WO2006074046A2 - Process for preparing 2-methyl-1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine - Google Patents

Process for preparing 2-methyl-1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine Download PDF

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Publication number
WO2006074046A2
WO2006074046A2 PCT/US2005/047375 US2005047375W WO2006074046A2 WO 2006074046 A2 WO2006074046 A2 WO 2006074046A2 US 2005047375 W US2005047375 W US 2005047375W WO 2006074046 A2 WO2006074046 A2 WO 2006074046A2
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Prior art keywords
methylpropyl
naphthyridine
nitro
mixture
naphthyridin
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PCT/US2005/047375
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English (en)
French (fr)
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WO2006074046A3 (en
Inventor
Hugues Martin
David Ach
Clement Toussaint
Fabrice Dubois
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Meda AB
3M Innovative Properties Co
Graceway Pharmaceuticals LLC
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Meda AB
3M Innovative Properties Co
Graceway Pharmaceuticals LLC
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Priority to US11/794,584 priority Critical patent/US8436176B2/en
Priority to PL05855868T priority patent/PL1833827T3/pl
Priority to MX2007008131A priority patent/MX2007008131A/es
Priority to DK05855868.5T priority patent/DK1833827T3/da
Priority to JP2007549617A priority patent/JP2008526758A/ja
Priority to AU2005322844A priority patent/AU2005322844A1/en
Priority to BRPI0519797-0A priority patent/BRPI0519797A/pt
Priority to AT05855868T priority patent/ATE510838T1/de
Priority to CA002592957A priority patent/CA2592957A1/en
Priority to EP05855868A priority patent/EP1833827B9/en
Application filed by Meda AB, 3M Innovative Properties Co, Graceway Pharmaceuticals LLC filed Critical Meda AB
Publication of WO2006074046A2 publication Critical patent/WO2006074046A2/en
Priority to IL184310A priority patent/IL184310A/en
Anticipated expiration legal-status Critical
Publication of WO2006074046A3 publication Critical patent/WO2006074046A3/en
Priority to NO20076651A priority patent/NO339859B1/no
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the compound 2-methyl- 1 -(2-methylpropyl)- 1 H-imidazo [4,5 -c] [ 1 ,5]naphthyridin- 4-amine has been found to be a useful immune response modifier (IRM) due to its ability to induce cytokine biosynthesis.
  • IRM immune response modifier
  • manufacturing pharmaceutical products can present many unforeseen challenges and new methods of preparation are needed.
  • the invention provides a method for preparing 2-methyl- 1 -(2- methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin-4-amine.
  • the method includes: providing 2-methyl-l-(2-methylpropyl)-5-oxido-lH-imidazo[4,5-c][l,5]naphthyridine in a carrier that includes a lower alcohol; combining the 2-methyl-l-(2-methylpropyl)-5-oxido- lH-imidazo[4,5-c][l,5]naphthyridine in the carrier with an ammonia- or ammonium- containing reagent and an arylsulfonyl halide to form a mixture; allowing the components of the mixture to react for a period of time sufficient to form 2-methyl- l-(2-methylpropyl)- lH-imidazo[4,5-c][l,5]naphthyridin-4-amine.
  • the method also includes combining the mixture with an aqueous base.
