WO2003045909A2 - Procedes et produits intermediaires pour la synthese d'azepines - Google Patents

Procedes et produits intermediaires pour la synthese d'azepines Download PDF

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Publication number
WO2003045909A2
WO2003045909A2 PCT/US2002/037423 US0237423W WO03045909A2 WO 2003045909 A2 WO2003045909 A2 WO 2003045909A2 US 0237423 W US0237423 W US 0237423W WO 03045909 A2 WO03045909 A2 WO 03045909A2
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alkyl
group
formula
compound
het
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PCT/US2002/037423
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WO2003045909A3 (fr
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Jose J. Conde
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Smithkline Beecham Corporation
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Publication of WO2003045909A3 publication Critical patent/WO2003045909A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
    • C07C223/02—Compounds containing amino and —CHO groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical

Definitions

  • This invention relates to methods and intermediates for the synthesis of azepine derivatives.
  • Azepine derivatives are useful in the synthesis of organic compounds and particularly as intermediates in the preparation of medicinal compounds, as prodrugs, and as drugs for medicinal uses.
  • Azepine derivatives have been shown to have medicinal uses.
  • azepine derivatives are identified as having specific binding to opioid receptors, and therefore are useful for treating schizophrenia.
  • Russo- Rodriguez et al. “Azepine or Larger Medium Ring Derivatives and Methods of Use”
  • azepine derivatives were identified as effective for prophylaxis and treatment of inflammation, tissue degradation and related diseases.
  • Azepine rings are present in the cysteine protease inhibitors disclosed in International Application No. PCT/US01/07094, filed March 7, 2001 , and published as WO 01/70232, which is hereby inco ⁇ orated herein by reference in its entirety.
  • the synthesis processes of the present invention involve fewer steps and are more efficient and more cost effective for industrial scale production.
  • the present processes provide a much faster route to producing the desired azepines and avoid the disadvantages of an aqueous work-up, such as the additional time required and the need to remove possible pollutants from the aqueous waste stream before disposal. For these reasons, the present processes are better suited to industrial production.
  • the process disclosed in WO 01/70232 involves a ring closure metathesis reaction to create an N-carbobenzyloxy-azapine, which then undergoes epoxidation.
  • the resulting epoxide is opened by reaction with NaN 3 .
  • NaN 3 is not desired on an industrial scale, however, because it is explosive.
  • the processes of the present invention avoid epoxide formation and therefore avoid the associated problems with NaN reduction of an epoxide.
  • nitrodiols by a synthesis reaction between an aldehyde and a nitroalcohol in the presence of Amberlyst® A 21, a weakly basic macroreticular resin with alkyl amine functionality manufactured by Rohm and Haas, Philadelphia, PA, and in the absence of solvent was disclosed in Ballini et al., "A New Stereoselective Synthesis of (E)- V, ⁇ - Unsaturated-(-dicarbonyl Compounds by the Henry Reaction", J. Org. Chem., 59:5466-5467 (1994).
  • Applicants' processes involve cyclization to form an azepine ring by reacting one molecule having both an aldehyde and a nitro group. Ballini, in contrast, teaches reacting two separate molecules.
  • An object of the present invention is to provide methods for the preparation of azepine derivatives, particularly for the preparation of C 1 6 alkyl-4-amino-azepan-3-one carbonyl protease inhibitors, more particularly such compounds that inhibit cysteine proteases and that are useful for treating diseases that may be therapeutically modified by altering the activity of such proteases. More particularly, the methods of the present invention are useful to prepare the compounds of Formula 1.
  • Another object of the invention is to prepare intermediates useful for the preparation of azepine derivatives, particularly intermediates useful for the preparation of compounds of Formula 1.
