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US 12,600,703 B2Granted
Methods of synthesizing farnesyl dibenzodiazepinones
AssigneeAMO Pharma Ltd.
InventorsBernard Matthew Kiernan, Thomas R. Bailey, Binfeng Li
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Abstract
The present invention is directed to synthetic means for producing farnesyl dibenzodiazepinone compounds, including AMO-01.
Claims4
A method of synthesizing a farnesyl dibenzodiazepinone of Formula I and salts thereof:
- wherein,
- A is —NH—;
- R7 is —CH3, —(CH2)xCH3, —CH2CH2W1CH3, —CH2CH2W1CH2CH2W2CH3 or —CH2W1CH2CH2W2CH2CH2W3CH3, where x is an integer of from 1 to 11, and where each of W1, W2 and W3 is independently
- R2 is —H, —OH, —OCH3 or —OP═O(OR8), where R8 is —Na, —CH3 or —CH2CH3;
- and
- R3 and R4 are the same and selected from —H, —OH, —OCH3 or —OP═O(OR8), where R8 is —Na, —CH3 or —CH2CH3,
- said method comprising:
- (a) preparing AP2312-A;
- (b) preparing AP2312-B;
- (c) performing Ullmann coupling;
- (d) performing de-benzylation;
- (e) performing silylation;
- (f) preparing R7;
- wherein X is Br, I, or Cl
- (g) performing farnesylation;
- and
- (h) performing de-silylation
14 more elements
A method of synthesizing a farnesyl dibenzodiazepinone of Formula II and salts thereof:
- wherein,
- A is —NH—;
- R7 is —CH3, —(CH2)xCH3, —CH2CH2W1CH3, —CH2CH2W1CH2CH2W2CH3 or —CH2W1CH2CH2W2CH2CH2W3CH3, where x is an integer of from 1 to 11, and where each of W1, W2 and W3 is independently
- R2 is —H, —OH, —OCH3 or —OP═O(OR8), where R8 is —Na, —CH3 or —CH2CH3;
- and
- R5 and R6 are the same and selected from —H, —OH, —OCH3 or —OP═O(OR8), where R8 is —Na, —CH3 or —CH2CH3,
- said method comprising:
- (a) preparing AP2312-A;
- (b) preparing AP2312-B;
- (c) performing Buchwald coupling;
- (d) performing de-benzylation;
- (e) performing silylation;
- (f) preparing R7;
- wherein X is Br, I, or Cl
- (g) performing farnesylation;
- and
- (h) performing de-silylation
14 more elements
A method of synthesizing the farnesyl dibenzodiazepinone AMO-01 (10-farnesyl-4,6,8-trihydroxy-dibenzodiazepin-11-one),
- said method comprising:
- (a) preparing AP2312-A;
- (b) preparing AP2312-B;
- (c) performing Ullmann coupling;
- (d) performing de-benzylation;
- (e) performing silylation;
- (f) preparing farnesyl bromide;
- (g) performing farnesylation;
- and
- (h) performing de-silylation
7 more elements
A method of synthesizing the farnesyl dibenzodiazepinone AMO-01, said method comprising:
- (a) preparing AP2312-A;
- (b) preparing AP2312-B;
- (c) performing Ullmann coupling by reacting molecular equivalent amounts of AP2312-A and AP2312-B in the presence of CuI (0.0525 eq), K2CO3 (2.0 eq), L-proline (0.1 eq) and DMF to yield AP2312-3;
- (d) performing de-benzylation of AP2312-3 in the presence of THF, MeOH and Pd/C under H2 to yield AP2312-4;
- (e) performing silylation of AP2312-4 in the presence of TIPSCl (4.0 eq) Et3N (5.0 eq) and DMF to yield AP2312-5;
- (f) reacting AP23132-C in the presence of Ms2O, LiBr (1.6 eq), 2,6-lutidine (1.6 eq) and DMF to yield AP2312-6;
- (g) performing farnesylation of AP2312-5 with AP2312-6 in the presence of dioxane, tBuOH and tBuOK (1.15 eq) to yield AP2312-8;
- and
- (h) performing de-silylation of AP2312-8 in the presence of THF (1.0 eq), AcOH (8.0 eq) and TBAF (4.0 eq) to yield AMO-01
6 more elements
Dependencies are inferred from the claim text.