  • providing 2-methyl-l-(2-methylpropyl)-5-oxido-lH-imidazo[4,5- c][l,5]naphthyridine includes: providing 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5- c][l,5]naphthyridine (referred to above) in a carrier that includes a non-chlorinated solvent at a temperature of 25 °C to 70 °C; combining the 2-methyl- 1 -(2-methylpropyl)- IH- imidazo[4,5-c][l,5]naphthyridine in the carrier with an oxidizing agent to form a mixture and maintaining the mixture at a temperature of 25 °C to 70 °C for a period of time sufficient to form 2-methyl-l-(2-methylpropyl)-5-oxido-l//-imidazo[4,5- c][l,5]naphthyridine; and isolating at
  • providing 2-methyl- 1 -(2-methylpropyl)- li/-imidazo [4,5 - c][l,5]naphthyridine includes: providing N 4 -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine in a carrier that includes a non-chlorinated solvent at a temperature of 18 °C to 30 0 C; combining the N*-(2- methylpropyl)[l,5]naphthyridine-3,4-diamine in the carrier with an organic acid to form a mixture; combining the mixture that includes the iV 4 -(2-methylpropyl)[l,5]naphthyridine- 3,4-diamine and organic acid with a trialkyl orthoacetate at a temperature of 70 0 C to 100 0 C; and maintaining the temperature at 70 0 C to 100 °C for a period of time sufficient to form 2-
  • providing ⁇ -P-methylpropylXl ,5]naphthyridine-3,4-diamine includes: providing N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine in a carrier that includes a non-chlorinated solvent; combining the iV 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst to form a mixture; subjecting the mixture that includes the N 4 -(2-methylpropyl)-3- nitro[l ,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form ⁇ -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine; and removing at least a portion of the hydrogenation catalyst from the N 4 - ⁇ - methylpropyl)[l,
  • providing A/ 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine includes: providing 4-chloro-3-nitro[l,5]naphthyridine in a carrier that includes a water-miscible organic liquid; combining the 4-chloro-3- nitro[l,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture that includes the N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine; combining the mixture that includes the iV 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4- amine with water to form solid 7V 4 -(2-methylpropyl)-3-nitro[l ,5]naphthyridin-4-amine; and separating at least a portion of solid N 4 -(2-methylpropyl) in a carrier that includes
  • providing 4-chloro-3-nitro[l,5]naphthyridine includes: providing 3-nitro[l,5]naphthyridin-4-ol in a carrier that includes N 1 N- dimethylformamide; combining the 3-nitro[l,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3- nitro[l ,5]naphthyridine; combining the mixture that includes the 4-chloro-3- nitro[l,5]naphthyridine with water under conditions effective to form solid 4-chloro-3- nitro[l,5]naphthyridine; and separating at least a portion of the solid 4-chloro-3- nitro[l,5]naphthyridine from at least a portion of the mixture that includes the water.
  • providing 2-methyl-l-(2-methylpropyl)-5-oxido-l/z r - imidazo[4,5-c][l,5]naphthyridine includes: providing 3- nitro[l,5]naphthyridin-4-ol in a carrier including iV.N-dimethylformamide; combining the 3-nitro[l,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[l,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[l,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[l,5]naphthyridine; separating at least a portion of the solid 4-chloro-3.- nitro[l,5]naphthyridine from at least a portion of the mixture that
  • the invention provides a method for making 7V 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine.
  • the method includes: providing 3- nitro[l,5]naphthyridin-4-ol in a carrier including ⁇ N-dimethylformamide; combining the 3-nitro[l,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[l,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[l,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[l,5]naphthyridine; separating at least a portion of the solid 4-chloro-3- nitro[l ,5]naphthyridine from at least a portion of the mixture that includes the water; combining the separated solid 4-chlor
  • the invention provides a method for making 2-methyl- 1 -(2- methylpropyl)-5-oxido-l//-imidazo[4,5-c][l,5]naphthyridine.
  • the method includes: providing N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine in a carrier including toluene; combining the iV 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture; subjecting the mixture that includes the N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N 4 -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine; removing at least a portion of the hydrogen
  • providing iV 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine includes: providing 3- nitro[l,5]naphthyridin-4-ol in a carrier including Af N-dimethylformamide; combining the 3-nitro[l,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[l,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[l ,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[l,5]naphthyridine; separating at least a portion of the solid 4-chloro-3- nitro[l,5]naphthyridine from at least a portion of the mixture that includes the water; combining the separated solid 4-chloro-3
  • these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms.
  • Cyclic groups can be monocyclic or poly cyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, and cyclohexyl.
  • aryl in reference to "arylsulfonyl halide” includes carbocyclic aromatic rings or ring systems that may be unsubstituted or substituted. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • substituents that may be present on the aryl group include alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, cyano, aryl, aryloxy, and arylalkyleneoxy.
  • a "lower alcohol” i.e., a Ci -4 alcohol
  • Ci -4 alcohol is understood to be a straight chain or branched chain alcohol containing one to four carbon atoms. Examples include, methanol, ethanol, n-propanol, isopropanol, r ⁇ -butanol, .yeobutanol, and tert-butanol.
  • steps (1) and (2) can be carried out as discussed herein, and various other methods can be used to convert the product of step 2 (iV 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine) into the product of step 5 (2-methyl-l-(2-methylpropyl)- 5-oxido-l/i-imidazo[4,5-c][l,5]naphthyridine), which can then be used in the process of step (6) as described herein. Any one of steps (1) through (5) can also be carried out according to the methods described in U.S. Patent No. 6,194,425 (Gerster, et al).
  • the present invention provides a method for preparing 4-chloro-3-nitro[l,5]naphthyridine.