  • the invention provides a process for preparing a compound of Formula 2 wherein R 1 is selected from group consisting of:
  • R 2 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar-
  • R 3 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C 0.6 alkyl, C 2 6 alkenyl, C 26 alkynyl, HetC ⁇ alkyl and ArC ⁇ alkyl; R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R 4 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar- C ⁇ alkyl, Het-C M alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R 12 NC(S)-;
  • R 5 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, C ⁇ cycloalkyl-C ⁇ alkyl, C 2.6 alkanonyl, Ar-C M alkyl and Het-C M alkyl;
  • R 6 is selected from the group consisting of: H, C, 6 alkyl, Ar-C (Wj alkyl, and Het- C torque 6 alkyl;
  • R 7 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar- C 0.6 alkyl, Het-C 0.6 alkyl, R"'C(0)-, R ,0 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R ,0 R ,3 NC(O)-, and R'°R ,3 NC(S)-;
  • R s is selected from the group consisting of: H, C ] 6 alkyl, C 26 alkenyl, C 26 alkynyl, HetC ⁇ alkyl and ArC M alkyl;
  • R 9 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar- C M alkyl and Het-C M alkyl;
  • R 10 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar- C ⁇ alkyl and Het-C 0.6 alkyl;
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C 06 alkyl,
  • R 12 is selected from the group consisting of: H, C, .6 alkyl, Ar-C 06 alkyl, and Het- C torque .6 alkyl;
  • R 13 is selected from the group consisting of: H, C, 6 alkyl, Ar-C M alkyl, and Het- C M alkyl;
  • R' is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, and Het- C,, 6 alkyl;
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, or Het- C ⁇ alkyl;
  • R'" is C, 6 alkyl, and is at position 5, 6, or 7 of the azepine ring;
  • X is selected from the group consisting of: CH 2 , S, and O;
  • R' is at position 5, 6, or 7 of the azepine ring
  • R'" is at position 5, 6, or 7 of the azepine ring
  • the invention provides a process for preparing a compound of Formula 6
  • R'" is at position 5, 6, or 7 of the azepine ring
  • R 22 is C ⁇ alkyl, aryl, R 9 CS, or R 9 CO in which R 9 is C, 6 alkyl, C 3 6 cycloalkyl-C 0.6 alkyl, Ar-C 06 alkyl or Het-C 06 alkyl, and salts, hydrates, and solvates thereof, which process comprises
  • the invention provides a process for preparing a compound of Formula 4
  • R , R , and R independently are hydrogen or C, 6 alkyl and at least two of R 18 , R 19 , and R 20 are hydrogen;
  • R 2 ' is hydrogen or C, .6 alkyl;
  • R 22 is C, .6 alkyl, aryl, R 9 CS, or R 9 CO in which R 9 is C,. 6 alkyl, C, .6 cycloalkyl-C (16 alkyl, Ar-Chorizon 6 alkyl or Het-C 06 alkyl; comprising reacting a compound of Formula 3
  • the invention provides a process for preparing a compound of Formula 6
  • R'" is at position 5, 6, or 7 of the azepine ring
  • R 22 is C, .6 alkyl, aryl, R 9 CS, or R 9 CO,and R 9 is C w alkyl, C 3 6 cycloalkyl - C M alkyl, Ar-C M alkyl or Het-C M alkyl, and salts, hydrates, and solvates thereof, which process comprises cyclizing a compound of Formula 5
  • R 18 , R 19 , and R 20 independently are hydrogen or C, 6 alkyl and at least two of R 18 , R 19 , and R 20 are hydrogen.
  • the invention provides a process for preparing a compound of Formula 2
  • R' is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar-C ⁇ 6 alkyl, Het-C M alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R n NC(O)-, R 9 R"NC(S)-, R 9 (R n )NSO ,
  • R 3 is selected from the group consisting of: H, C,ticianalkyl, C 36 cycloalkyl-C ⁇ 6 alkyl,
  • R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R 4 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C ⁇ 6 alkyl, Ar- C M alkyl, Het-C 06 alkyl, R 5 C(0)-, R 5 C(S)-, R s S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R 1 NC(S)-;
  • R 5 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, C 3 ⁇ ycloalkyl-C ⁇ alkyl, C 26 alkanonyl, Ar-C 06 alkyl and Het-C ⁇ alkyl;
  • R 6 is selected from the group consisting of: H, C, 6 alkyl, Ar-C 06 alkyl, and Het- C o ⁇ alkyl
  • R 7 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C (Mi alkyl, Ar-
  • R 8 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, HetC () 6 alkyl and A ⁇ C M alkyl
  • R 9 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar ⁇
  • R 10 is selected from the group consisting of: C,ticianalkyl, C 36 cycloalkyl-C 06 alkyl, Ar- C ⁇ alkyl and Het-C ().6 alkyl;
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, C 3 6 cycloalky 1-C ⁇ alkyl, and Het-C ⁇ alky 1 ;
  • R 12 is selected from the group consisting of: H, C, 6 alkyl, Ar-C (W alkyl, and Het- C, 6 lkyl;
  • R 13 is selected from the group consisting of: H, C, 6 alkyl, Ar-C (M alkyl, and Het- C M alkyl; R' is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, and Het-
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, or Het- C « , 6 alkyl;
  • R'" is C, 6 alkyl, and is at position 5, 6, or 7 of the azepine ring;
  • X is selected from the group consisting of: CH 2 , S, and O;
  • Z is selected from the group consisting of: C(O) and CH 2 ; and pharmaceutically acceptable salts, hydrates and solvates thereof, which process comprises the steps of:
  • R'" is at position 5, 6, or 7 of the azepine ring
  • X' is selected from the group consisting of OH, F, Cl, Br, and I; and Z' is selected from the group consisting of C(O), S(O), and S(0) 2 ; and, if R 22 is unequal to R 2 , replacing R 22 with R 2 either prior to or after acylation, and, if R" is unequal to H, adding R" either prior to or after acylation to produce the compound of Formula 2.
