen, cyano, hydroxy, phenoxy, C1-C6 alkyl or C1-C6 alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C1-C3 alkoxy;
the process comprising the step of subjecting the compound of formula (VI) to a reduction reaction in the presence of lithium borohydride (LiBH4);
wherein R1 and R2 independently represent, hydrogen;
halogen;
amino;
cyano;
nitro;
phenoxy;
C1-C12 alkyl or C1-C12 alkoxy or C2-C12 alkenoxy optionally and independently substituted with halogen, amino, cyano, hydroxy, phenyl or C1-C3 alkoxy; and
R3 is the same as defined that for formula (I);
R4 and R5 independently represent;
hydrogen, halogen, cyano, hydroxy, phenoxy, C1-C6 alkyl or C1-C6 alkoxy optionally and independently substituted with halogen, amino, nitro, cyano, hydroxy, phenyl or C1-C3 alkoxy; and
when any one of R1, R2, R4 and R5 of the resulting compound of formula (I) is phenoxy or C1-C12 alkoxy substituted with phenyl, an optional step of converting said any one of R1, R2, R4 and R5 of formula (I) to a hydroxy group.- View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)
-
Specification
-
- Resources
Litigation Campaign Assessment
Thank you for your request. You will receive a custom alert email when the Litigation Campaign Assessment is available.
×
-
Current AssigneeKaohsiung Medical University
-
Original AssigneeKaohsiung Medical University
-
InventorsWang, Jeh-Jeng
-
Primary Examiner(s)Kifle, Bruck
-
Application NumberUS10/094,140Publication NumberTime in Patent Office641 DaysField of Search540/496US Class Current540/496CPC Class CodesC07D 487/04 Ortho-condensed systems