  • the method includes: providing 3-nitro[l,5]naphthyridin-4-ol in a carrier that includes ⁇ iV-dimethylformamide (DMF); combining the 3-nitro[l ,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[l,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[l,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[l,5]naphthyridine; and separating at least a portion of the solid 4-chloro-3-nitro[l,5]naphthyridine from at least a portion of the mixture that includes the water.
  • DMF ⁇ iV-dimethylformamide
  • this method is carried out under nitrogen, although other inert gases can be used (e.g., argon) if desired.
  • inert gases e.g., argon
  • the DMF not only functions as a reaction solvent, but it typically reacts first with phosphorus oxychloride to form an active intermediate.
  • combining the 3-nitro[l,5]naphthyridin-4-ol with phosphorous oxychloride involves using at least one equivalent of phosphorous oxychloride.
  • the phosphorous oxychloride is added to the 3-nitro- [l,5]naphthyridin-4-ol. Preferably, this addition occurs relatively slowly (e.g., over a period of at least 30 minutes).
  • the conditions effective to form 4-chloro-3- nitro[l,5]naphthyridine include a temperature of at least 15 °C. In some embodiments, the temperature is at least 20 0 C. In some embodiments, the conditions effective to form 4- chloro-3-nitro[l,5]naphthyridine include a temperature of no greater than 35 °C. In some embodiments, the temperature is no greater than 20 °C. In some embodiments, these conditions include a time period of at least one hour, and, if desired, up to 21 hours.
  • This method then involves forming solid (i.e., precipitating) 4-chloro-3- nitro[l,5]naphthyridine using water.
  • the mixture that includes the 4-chloro-3- nitro[l,5]naphthyridine is added to the water.
  • the conditions that allow for the formation of the solid include cooling the mixture that includes the water to a temperature of less than 20 °C. In certain embodiments, the temperature is less than 15 0 C. Generally, the water is pre-cooled, and during the addition, the mixture is maintained at a temperature of less than 20 0 C. In certain embodiments, the temperature is at least 5 0 C.
  • separating at least a portion of the solid 4-chloro-3- nitro[l,5]naphthyridine involves filtering the solid 4-chloro-3-nitro[l,5]naphthyridine from the mixture that includes the water.
  • a precipitate there are many other ways to separate the solid (i.e., a precipitate) from the mixture, such as decanting and centrifugation. After separation, the precipitate may optionally be washed with water to remove impurities.
  • separating at least a portion of the solid 4-chloro-3- nitro[l,5]naphthyridine occurs less than 30 minutes after combining the mixture that includes the 4-chloro-3-nitro[l,5]naphthyridine with water.
  • the solid 4-chloro-3-nitro[l,5]naphthyridine is used in the next step (step 2 of Scheme I, e.g., combined with isobutylamine, as discussed in greater detail below) within less than 4 hours of its preparation.
  • the present invention provides a method for preparing N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine.
  • This method includes: providing 4-chloro-3-nitro[l,5]naphthyridine in a carrier that includes a water-miscible organic liquid; combining the 4-chloro-3-nitro[l,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture including N 4 -(2- methylpropyl)-3-nitro[l,5]naphthyridin-4-amine; combining the mixture that includes the N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine with water; and separating at least a portion of solid N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine from at least a portion of the mixture
  • the water-miscible organic liquid is selected from the group consisting of tetrahydrofuran, dichloromethane, acetonitrile, and mixtures thereof. In some embodiments, the water-miscible organic liquid is tetrahydrofuran.
  • the 4-chloro-3-nitro[l,5]naphthyridine is combined with at least two equivalents of isobutylamine. This provides one equivalent used to scavenge the HCl formed during the reaction and another one to react with 4-chloro-3- nitro[l,5]naphthyridine. In some embodiments, at least 2.05 equivalents are used, and in some embodiments up to 2.4 equivalents are used if desired.
  • the isobutylamine is added to the 4-chloro-3-nitro[l,5]naphthyridine in the water-miscible organic liquid. This addition preferably occurs relatively slowly (e.g., over a period of at least 30 minutes).
  • the conditions effective to form N 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine include a temperature of at least 15 0 C. In some embodiments, the temperature is at least 20 °C. In some embodiments, the temperature is at most 30 0 C. In some embodiments, this temperature is maintained for at least 30 minutes, and in some embodiments for at least 3 hours.