  • the invention provides a process for preparing a compound of Formula 9 wherein R , , an n epen ent y are y rogen or , 6 a y an at east two o R , , and R 20 are hydrogen, and R 22 is C, .6 alkyl, aryl, R 9 CS, or R 9 CO in which R 9 is C 1 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar-C ⁇ alkyl or Het-C 06 alkyl and salts, hydrates, and solvates thereof, the process comprising
  • the invention provides a process for preparing a compound of Formula 6
  • R'" is at position 5, 6, or 7 of the azepine ring
  • R 22 is C, .6 alkyl, aryl, R 9 CS, or R 9 CO
  • R 9 is C, .6 alkyl, C ⁇ cycloalkyl-C ⁇ alkyl, Ar-C ⁇ -alkyl or Het-C M alkyl, and salts, hydrates, and solvates thereof, which process comprises oxidizing and cyclizing a compound of Formula 9
  • R , R , and R independently are hydrogen or C, 6 alkyl and at least two of R 18 , R 19 , and R 20 are hydrogen.
  • Yet another embodiment of the invention relates to a compound of the formula or a salt, hydrate, or solvate thereof.
  • the present invention provides methods for preparing compounds of Formula 1 :
  • R is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, C, 6 alkyl, C 3 ⁇ cycloalkyl-C ⁇ alkyl, Ar- C ( , 6 alkyl, Het-C M alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R"NC(0)-, R 9 R"NC(S)-,
  • R 3 is selected from the group consisting of: H, C, 6 alkyl, C 3 6 cycloalkyl-C 06 alkyl, C 2.6 alkenyl, C 26 alkynyl, HetC 0.6 alkyl and ArC ⁇ alkyl;
  • R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R 4 is selected from the group consisting of: H, C, 6 alkyl, C ⁇ cycloalkyl-C ⁇ alkyl, Ar- C M alkyl, Het-C M alkyl, R 3 C(0)-, R 5 C(S)-, R s S0 2 -, R 5 OC(0)-, R 5 R ,2 NC(0)-, and R 5 R 12 NC(S)-;
  • R 5 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, C 36 cycloalkyl-C M alkyl, C 26 alkanonyl, Ar-C ⁇ alkyl and Het-C ⁇ alkyl;
  • R 6 is selected from the group consisting of: H, C, 6 alkyl, Ar-C M alkyl, and Het- C 6 alkyl;
  • R 7 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar- C M alkyl, Het-C ⁇ alkyl, R 10 C(O)-, R 10 C(S)-, R'°SO 2 -, R'°OC(O)-, R 10 R I3 NC(O)-, and R'°R 13 NC(S)-;
  • R 8 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 2 e alkynyl, HetC ⁇ alkyl and ArC 06 alkyl;
  • R 9 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar- C 06 alkyl and Het-C ⁇ alkyl;
  • R 10 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar-
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C M alkyl, C j .cycloalkyl-C ⁇ alkyl, and Het-C ⁇ alkyl;
  • R' 2 is selected from the group consisting of: H, C, 6 alkyl, Ar-C 06 alkyl, and Het- C (l 6 alkyl;
  • R 13 is selected from the group consisting of: H, C, 6 alkyl, Ar-C M alkyl, and Het- C M alkyl;
  • R' is selected from the group consisting of: H, C, 6 alkyl, Ar-C M alkyl, and Het- C 06 alkyl;
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C M alkyl, or Het-
  • R'" is C, 6 alkyl, and is at position 5, 6, or 7 of the azepine ring;
  • X is selected from the group consisting of: CH 2 , S, and O;
  • Z is selected from the group consisting of: C(O) and CH 2 ; and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R 1 when R 1 is R 3 is selected from the group consisting of: H, C, 6 alkyl, C 3 ⁇ ycloalkyl-C ⁇ alkyl, C 2 fi alkenyl, C 26 alkynyl, Het-C M alkyl and Ar-C M alkyl;
  • R 3 is preferably selected from the group consisting of: H, C 3 Ar-C M alkyl, and C 1 6 alkyl; R 3 is more preferably selected from the group consisting of:
  • R is even more preferably selected from the group consisting of: toluyl, isobutyl and cyclohexylmethyl.
  • R is most preferably isobutyl.
  • R 4 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl- C diligent 6 alkyl, Ar-C ⁇ alkyl, Het-C 06 alkyl, R 5 C(O)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R ,2 NC(S)-.
  • R 4 is preferably selected from the group consisting of: R 5 OC(0)-, R 5 C(0)- and
  • R 4 is most preferably R 5 C(0)-.
  • R 4 is preferably methanesulfonyl.
  • R 5 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, C 3 6 cycloalkyl-C 06 alkyl, C 26 alkanonyl, Ar-C ⁇ alkyl or Het-C 06 alkyl.
