Methods of synthesizing farnesyl dibenzodiazepinones
Inventors
Kiernan, Bernard Matthew • Bailey, Thomas R. • Li, Binfeng
Assignees
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Publication Number
US-12600703-B2
Publication Date
2026-04-14
Expiration Date
Abstract
The present invention is directed to synthetic means for producing farnesyl dibenzodiazepinone compounds, including AMO-01.
Core Innovation
The invention relates to methods of synthesizing farnesyl dibenzodiazepinone compounds of Formula I and Formula II, including salts thereof, and to the synthesis of AMO-01 (10-farnesyl-4,6,8-trihydroxy-dibenzodiazepin-11-one). The methods are based on preparing AP2312-A and AP2312-B, followed by a coupling step and multiple subsequent transformations to reach the farnesylated dibenzodiazepinone framework.
For Formula I and AMO-01, the method comprises performing Ullmann coupling, then performing de-benzylation, silylation, preparing R7 or farnesyl bromide, farnesylation, and performing de-silylation. For Formula II, the method comprises preparing AP2312-A and AP2312-B, then performing Buchwald coupling, followed by de-benzylation, silylation, preparing R7, farnesylation, and de-silylation.
The described approaches use named intermediates including AP2312-3 through AP2312-8. The Formula II method defines substituent options including A being —NH—, R7 with specific substituent patterns involving an integer x from 1 to 11, and additional substituent definitions for R2, R5, and R6, while farnesylation specifies X as Br, I, or Cl.
Claims Coverage
The partial claim set includes four independent claims, covering Formula I and salts, Formula II and salts, and two AMO-01 synthesis methods. Across the independent claims, the inventive coverage centers on preparing AP2312-A and AP2312-B, selecting Ullmann or Buchwald coupling, and carrying out a fixed downstream sequence including de-benzylation, silylation, farnesylation, and de-silylation.
Ullmann coupling synthesis of Formula I farnesyl dibenzodiazepinone
A method comprising preparing AP2312-A and AP2312-B, performing Ullmann coupling, performing de-benzylation, performing silylation, preparing R7, performing farnesylation, and performing de-silylation to synthesize a farnesyl dibenzodiazepinone of Formula I and salts thereof, with X being Br, I, or Cl and with A, R7, W1–W3, R2, and R3/R4 defined by the claim.
Buchwald coupling synthesis of Formula II farnesyl dibenzodiazepinone
A method comprising preparing AP2312-A and AP2312-B, performing Buchwald coupling, performing de-benzylation, performing silylation, preparing R7, performing farnesylation, and performing de-silylation to synthesize a farnesyl dibenzodiazepinone of Formula II and salts thereof, with X being Br, I, or Cl and with A, R7, W1–W3, R2, and R5/R6 defined by the claim.
Ullmann coupling synthesis of AMO-01 using farnesyl bromide
A method comprising preparing AP2312-A and AP2312-B, performing Ullmann coupling, performing de-benzylation, performing silylation, preparing farnesyl bromide, performing farnesylation, and performing de-silylation to synthesize AMO-01 (10-farnesyl-4,6,8-trihydroxy-dibenzodiazepin-11-one).
Defined intermediate sequence to AMO-01
A method comprising preparing AP2312-A and AP2312-B, performing Ullmann coupling to yield AP2312-3, performing de-benzylation to yield AP2312-4, performing silylation to yield AP2312-5, reacting AP2312-C in the presence of Ms2O, LiBr, 2,6-lutidine and DMF to yield AP2312-6, performing farnesylation of AP2312-5 with AP2312-6 to yield AP2312-8, and performing de-silylation to yield AMO-01.
Overall, the independent claims cover two complementary synthetic strategies distinguished by the coupling step: Ullmann coupling for Formula I and AMO-01, and Buchwald coupling for Formula II. In both cases, the claims recite a consistent downstream sequence through named intermediates, protecting-group transformations, farnesylation, and final de-silylation.
Stated Advantages
Ullmann coupling provides regioselectivity and stereochemical outcomes distinct from Buchwald coupling.
98.3% purity (HPLC) is reported.
Documented Applications
Synthesis of the farnesyl dibenzodiazepinone AMO-01 (10-farnesyl-4,6,8-trihydroxy-dibenzodiazepin-11-one).
Synthesis of farnesyl dibenzodiazepinones of Formula I and Formula II (and salts thereof).
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