  • Water is then typically used to precipitate solid N 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine, although solid 7V 4 -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine can form before the reaction mixture is added to water or water is added to the reaction mixture.
  • separating at least a portion of the solid N 4 -(2- methylpropyl)-3-nitro[l,5]naphthyridin-4-amine involves filtering the solid N 4 -(2- methylpropyl)-3-nitro[l,5]naphthyridin-4-amine.
  • the method can further include washing and drying this solid if desired.
  • the precipitate may optionally be washed with water to remove impurities.
  • there are many ways to dry the precipitate This includes, for example, using elevated temperatures, desiccation, reduced pressure, using a dry (e.g., nitrogen) atmosphere, and the like.
  • drying the precipitate occurs at a temperature range of 45 0 C to 55 0 C while under at least a partial vacuum.
  • at least partially drying the precipitate occurs under at least a partial vacuum.
  • the present invention provides a method for preparing N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine.
  • This method involves: providing N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine in a carrier that includes a non-chlorinated solvent; combining the N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4- amine in the carrier with a hydrogenation catalyst to form a mixture; subjecting the mixture that includes the ⁇ / 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form ⁇ / 4 -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine; and removing at least a portion of the hydrogenation catalyst from the
  • the non-chlorinated solvent is selected from the group consisting of toluene, butyl acetate, ethyl acetate, and combinations thereof. In some embodiments, the non-chlorinated solvent is toluene.
  • combining the N 4 -(2-methylpropyl)-3- nitro[l ,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst includes combining the N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture.
  • the hydrogenation catalyst and isopropanol can be added simultaneously or sequentially in either order.
  • the hydrogenation catalyst includes platinum, although it is believed that palladium may also work.
  • the hydrogenation catalyst is platinum on carbon.
  • a preferred load level of platinum on carbon is at least 1.5 weight percent of platinum metal on carbon. Typical load levels of platinum on carbon at up to 10 weight percent of platinum metal on carbon.
  • the conditions effective to form N 4 -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine include a temperature of at least 15 0 C. In some embodiments, this temperature is at least 18 °C. In some embodiments, the conditions effective to form N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine include a temperature of no greater than 30 0 C. In some embodiments, this temperature is no greater than 25 0 C.
  • the conditions effective to form N 4 -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine include a hydrogen pressure of 1 x 10 5 Pa to 3 x 10 5 Pa (i.e., 1 bar to 3 bars), although higher pressures can be used. It is desirable to use the lowest hydrogen pressure possible to avoid equipment concerns.
  • the conditions effective to form I ⁇ -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine include a time period of at least 3 hours. Shorter reaction times may be possible, however, this can depend on the hydrogenation vessel (stirrer) and on the operating conditions (e.g., dilution, quantity of catalyst). Longer reaction times (e.g., up to 22 hours) are also possible.
  • the method involves subsequently removing at least a portion of the isopropanol from the mixture of N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4- diamine in a carrier that includes toluene and isopropanol.
  • the hydrogenation catalyst is removed and, in some embodiments, the
  • N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine is used in the next step (step 4 of Scheme I, e.g., combined with an organic acid, as discussed in greater detail below) without being isolated.
  • the present invention provides a method for preparing 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine.
  • the method includes: providing N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine in a carrier including a non-chlorinated solvent at a temperature of at least 18 0 C (and typically no more than 30 0 C); combining the N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine in the carrier with an organic acid to form a mixture; combining the mixture that includes the N 4 -(2-methylpropyl)[l 5 5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate at a temperature of at least 70 0 C (and typically no more than 100 0 C, and preferably no more than 90
  • the non-chlorinated solvent is selected from the group consisting of toluene, butyl acetate, ethyl acetate, and combinations thereof. In some embodiments, the non-chlorinated solvent is toluene.
  • the organic acid is selected from the group consisting ofp- toluenesulfonic acid, trifluoroacetic acid, ethanesulfonic acid, and mixtures thereof. In some embodiments, the organic acid is p-toluenesulfonic acid.
  • At least 0.02 equivalent of an organic acid is used. In some embodiments, up to 0.08 equivalent of an organic acid is used.
  • the organic acid is added to the ⁇ /4 -(2-methylpropyl)[l,5]naphthyridine- 3,4-diamine in a carrier including a non-chlorinated solvent (e.g., the material from step (3) of Scheme I).
  • a carrier including a non-chlorinated solvent e.g., the material from step (3) of Scheme I.