  • R 5 is selected from the group consisting of: C, 6 alkyl, C 26 alkenyl, C 36 cycloalkyl-C (16 alkyl, C 26 alkanonyl, Ar-C ⁇ alkyl and Het-C 06 alkyl.
  • R 3 is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl, especially
  • R 3 is preferably pyridin-2-yl or l-oxo-pyridin-2-yl.
  • R' is selected from the group consisting of: H, C, 6 alkyl, Ar-C () 6 alkyl, and Het- C,, 6 alkyl.
  • R' is selected from the group consisting of: H and naphthalen-2-yl- methyl.
  • R' is H.
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, and Het- C M alkyl.
  • R" is H.
  • R'" is C, 6 alkyl, preferably selected from the group consisting of: methyl, ethyl, propyl, butyl, pentyl and hexyl, more preferably methyl, most preferably 7-methyl.
  • R 2 is selected from the group consisting of: H, C, .6 alkyl, C 3 6 cycloalkyl-C M alkyl, Ar-C M alkyl, Het-C 06 alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R"NC(O)-, R 9 R"NC(S)-, R 9 R"NSO 2 -,
  • R 2 is selected from the group consisting of: Ar-C M alkyl, R 9 C(0)-, R 9 S0 2 ,
  • R 2 is selected from the group consisting of: Ar-C 06 alkyl, R 9 C(0)-, and R 9 S0 2 . Most preferably R 2 is R 9 S0 2 .
  • R 6 is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, or Het- C ⁇ alkyl, and is preferably H.
  • R 7 is selected from the group consisting of: H, C, 6 alkyl, C 3 6 cycloalkyl-C M alkyl, Ar- C ⁇ alkyl, Het-C ⁇ alkyl, R 10 C(O)-, R ,0 C(S)-, R'°S0 2 -, R 10 OC(O)-, R 10 R I3 NC(O)-, and R'°R ,3 NC(S)-.
  • R 7 is preferably R 10 OC(O).
  • R 8 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, HetC M alkyl and ArC ⁇ alkyl.
  • R 8 is preferably C, 6 alkyl, and more preferably isobutyl.
  • R 9 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar- C M alkyl, and Het-C 06 alkyl.
  • R 9 is most preferably pyridin-2-yl.
  • R 1 " is selected from the group consisting of: C, 6 alkyl, C 3 ⁇ cycloalkyl-C ⁇ alkyl, Ar- C M alkyl or Het-C ⁇ alkyl; preferably C, 6 alkyl, Ar-C 6 alkyl and Het-C M alkyl.
  • Z is selected from the group consisting of: C(O) and CH 2 .
  • R 2 is also preferably:
  • R 2 is selected from the group consisting of: H, C 1 6 alkyl, C ⁇ cycloalkyl-C ⁇ alkyl, Ar-C profession 6 alkyl, Het-C ⁇ alkyl, R 9 C(0)-, R 9 C(S)-, R 9 SO , R 9 OC(0)-, R 9 R n NC(0)-, R 9 R"NC(S)- , R 9 (R")NS0 2 -,
  • R 3 is selected from the group consisting of: H, C, 6 alkyl, C 3 6 cycloalkyl-C M alkyl, and Ar-C 06 alkyl;
  • R 4 is selected from the group consisting of: R'C(O)-, R 5 S0 2 -, and R 5 OC(0)-;
  • R 5 is selected from the group consisting of: C, 6 alkyl, C 26 alkenyl, C 36 cycloalkyl- C M alkyl, C 26 alkanonyl, Ar-C ⁇ alkyl and Het-C ⁇ alkyl;
  • R 6 is selected from the group consisting of: H, C 1 6 alkyl, Ar-C ⁇ alkyl, and Het- C ⁇ alkyl
  • R 7 is selected from the group consisting of: H, C, 6 alkyl, C 3 ⁇ cycloalkyl-C ⁇ alkyl, Ar-
  • R 8 is selected from the group consisting of: H, C, 6 alkyl, C 26 alkenyl, C 26 alkynyl, HetC ⁇ alkyl and ArC M alkyl;
  • R 9 is selected from the group consisting of: C, 6 alkyl, C 3 6 cycloalkyl-C ⁇ 6 alkyl, Ar-
  • R , ⁇ is selected from the group consisting of: C 1 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar- C 0.6 alkyl and Het-C ⁇ alkyl;
  • R" is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, C ⁇ cycloalkyl-C ⁇ alkyl, and Het-C ⁇ alkyl;
  • R 12 is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, and Het- C, 6 alkyl;
  • R 13 is selected from the group consisting of: H, C, 6 alkyl, Ar-C 06 alkyl, and Het- C M alkyl; R' is H;
  • R" is H
  • R"' is C 1 6 alkyl
  • Z is selected from the group consisting of: C(O) and CH 2 .
