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US 6,660,856 B2Granted
Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues
AssigneeKaohsiung Medical University
InventorJeh-Jeng Wang
Life of this patent
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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.
Claims35
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.
33 more elements
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.
4 more elements
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.
27 more elements
Dependencies are inferred from the claim text.