  • the trialkyl orthoacetate can be triethyl orthoacetate or trimethyl orthoacetate. In some embodiments, the trialkyl orthoacetate is triethyl orthoacetate. In some embodiments, at least one equivalent of the trialkyl orthoacetate is used.
  • At least 1.1 equivalents of a trialkyl orthoacetate are used. In some embodiments, up to 1.4 equivalents of a trialkyl orthoacetate are used.
  • combining the mixture that includes the iV 4 -(2- methylpropyl)[l,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate occurs by heating the mixture of N 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine and organic acid to a temperature of 70 °C to 100 0 C, followed by adding the trialkyl orthoacetate to the mixture. Generally, this addition occurs relatively slowly (e.g., over a period of at least 30 minutes).
  • maintaining the temperature at 70 0 C to 100 0 C for a period time sufficient to form 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine involves maintaining the temperature at 70 0 C to 100 0 C for at least 30 minutes. In some embodiments, the temperature is maintained at 70 0 C to 100 °C for at least 2 hours. In some embodiments, the temperature is maintained at 70 0 C to 100 °C for up to 6 hours.
  • the method further includes a step of cooling the mixture that includes 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine to a temperature of no greater than 70 °C, preferably no greater than 55 0 C. Typically, this temperature is at least 25 0 C, preferably at least 40 °C, and more preferably at least 45 °C.
  • the 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5- c][l,5]naphthyridine is used in the next step of the process (step 5 of Scheme I, e.g., and combined with an oxidizing agent) without being isolated.
  • the present invention provides a method for preparing 2-methyl-l-(2-methylpropyl)-5-oxido-lH-imidazo[4,5-c][l,5]naphthyridine.
  • This method includes: providing 2-methyl-l-(2-methylpropyl)-l//-imidazo[4,5- c][l,5]naphthyridine in a carrier that includes a non-chlorinated solvent at a temperature of at least 25 °C (and typically up to 70 0 C); combining the 2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c] [1 ,5]naphthyridine in the carrier with an oxidizing agent to form a mixture and maintaining the mixture at a temperature of at least 25 0 C (and typically up to 70 0 C) for a period of time sufficient to form 2-methyl-l-(2-methylpropyl)-5-oxido-li : /- imi
  • the non-chlorinated solvent is selected from the group consisting of toluene, butyl acetate, ethyl acetate, and combinations thereof. In some embodiments, the non-chlorinated solvent is toluene.
  • the temperature of the 2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c][l,5]naphthyridine in a carrier that includes a non-chlorinated solvent is a temperature of at least 40 °C, and in other embodiments, the temperature is at least 45 °C. In some embodiments, the temperature of the 2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c][l,5]naphthyridine in a carrier that includes a non-chlorinated solvent is a temperature of at most 55 0 C.
  • the oxidizing agent includes peracetic acid, although other similar oxidizing agents could be used if desired. In some embodiments, at least one equivalent of oxidizing agent (preferably peracetic acid) is used. In some embodiments, at least 1.2 equivalents of oxidizing agent are used.
  • the oxidizing agent is added to the 2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c][l,5]naphthyridine.
  • the oxidizing agent addition is generally exothermic. With peracetic acid, there is a theoretical adiabatic temperature rise of 29 0 C if all the acid is added at once. Therefore, this addition is preferably carried out in a controlled manner to maintain the reaction mixture in the desired temperature range. Preferably, the addition is carried out over at least 2 hours. Preferably, subsequent stirring is carried out for a period of at least 4 hours.
  • the mixture of 2-methyl-l-(2-methylpropyl)-lH- imidazo[4,5-c][l,5]naphthyridine in the carrier with an oxidizing agent is maintained at a temperature of at least 40 0 C. In some embodiments, the mixture of 2 -methyl- 1 -(2- methylpropyl)-l/f-imidazo[4,5-c][l,5]naphthyridine in the carrier with an oxidizing agent is maintained at a temperature of at least 45 °C.
  • the mixture of 2- methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine in the carrier with an oxidizing agent is maintained at a temperature of at most 55 °C.
  • the period of time sufficient to form 2 -methyl- 1 -(2- methylpropyl)-5-oxido-l/J-imidazo[4,5-c][l,5]naphthyridine includes a period of time sufficient to react at least 80% of the 2-methyl-l-(2-methylpropyl)-li ⁇ -imidazo[4,5- c][l,5]naphthyridine.
  • the period of time sufficient to react at least 80% of the 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridine is at least 5 hours (and often up to 7 hours).