  • R 2 is selected from the group consisting of: Ar-C (W ⁇ alkyl, R 9 C(0)-, R 9 S0 2 ,
  • R 3 is selected from the group consisting of: H, C, 6 alkyl, C 36 cycloalkyl-C M alkyl, and Ar-C M alkyl;
  • R 4 is selected from the group consisting of: R 5 OC(0)-, R 5 C(0)- and R 5 S0 2 -;
  • R 5 is selected from the group consisting of: C, .6 alkyl, C 26 alkenyl, C 3.6 cycloalkyl- C M alkyl, C 26 alkanonyl, Ar-C ⁇ alkyl and Het-C ⁇ alkyl;
  • R 6 is H
  • R 7 is R ,0 OC(0)
  • R 8 is C 1 6 alkyl
  • R 9 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar- C M alkyl and Het-C conduct .6 alkyl;
  • R 10 is selected from the group consisting of: C, 6 alkyl, Ar-C M alkyl and Het-C 06 alkyl;
  • R 11 is selected from the group consisting of: C, 6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar- C M alkyl and Het-C ⁇ 6 alkyl;
  • R'" is methyl, preferably 7-methyl
  • Z is selected from the group consisting of: C(O) and CH 2 .
  • R 2 is selected from the group consisting of: Ar-C 06 alkyl, R 9 C(O)-, and R 9 S0 2 .
  • R 9 S0 2 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: Ar-C 06 alkyl, R C(0)- and R 9 S0 2 ;
  • R 3 is selected from the group consisting of: H, methyl, ethyl, n-propyl, prop-2-yl, n- butyl, isobutyl, but-2-yl, cyclopropylmethyl, cyclohexylmethyl, 2-methanesulfinyl-ethyl, 1- hydroxyethyl, toluyl, naphthalen-2-ylmethyl, benzyloxymethyl, and hydroxymethyl;
  • R 4 is R 5 C(0)-
  • R 5 is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl, especially C, 6 alkoxy and aryloxy substituted methyl, more especially phenoxy-methyl, 4-fluoro-phenoxy-methyl, especially heterocycle substituted methyl, more especially 2-thiophenyl-methyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; pentanonyl, especially 4-pentanonyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and 4-fluorophenyl, especially phenyl substituted with one or more C, 6 alkoxy groups, more
  • R 9 is selected from the group consisting of: methyl; ethyl, especially C, 6 alkyl-substituted ethyl, more especially 2-cyclohexyl-ethyl; butyl, especially C butyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(0); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, especially C, 6 alkoxy phenyl, more especially 3-methoxyphenyl, 4-methoxyphenyl, 3,4- dimethoxyphenyl, especially cyanophenyl, more especially 2-cyanophenyl; toluyl, especially Het-substituted toluyl, more especially 3-(pyridin-2
  • R' is H
  • R" is H
  • R"' is methyl, preferably 7-methyl.
  • R 2 is R 9 S0 2 ;
  • R 3 is isobutyl
  • R 4 is R 5 C(0)
  • R 5 is selected from the group consisting of: 5-methoxybenzofuran-2-yl, benzo[b]thiophen-2-yl, 3-methyl-benzofuran-2-yl, thieno[3,2-b]thiophen-2-yl, benzofuran- 2-yl, furo[3,2-b]pyridin-2-yl, and 3-methyl-furo[3,2-b]pyridin-2-yl; preferably benzofuran- 2-yl, furo[3,2-b]pyridin-2-yl, and 3-methyl-furo[3,2-b]pyridin-2-yl; most preferably benzofuran-2-yl.
  • R 9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl, preferably pyridin-2-yl.
  • R' is H
  • R" is H
  • R'" is selected from the group consisting of: 6- and 7-methyl, preferably 7-methyl.
  • a most particularly preferred embodiment of the present invention is a process to prepare benzofuran-2-carboxylic acid ⁇ (S)-3-methyl-l-[(4S,7R)-7-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ -amide:
  • Schema A a compound of Formula 1 can be made by a process comprising
  • R'" is at position 5, 6, or 7 of the azepine ring
  • X' is selected from the group consisting of OH, F, Cl, Br, and I; and Z' is selected from the group consisting of C(O), S(O), and S(0) 2 ; and, if R 22 is unequal to R 2 , replacing R 22 with R 2 either prior to or after acylation, and if R" is unequal to H, adding R" either prior to or after acylation to produce the compound of Formula 2
  • R' is at position 5, 6, or 7 of the azepine ring
  • a solvent such as ethanol/NaOEt, methanol/CH 3 ONa, or toluene/Bu 3 P, more preferably NaOEt at 0.1 equivalent and ethanol.
  • the reaction of the compound of Formula 3 with R 22 HCH 2 COOR 21 is preferably in the presence of NaBH(OAc) 3 , NaCNBH 3 , NABH 4 and AcOH, or BH 3 Pyridine and AcOH as the reducing agent, most preferably with NaBH(OAc) 3 as the reducing agent.
