Process for synthesizing oxidized lactam compounds

• US 8,536,328 B2
• Filed: 05/04/2011
• Issued: 09/17/2013
• Est. Priority Date: 05/04/2010
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Remenar, Julius F., Blumberg, Laura Cook, Zeidan, Tarek A.
• Primary Examiner(s): Ward, Paul V.
• Application Number:
  US13/100,515
• Publication Number:
  US 20110275803A1
• Time in Patent Office: 867 Days
• Field of Search: 544/63
• US Class Current: 544/63
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07F 9/650952 having the nitrogen atoms in the positions 1 and 4
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The invention provides a method for the synthesis of dehydrogenated lactam drugs of Formula I:

Claims

1. A method for preparing a compound of Formula I, comprising the step of reacting a compound of Formula IA:

2. The method according to claim 1, wherein R₁ is selected from H, —

C(R_J)(R_K)—

OR₂₀, —

C(R_J)(R_K)—

OC(O)OR₂₀, —

C(R_J)(R_K)—

OC(O)R₂₀, —

C(R_J)(R_K)—

OC(O)NR₂₀R₂₁, —

(C(R_J)(R_K))—

OPO₃MY, —

(C(R_J)(R_K))—

OP(O)(OR₂₀)(OR₂₁), —

[C(R_J)(R_K)O]_z—

R₂₀, —

[C(R_J)(R_K)O]_z—

C(O)OR₂O, —

[C(R_J)(R_K)O]_z—

C(O)R₂₀, —

[C(R_J)(R_K)O]_z—

C(O)NR₂₀R₂₁, —

[C(R_J)(R_K)O]_z—

OPO₃MY, —

[C(R_J)(R_K)O]_z—

P(O)₂(OR₂₀)M and —

[C(R_J)(R_K)O]_z—

P(O)(OR₂₀)(OR₂₁);

wherein each R_J and R_K is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

Y and M are the same or different and each is a monovalent cation;

or M and Y together is a divalent cation; and

z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

3. A method according to claim 2, wherein R₁ is selected from Tables 1-4:

4. The method according to claim 1, wherein said compound of Formula II is selected from 3,4-dichloro-5,6-dicyano-1,4-benzoquinone, 3,4,5,6-tetrachloro-1,2-benzquinone, ortho-benzoquinone and para-benzoquinone.

5. The method according to claim 1, wherein said acid is selected from trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, dichloroacetic acid, trichloroacetic acid, acetic acid, propionic acid, sulfuric acid, phosphoric acid, nitric acid, camphorsulfonic acid, hydrochloric acid, oxalic acid, formic acid, propanoic acid, butanoic acid, pentanoic acid, benzoic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, hydrobromic acid, and mixtures thereof.

6. The method according to claim 1, wherein the reaction is conducted in a solvent selected from tetrahydrofuran, tert-butylmethylether, dimethoxy-ethane, dioxane, benzene, toluene, xylene, dimethylformamide, acetone, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, methyl-t-butyl ether, methyl butyl ketone and combinations thereof.

7. The method according to claim 1, wherein said pKa range of primary, secondary or tertiary amine is between about 6 to about 30.