  • isolating the 2-methyl-l-(2-methylpropyl)-5-oxido-lH- imidazo[4,5-c][l,5]naphthyridine includes: combining the mixture that includes the 2- methyl-l-(2-methylpropyl)-5-oxido-lH-imidazo[4,5-c][l,5]naphthyridine with an aqueous solution of a reducing agent followed by an aqueous base; cooling the mixture to form solid 2-methyl-l -(2-methylpropyl)-5-oxido-lH-imidazo[4,5-c][l ,5]naphthyridine; and separating at least a portion of the solid 2-methyl-l-(2-methylpropyl)-5-oxido-lH- imidazo[4,5-c][l,5]naphthyridine from at least a portion of the mixture.
  • the reducing agent is selected from the group consisting of sodium metabisulfrte, sodium sulfite, ferrous sulfate, and combinations thereof. In some embodiments, the reducing agent is sodium metabisulfite.
  • an aqueous solution of at least 0.1 equivalent sodium metabisulfite is used. In some embodiments, an aqueous solution of at least 0.3 equivalent sodium metabisulfite is used.
  • a sufficient amount of aqueous base is used to adjust the mixture to a pH of greater than 10.
  • 4 to 4.5 equivalents of sodium hydroxide are used to reach the targeted pH.
  • six to ten milliliters of water per gram of 2-methyl-l-(2- methylpropyl)-5-oxido-lH-imidazo[4,5-c][l,5]naphthyridine are combined with a mixture of eight to twelve milliliters of toluene per gram of 2-methyl-l-(2-methylpropyl)-5-oxido- lH-imidazo[4,5-c][l,5]naphthyridine.
  • the volume ratio of water to toluene is 0.8:1.
  • the cooling step involves cooling to a temperature of no greater than 20 °C. In some embodiments, the cooling step involves cooling to a temperature of no greater than 7 0 C. In some embodiments, the cooling step involves cooling to a temperature of at least 0 °C. In some embodiments, the cooling step involves cooling to a temperature of at least 3 0 C.
  • separating at least a portion of the solid 2-methyl-l-(2- methylpropyl)-5-oxido-lH-imidazo[4,5-c][l,5]naphthyridine involves separating by centrifugation.
  • a precipitate there are many other ways to separate the solid (i.e., a precipitate) from the mixture, such as decanting and filtering.
  • the present invention provides a method for preparing 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin-4-amine.
  • the method includes providing 2-methyl-l-(2-methylpropyl)-5-oxido-lH-imidazo[4,5- e][l,5]naphthyridine in a carrier that includes a lower alcohol; combining the 2-methyl-l- (2-methylpropyl)-5-oxido-lH-imidazo[4,5-c][l,5]naphthyridine in the carrier with an ammonia- or ammonium-containing reagent and an arylsulfonyl halide to form a mixture; allowing the components of the mixture to react for a period of time sufficient to form 2- methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin
  • the step of providing 2-methyl-l-(2-methylpropyl)-5-oxido- lH-imidazo[4,5-c][l,5]naphthyridine in a carrier that includes a lower alcohol occurs at a temperature of at least 20 0 C. In some embodiments, this temperature is no greater than 30 0 C.
  • the ammonia- or ammonium- containing reagent is preferably added prior to the arylsulfonyl halide.
  • the ammonia- or ammonium-containing reagent includes ammonium hydroxide in water.
  • the ammonia- or ammonium-containing reagent includes less than ten equivalents of ammonium hydroxide.
  • combining the 2-methyl- l-(2-methyrpropyl)-5-oxido- IH- imidazo[4,5-c] [1 ,5]naphthyridine in the carrier with an ammonia- or ammonium- containing reagent is carried out at a temperature of at least 20 0 C. In some embodiments, this temperature is no greater than 30 0 C.
  • the ammonia- or ammonium-containing reagent is added to the 2-methyl- 1 -(2-methylpropyl)-5-oxido- 1 H-imidazo [4,5 -c] [ 1 ,5]naphthyridine. This addition preferably occurs relatively quickly with continuous agitation.
  • agitating a mixture such as stirring, shaking, and sonicating.
  • the arylsulfonyl halide is benzenesulfonyl chloride orp- toluenesulfonyl chloride.
  • combining an arylsulfonyl halide (typically after the ammonia- or ammonium- containing compound is added) is carried out at a temperature of at least 20 0 C. In some embodiments, this temperature is no greater than 30 0 C.