  • the hydride donor is selected from the group consisting of sodium borohydride and alkyl aluminum hydrides such as diisobutylaluminum hydride, and most preferably is diisobutylaluminum hydride.
  • the cyclization step may be accomplished in the presence of a weak base, preferably in the presence of a weakly basic resin or gel, such as Amberlite ® IRA-67 or Amberlyst ® A-21, both manufactured by Rohm and Haas, Philadelphia, PA.
  • a weakly basic resin or gel such as Amberlite ® IRA-67 or Amberlyst ® A-21, both manufactured by Rohm and Haas, Philadelphia, PA.
  • the cyclization step occurs via a Henry reaction accomplished with Amberlyst® A-21, a weakly basic macroreticular resin with alkyl amine functionality.
  • the weak base may be a pyridine derivative, diisopropyl ethyl amide, or another weak base known to those of skill in the art.
  • the acylating agent used in the acylation of the primary amine of the compound of Formula 7 is an acid, acid halide, sulfonyl halide, or sulfinyl halide, more preferably is an acid, still more preferably is BOC-leucine.
  • the acylation to produce the compound of Formula 2 use coupling reagents such as HBTU, HOBT, or EDC. Coupling methods to form amide bonds are generally well known in the art.
  • R 22 is unequal to R 2
  • replacement of R 22 with R 2 is accomplished by removing R 22 by hydrogenation, then acylating the amino group with an acylating agent such as 2- pyridinesulfonyl chloride.
  • an acylating agent such as 2- pyridinesulfonyl chloride.
  • R" is added to the compound of Formula 7 either prior to or after acylation.
  • R" is added to the compound of Formula 7 preferably by reductive animation or alkylation with an alkyl halide. If R" is added prior to acylation, then preferably addition occurs via reductive amination. If R" is added after acylation, then preferably addition occurs by alkylation with an alkyl halide.
  • the compound of Formula 2 is oxidized with sulfur trioxide-pyridine complex to provide the compound of Formula 1.
  • the compound of Formula 4 undergoes chiral chromatographic separation to separate the enantiomers and the reaction proceeds with an enantiomerically pure compound of Formula 4.
  • Enantiomeric separation may occur by any means known to those skilled in the art, such as by chiral chromatography.
  • the invention is also directed to a second general pathway for preparing compounds of Formula 1, Schema B.
  • a compound of Formula 1 can be made by a process comprising:
  • R'" is at position 5, 6, or 7 of the azepine ring, then proceeding with steps 5-7 of Schema A to produce a compound of Formula 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
  • the reaction of methyl vinylketone with CH 3 N0 2 occurs in EtOH and NaOEt.
  • the reaction of the compound of Formula 3 with R 22 NH(CH 2 ) 2 OR 23 occurs in the presence of NaBH(OAc) 3 , CH 3 CN, and acetic acid.
  • R 22 NH(CH 2 ) 2 OR 23 is n-[2-hydroxyethyl]- benzoamine.
  • R 23 The replacement of R 23 with H can occur using any procedure known to those of skill in the art. For example, if R 23 is C, 6 alkyl, then replacement of R 23 with H may occur by addition of excess acid. If R 23 is aryl, then replacement may occur by the addition of cerium ammonium nitrate.
  • the step of oxidation and cyclization can be accomplished using any suitable oxidation reagent, as would be evident to one of skill in the art. Preferably any oxidation reagent known to form aldehydes primarily from alcohols is used. Suitable oxidation reagents are disclosed in "Comprehensive Organic Transformations," by Richard C. LaRock, NCH Publishers, Inc. (New York, New York; Cambridge UK; and Weinheim, Germany) (1989), which is inco ⁇ orated herein in its entirety by reference. Suitable oxidation reagents include the following:
  • the oxidation reagent is sulfur trioxide-pyridine complex, DMSO, and Et 3 N.
  • Synthetic methods to prepare amines as are present in the intermediates of the present processes often employ protective groups to mask a reactive functionality or minimize unwanted side reactions.
  • protective groups are described generally in Green, T.W. "Protective Groups in Organic Synthesis," John Wiley & Sons, New York (1981).
  • Amino protecting groups generally refers to the Boc, acetyl, Fmoc, and Cbz groups and derivatives thereof.
  • Acid addition salts of the compounds of Formula 1 are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwiterions that may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate, or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li + , Na ⁇ K ⁇ Ca + ⁇ Mg and NH 4 + are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates, benzoates and sulfonates are examples of anions present in pharmaceutically acceptable salts.
  • the compounds of Formulae 2-9 and their salts, hydrates, and solvates are useful as intermediates in the synthesis of medicinal compounds.
  • the present invention is also directed to novel methods for their preparation.
