Method of synthesizing camptothecin-relating compounds
AssigneeKabushiki Kaisha Yakult Honsha
InventorsTakanori Ogawa, Hiroyuki Nishiyama, Miyuki Uchida, Seigo Sawada
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Abstract
The present invention is to prepare efficiently 2′-amino-5′-hydroxypropiophenone corresponding to the AB-ring part of camptothecin (CPT) skeleton and a tricyclic ketone corresponding to the CDE-ring part in order to provide efficiently CPT by the total synthesis, which is a starting material for irinotecan hydrochloride and various kinds of camptothecin derivatives, and to provide stably CPT and its derivatives.
Claims34
A process for preparing 2′-amino-5′-hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a):
- 64
- compound (b):
- 65
- is produced;
- and from Compound (b) Compound (c):
- 66
- is produced;
- and from Compound (c) Compound (d):
- 67
- is produced;
- and from Compound (d) Compound (e):
- 68
- is produced;
- wherein R is a protective group which can be deprotected by a catalytic reduction.
Compound represented by formula (c′):
- 69
- (wherein Bn is a benzyl group.).
Compound represented by formula (d′):
- 70
- (wherein Bn is a benzyl group.).
A process for preparing 2′-amino-5′-hydroxypropiophenone to synthesize camptothecin analogs, wherein from Compound (a):
- 71
- Compound (c″):
- 72
- is produced;
- and from Compound (c″) Compound (d″):
- 73
- is produced;
- and from Compound (d″) Compound (e):
- 74
- is produced.
A process for preparing the tricyclic ketone to synthesize camptothecin analogs, wherein from Compound (k):
- 75
- (wherein TMS is a trimethylsilyl group, and Me is a methyl group.), or Compound (v):
- 76
- (wherein TMS is a trimethylsilyl group, and Me is a methyl group.), Compound (l):
- 77
- (wherein TMS is a trimethylsilyl group, and Me is a methyl group.)
- is produced;
- and from Compound (l) Compound (m):
- 78
- (wherein TMS is a trimethylsilyl group, and Me is a methyl group.)
- is produced;
- and from Compound (m) Compound (n):
- 79
- (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.)
- is produced;
- and from Compound (n) Compound (o):
- 80
- (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.)
- is produced;
- and from Compound (o) Compound (p):
- 81
- (wherein TMS is a trimethylsilyl group, Me is a methyl group, and Et is an ethyl group.)
- is produced;
- and from Compound (p) Compound (q):
- 82
- (wherein Me is a methyl group, and Et is an ethyl group.)
- is produced;
- and from Compound (q) Compound (r):
- 83
- (wherein Me is a methyl group, Et is an ethyl group, and Pr is a propyl group.)
- is produced;
- and from Compound (r) Compound (s):
- 84
- (wherein Et is an ethyl group, and Pr is a propyl group.)
- is produced;
- and from Compound (s) Compound (t):
- 85
- (wherein Et is an ethyl group, and tBu is a t-butyl group.)
- is produced;
- and from Compound (t) Compound (h):
- 86
- (wherein Et is an ethyl group.)
- is produced, wherein it contains one or more steps selected from the group consisting of;
- (1) a step to obtain Compound (l) mixing Compound (k), a lithiating agent, a formylation reagent and an iodination reagent;
- (2) a step to obtain Compound (m) mixing Compound (l), crotyl alcohol, triethylsilane and an acid, and reacting said mixture without use of solvent;
- (3) a step to obtain Compound (l) mixing Compound (v), a byproduct in the step (2), with an oxidizing agent and a base;
- (4) a step to obtain Compound (n) mixing Compound (m), a palladium catalyst, a base and a phase-transfer catalyst, and refluxing said mixture in solvent;
- (5) a step to obtain Compound (o) mixing Compound (n), an osmium catalyst, a co-oxidizing agent, a base and an asymmetric reagent;
- (6) a step to obtain Compound (p) mixing Compound (o), a base and iodine, and refluxing said mixture in an alcohol-water mix liquid;
- (7) a step to obtain Compound (q) mixing Compound (p) and a desilylation-iodination reagent;
- (8) a step to obtain Compound (r) mixing Compound (q), a palladium catalyst and a base, and reacting said mixture in 1-propanol under a carbon monoxide gas atmosphere;
- (9) a step to obtain Compound (s) mixing Compound (r) and a demethylation reagent, and reacting said mixture at room temperature;
- (10) a step to obtain Compound (t) reacting Compound (s) under the presence of t-butyl acrylate and a base.
Dependencies are inferred from the claim text.