  • allowing the components of the mixture to react for a period of time sufficient to form 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5- c] [1 ,5]naphthyridin-4-amine is carried out at a temperature of at least 20 0 C. In some embodiments, this temperature is no greater than 30 0 C.
  • the period of time sufficient to form 2-methyl- 1 -(2- methylpropyl)-lH " -imidazo[4,5-c][l,5]naphthyridin-4-amine is at least 45 minutes. In some embodiments, this period of time is no greater than 75 minutes.
  • the method further includes a step of combining the mixture with an aqueous base. Typically, sufficient aqueous base is added to adjust the mixture to a pH of greater than 8, and preferably greater than 10.
  • the aqueous base is aqueous sodium hydroxide, although other alkali metal hydroxides (e.g., potassium hydroxide) or other aqueous bases (e.g., sodium carbonate, potassium carbonate) could be used if desired.
  • the method further includes a step of cooling the mixture to a temperature of no greater than 15 0 C. In some embodiments, this temperature is at least 15 0 C.
  • this method can further include separating at least a portion of the resultant 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5-c][l,5]naphthyridin-4-amine from at least a portion of the mixture, and, if desired, further include washing and at least partially drying the resultant 2-methyl-l-(2-methylpropyl)-lH-imidazo[4,5- c] [1 ,5]naphthyridin-4-amine.
  • a precipitate from the mixture, such as filtering, decanting, and centrifugation. After separation, the precipitate may optionally be washed with water to remove impurities. Furthermore, one skilled in the art will appreciate that there are many ways to at least partially dry the precipitate. This includes, for example, using elevated temperatures, desiccation, reduced pressure, using a dry (e.g., nitrogen) atmosphere, and the like. In one embodiment, at least partially drying the precipitate occurs at a temperature range of 25 0 C to 60 0 C under at least a partial vacuum.
  • Isobutylamine (9.4 kg, 12.8 L, 130 mol) was added to a stirred suspension of the material from Part A (20.55 kg) in tetrahydrofuran (67 L) over a period of 77 minutes while maintaining a reaction temperature of 20 0 C to 27 0 C.
  • the addition of isobutylamine was followed by a rinse with tetrahydrofuran (5 L).
  • the reaction was stirred for 190 minutes at a temperature of 20 0 C to 24 0 C, and then water (288 L) was added over a period of about one hour while maintaining the reaction temperature at 21.4 0 C to 23.8 0 C.
  • the resulting mixture was stirred at 20 0 C to 24 0 C for 75 minutes and then filtered.
  • the isolated solid was washed with water (4 x 25 L) that had also been used to rinse the reaction vessel, pulled dry under vacuum, and further dried under vacuum for 60 hours at a temperature of 45 0 C to 55 0 C to provide 13.7 kg of N 4 -(2-methylpropyl)-3- nitro[l ,5]naphthyridin-4-amine.
  • the resulting mixtures were cooled to a temperature of approximately 10 0 C over a period of 60 minutes.
  • a solid formed in each mixture and was isolated by filtration, and each solid was washed with demineralized water (2 x 2 L and 1 x 1 L) until the pH of the filtrate equaled the pH of demineralized water.
  • Isobutylamine (784 g, 10.7 mol) was added to a suspension of the material from Part A in tetrahydrofuran (6 L) over a period of 45 minutes while maintaining a reaction temperature of 17 0 C to 27 0 C. When the addition was 75% complete, yellow needles formed in the solution. After the addition was complete, the reaction was stirred for 30 minutes at a temperature of 21.5 0 C to 22.5 0 C and then added with stirring to two portions of demineralized water (12 L each). The resulting mixtures were stirred for 30 minutes. The solid formed in each mixture was isolated by filtration, and each solid was washed with demineralized water (2 x 2 L) until the pH of the filtrate equaled the pH of demineralized water. The solids were then dried overnight on the filter funnels to provide 1.225 kg of N 4 -(2-methylpropyl)-3-nitro[l,5]naphthyridin-4-amine as a yellow solid.
  • a hydro genation vessel was charged with ⁇ -(2-methylpropyl)-3- nitro[l,5]naphthyridin-4-amine (7.50 kg, 30.5 mol) and toluene (125.0 kg).
  • reaction mixture was then placed under hydrogen pressure (2.4 x 10 5 Pa, 2.4 bars) for six hours while stirring and maintaining the temperature at 22 0 C.
  • the reaction mixture was then filtered, and the filter cake was washed with toluene (30.0 kg).