  • the following compounds of the Formula 2 can be prepared according to the inventive processes: 3-methyl-l-(pyridine-2-sulfonyl)-2,3,4,7-tetrahydro-lH-azepine;
  • the present invention is also directed to intermediate compounds of Formulae 3-9 and salts, hydrates, or solvates thereof, and methods for their preparation.
  • the nitroalcohol of Formula 6 is useful as an intermediate to prepare azepine derivatives.
  • the invention is directed to a nitroalcohol of the formula
  • the present invention provides two general pathways, Schema A and B, for preparing the nitroalcohol of Formula 6.
  • Schema A a nitroalcohol of Formula 6 is prepared by a process comprising cyclizing a compound of Formula 5
  • R 18 , R 19 , and R 20 independently are hydrogen or C, 6 alkyl and at least two of R 18 , R 19 , and R 20 are hydrogen.
  • the compound of Formula 5 can be prepared by reacting a compound of Formula 4
  • R 18 , R 19 , and R 20 independently are hydrogen or C, 6 alkyl and at least two of
  • R 18 , R 19 , and R 20 are hydrogen; R 21 is hydrogen or C, 6 alkyl; and R 22 is C, 6 alkyl, aryl, R 9 CS, or R 9 CO in which R 9 is C, .6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar-C 06 alkyl or Het-C 0.6 alkyl, with a hydride donor.
  • the compound of Formula 4 can be prepared by reacting a compound of Formula 3
  • R 22 HNCH 2 COOR 21 wherein R 21 and R 22 are defined for a compound of Formula 5, in the presence of a reducing agent.
  • a nitroalcohol of Formula 6 may be prepared by a process comprising oxidizing and cyclizing a compound of Formula 9
  • R ,s , R' ⁇ and R 20 independently are hydrogen or C, 6 alkyl and at least two of R' s , R' 9 , and R 20 are hydrogen, R 22 is C, .6 alkyl, aryl, R 9 CS, or R 9 CO in which R 9 is C,. 6 alkyl, C 36 cycloalkyl-C M alkyl, Ar-C M alkyl or Het-C M alkyl.
  • the compound of Formula 9 may be produced by reacting a compound of Formula 3
  • R 22 HN(CH 2 ) 2 OR 23 wherein R 22 is C 1 6 alkyl, aryl, R 9 CS, or R 9 CO in which R 9 is C, .6 alkyl, C 36 cycloalkyl-C 06 alkyl, Ar-C ⁇ alkyl or Het-C (1 _ 6 alkyl, and R 23 is H, C 1 ( ,alkyl, or aryl, such that a compound of Formula 8 is produced
  • the invention is also directed to novel intermediates prepared by the processes of the invention.
  • the invention is directed to a compound at the formula
  • the invention is also directed to a compound of the formula
  • the invention is also directed to a compound of the formula
  • the invention is also directed to salts, hydrates, and solvates of the compounds of the invention.
  • the present invention also provides for methods for the synthesis of deuterated analogs of the compounds of Formula 1 and of the intermediates produced in the preparation thereof. Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound is added to the process.
  • the deuterating agent is CD 3 OD:D 2 O(10:l) in triethylamine.
  • the deuterated compounds exhibit superior chiral stability compared to the protonated isomer.
  • the invention also includes the keto isomer, and vice versa.
  • both tautomers are included when one is disclosed.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • protes are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis.
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • C, 6 alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • R 14 is selected from the group consisting of: H, C, 6 alkyl, Ar-C ⁇ alkyl, and Het-C M alkyl;
  • C 3 6 cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • C 26 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C 26 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C 26 alkanonyl as applied herein is meant to include unsubstituted and substituted acetyl, propanonyl, butanonyl, pentanonyl, and hexanonyl.
  • C 26 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C 26 alkynyl includes acetylene, 1- propyne, 2-propyne, 1 -butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen means F, Cl, Br, and I.
  • Ar or “aryl” means phenyl or naphthyl, optionally substituted by one or more of Ph-C ⁇ alkyl; Het-C M alkyl; C, .6 alkoxy; Ph-C conduc 6 alkoxy; Het-C conduc 6 alkoxy; OH, (CH ⁇ NR ⁇ R 16 ; 0(CH 2 ), .6 NR' 5 R 16 ; C, .6 alkyl, OR 17 , N(R I7 ) 2 , SR 17 , CF 3 , N0 2 , CN, C0 2 R 17 , CON(R 17 ), F, Cl, Br or I; where R 15 and R' 6 are H, C, contextalkyl, Ph-C M alkyl, naphthyl-C conduc 6 alkyl or Het-C ⁇ alkyl; and R 17 is phenyl, naphthyl, or C, 6 alkyl.
  • Het represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C M Ar, C w alkyl, OR 17 , N(R 17 ) 2 , SR ⁇ , CF 3 , N0 2 , CN, C0 2 R' 7 , CON(R 17 ), F, Cl, Br and I, where R 17 is phenyl, naphthyl, or C, 6 alkyl.
  • heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzoimid
  • heteroatom refers to oxygen, nitrogen and sulfur.
  • C 0 denotes the absence of the substituent group immediately following; for instance, in the moiety ArCo- 6 alkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo- 6 alkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0.
  • t-Bu refers to the tertiary butyl radical
  • Et refers to the ethyl radical
  • Pr refers to the propyl radical
  • Ac refers to the acetyl radical
  • Pr refers to the propyl radical
  • BOC or Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical
  • Ts refers to the tosyl radical.
  • m-CPBA refers to 3-chloroperoxybenzoic acid
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide
  • DMF refers to dimethyl formamide
  • DMSO refers to dimethyl sulfoxide
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • DIBALH diisobutylaluminum hydride
  • HOBT refers to 1-hydroxy-benzotriazole hydrate
  • HBTU refers to o-benzotriazole-l-yl-n,n,n',n', -tetramethyl uronium hexafluorophosphate
  • EDC refers to l-[3-dimethylaminopropyl]-3-ethyl-carbodiimide hydrochloride.
  • rt refers to room temperature
  • h refers to hour(s)
  • cat refers to catalytic amount.
  • the present invention provides processes for the preparation of enantiomerically pure azepine derivatives and processes and intermediates useful in the preparation thereof.
  • enantiomerically pure means the compound contains at least 90% by weight of one stereoisomer and 10% by weight or less of other stereoisomers.
  • the enantiomerically pure compound comprises at least 95% by weight of one stereoisomer and 5% by weight or less of other stereoisomers.
  • the enantiomerically pure compound comprises over 99% by weight of one stereoisomer and 1% or less by weight of other stereoisomers.
  • the desired stereoisomers can be produced by different methods.
  • an enantiomerically pure compound of Formula 4 can be produced by resolution of the stereoisomers of compounds of Formula 4 and then proceeding with the synthesis of the compound of Formula 5 according to Schema A using the enantiomerically pure compound of Formula 4.
  • the diasteriomers of the compound of Formula 6 can be separated to yield the desired enantiomerically pure compound.
  • stereoselective separation may occur using chiral chromatography at any stage after the preparation of the compound of Formula 4. Separation can be performed by techniques known to those of skill in the art, such as by high pressure liquid chromatography (HPLC), chiral chromatography, and by diastereomeric crystallization.
  • the cyclic compounds prepared in the processes of the present invention are in a form in which any non-hydrogen substituents on the azepine ring, such as R'" and NR'R", are in the syn relationship to each other.
  • the compound of Formula A was readily obtained from a Michael addition of nitromethane to methyl vinylketone. Reductive amination of the compound of Formula A with commercially available N-benzylglycine ethyl ester afforded the compound of Formula B in 80% yield. The mixtures of enantiomers of the compound of Formula B were separated by chiral chromatography. The preferred stereoisomer of Formula B was treated with DIBALH at -78E C to give the corresponding aldehyde of Formula C in excellent yield. The cyclization of the compound of Formula C via a Henry reaction was accomplished with Amberlyst ® A-21 weakly basic macroreticular resin to afford the nitroalcohol of Formula D.
  • the compound of Formula A was readily obtained from a Michael addition of nitromethane to methyl vinylketone in 70% yield. Reductive amination of the compound of Formula A with N-benzyl ethanol amine afforded the compound of Formula G at 50% yield. The compound of Formula G is reacted with sulfur trioxide-pyridine complex and Et 3 N in DMSO to yield the compound of Formula H.

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Abstract

L'invention concerne des procédés et des produits intermédiaires permettant de préparer des azépines représentées par la formule (I).
PCT/US2002/037423 2001-11-21 2002-11-20 Procedes et produits intermediaires pour la synthese d'azepines WO2003045909A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
EP1713790A2 (fr) * 2004-01-23 2006-10-25 Smithkline Beecham Corporation Procede de preparation d'acide benzofuran-2-carboxylique (s)-3-methyl-1- (4s, 7r)-7methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl -amide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070232A1 (fr) * 2000-03-21 2001-09-27 Smithkline Beecham Corporation Inhibiteur de proteinase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070232A1 (fr) * 2000-03-21 2001-09-27 Smithkline Beecham Corporation Inhibiteur de proteinase

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7563784B2 (en) 2000-03-21 2009-07-21 Smithkline Beecham Corporation Protease inhibitors
EP1713790A2 (fr) * 2004-01-23 2006-10-25 Smithkline Beecham Corporation Procede de preparation d'acide benzofuran-2-carboxylique (s)-3-methyl-1- (4s, 7r)-7methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl -amide
EP1713790A4 (fr) * 2004-01-23 2010-07-14 Glaxosmithkline Llc Procede de preparation d'acide benzofuran-2-carboxylique (s)-3-methyl-1- (4s, 7r)-7methyl-3-oxo-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl -amide

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