  • the filtrate was concentrated under reduced pressure (1 x 10 4 Pa, 0.1 bar) at approximately 50 0 C to provide a solution of iV 4 -(2-methylpropyl)[l,5]naphthyridine-3,4-diamine in toluene (75 L, approximately 10 mL/g).
  • Part C Peracetic acid (7.15 kg of 40% w/w) was added over a period of 60 minutes to the
  • aqueous ammonium hydroxide (four equivalents) was quickly added with continuous stirring to a suspension of 2-methyl-l-(2- methylpropyl)-l/f-imidazo[4,5-c][l,5]naphthyridin-5-oxide in methanol (6 mL/g) while maintaining the reaction temperature at 20 0 C to 24 0 C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred until all material was dissolved. With continuous stirring, benzenesulfonyl chloride (2 equivalents) was added over a period of 15 to 45 minutes while maintaining the reaction temperature at 20 0 C to 30 0 C. Methanol was used to rinse the addition vessel and added to the reaction.
  • reaction was stirred for 45 to 75 minutes at 20 0 C to 24 0 C.
  • Aqueous sodium hydroxide (3 equivalents of 10% w/w) was added to the reaction mixture over a period of 15 to 45 minutes while maintaining the reaction temperature between 20 0 C and 25 0 C.
  • Water (10 L) used to rinse the addition vessel, was added to the reaction mixture.
  • the resulting mixture was cooled to 10 0 C and stirred for 2 to 24 hours. A precipitate was present and was isolated by filtration and washed with deionized water until the filtrate was pH 7.
  • reaction was stirred for one hour at 22 0 C.
  • a solution of aqueous sodium hydroxide (15.0 kg of 25% w/w) and water (34.0 kg) was added to the reaction mixture over a period of 30 minutes at 22 0 C to adjust the mixture to p ⁇ 13.
  • the resulting mixture was cooled to 11 0 C and stirred at that temperature for three hours and then separated by centrifugation.

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PCT/US2005/047375 2004-12-30 2005-12-28 Process for preparing 2-methyl-1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine Ceased WO2006074046A2 (en)

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US11/794,584 US8436176B2 (en) 2004-12-30 2005-12-18 Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
AT05855868T ATE510838T1 (de) 2004-12-30 2005-12-28 Verfahren zur herstellung von 2-methyl-1-(2- methylpropyl)-1h-imidazoä4,5-cüä1,5ünaphthyridi - 4-amin
DK05855868.5T DK1833827T3 (da) 2004-12-30 2005-12-28 Fremgangsmåde til fremstilling af 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amin
JP2007549617A JP2008526758A (ja) 2004-12-30 2005-12-28 ２−メチル−１−（２−メチルプロピル）−１ｈ−イミダゾ［４，５−ｃ］［１，５］ナフチリジン−４−アミンの製造方法
AU2005322844A AU2005322844A1 (en) 2004-12-30 2005-12-28 Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
BRPI0519797-0A BRPI0519797A (pt) 2004-12-30 2005-12-28 método para a preparação de 2-metil-1-(2-metilpropil)-1h-imidazo [4, 5-c] [1, 5] naftiridin-4-amina, método para a obtenção de n4-(2-metilpropil)-3-nitro [1, 5] naftiridin-4-amina e método para a obtenção de 2-metil-1-(2-metilpropil)-5-oxido-1h-imidazo [4, 5-c] [1, 5] naftiridina
CA002592957A CA2592957A1 (en) 2004-12-30 2005-12-28 Process for preparing 2-methyl-1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine
PL05855868T PL1833827T3 (pl) 2004-12-30 2005-12-28 Sposób wytwarzania 2-metylo-1-(2-metylopropylo)-1H-imidazo[4,5-c][1,5]naftyrydyno-4-aminy
EP05855868A EP1833827B9 (en) 2004-12-30 2005-12-28 Process for preparing 2-methyl-1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine
MX2007008131A MX2007008131A (es) 2004-12-30 2005-12-28 Proceso para preparar 2-metil-1-(2-metilpropil)-1h-imidazo[4,5-c][ 1,5]naftiridin-4-amina.
IL184310A IL184310A (en) 2004-12-30 2007-06-28 Process for preparing 2-methyl-1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine
NO20076651A NO339859B1 (no) 2004-12-30 2007-12-21 Fremgangsmåte for fremstilling av 2-metyl-l-(2-metylpropyl)-1H-imidazo[4,5-c][1,5]naftyridin-4-amin

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