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(11) | EP 1 833 827 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
| Note: Bibliography reflects the latest situation |
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PROCESS FOR PREPARING 2-METHYL-1-(2-METHYLPROPYL)-1H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-4-AMINE VERFAHREN ZUR HERSTELLUNG VON 2-METHYL-1-(2-METHYLPROPYL)-1H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-4-AMIN PROCEDE DE PREPARATION DE 2-METHYL-1-(2-METHYLPROPYL)-1H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-4-AMINE |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present invention claims priority to U.S. Provisional Application Serial No. 60/641129, filed on December 30, 2004, and to U.S. Provisional Application Serial No. 60/708679, filed on August 16, 2005, both of which are incorporated herein by reference in their entirety.
BACKGROUND
[0002] The compound 2-methyl-1-(2-methylpropyl)-1H-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. However, manufacturing pharmaceutical products can present many unforeseen challenges and new methods of preparation are needed.
SUMMARY OF THE INVENTION
[0003] In one aspect, the invention provides a method for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The method includes: providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier that includes methanol or ethanol; combining the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier ammonium hydroxide and benzenesulfonyl chloride or p-toluenesulfonyl chloride to form a mixture; allowing the components of the mixture to react for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. Preferably, the method also includes combining the mixture with an aqueous base.
[0004] Preferably, providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine includes: providing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]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)-1H 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 25 °C to 70 °C for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
[0005] Preferably, providing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (referred to above) includes: providing N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier that includes a non-chlorinated solvent at a temperature of 18 °C to 30 °C; combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with an organic acid to form a mixture; combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate at a temperature of 70 °C to 100 °C; and maintaining the temperature at 70 °C to 100 °C for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine.
[0006] Preferably, providing N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine (referred to above) includes: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier that includes a non-chlorinated solvent; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; and removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthynidine-3,4-diamine.
[0007] Preferably, providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridine-4-amine (referred to above) includes: providing 4-chloro-3-nitro[1,5]naphthyridine in a carrier that includes a water-miscible organic liquid; combining the 4-chloro-3-mtro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; combining the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture that includes the water.
[0008] Preferably, providing 4-chloro-3-nitro[1,5]naphthyridine (referred to above) includes: providing 3-nitro[1,5]naphthyridin-4-ol in a carrier that includes N,N dimethylformamide; combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine; and separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture that includes the water.
[0009] In a preferred embodiment, providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine (referred to above) includes: providing 3-nitro[1,5]naphthyridin-4-ol in a carrier including N,N-methylformamide; combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine; separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture that includes the water; combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier that includes a water-miscible organic liquid; combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture that includes N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; combining the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture that includes the water; and converting the solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine to 2-ethyl-1-(2-methylpxopyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
[0010] In one aspect, the invention provides a method for making N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine. The method includes: providing 3-nitro[1,5]naphthyridin-4-ol in a carrier including N,N-dimethylformamide; combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine; separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture that includes the water; combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier that includes tetrahydrofuran; combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture including N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; combining the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture that includes the water.
[0011] In one aspect, the invention provides a method for making 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. The method includes: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier including toluene; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamuizxe in a carrier that includes toluene and isopropanol; heating the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20 °C to 55°C; combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture: combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70 °C to 100 °C; maintaining the temperature at 70 °C to 100 °C for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]napbthyridine; cooling the mixture that includes 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45°C to 55 °C; combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent including peracetic acid to form a mixture; maintaining the mixture that includes the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45 °C to 55 °C for a time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
[0012] In a preferred embodiment, providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (referred to above) includes: providing 3-nitro[1,5]naphthyridin-4-ol in a carrier including N,N-dimethylformamide; combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions elective to form solid 4-cldoro-3-nitro[1,5]naphthyridine; separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture that includes the water; combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier including tetrahydrofuran; combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture that includes N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; combining the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture that includes the water.
[0013] The terms "comprising" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.
[0014] As used herein, "a", "an", "the", "at least one", "at least a portion of" and "one or more" are used interchangeably.
[0015] The words "preferred" and "preferably" refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.
[0016] As used herein, the terms "alkyl" and the prefix "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms. In some embodiments, 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 polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, and cyclohexyl.
[0017] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Guidance is also provided herein through lists of examples, which can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0018] 2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine can be prepared according to the route shown in Scheme I. Each of these "steps" refers to a series of reactions and conditions described in greater detail below, and specifically as described in the EXAMPLES below.
[0019] It should be understood that each of these steps may be independently carried out with various of the other steps described herein and/or with various other methods not specifically described herein, such as, for example, in U.S. Patent No. 6,194,425 (Gerster, et al.). For example, 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 (N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine) into the product of step 5 (2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]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.).
[0020] Referring to Scheme 1 (step 1), the present invention provides a method for preparing 4-chloro-3-nitro[1,5]naphthyridine. In some embodiments, the method includes: providing 3-nitro[1,5]naphthyridin-4-ol in a carrier that includes N,N-dimethylformamide (DMF); combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine; combining the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine; and separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture that includes the water.
[0021] Generally, this method is carried out under nitrogen, although other inert gases can be used (e.g., argon) if desired.
[0022] In this method, the DMF not only functions as a reaction solvent, but it typically reacts first with phosphorus oxychloride to form an active intermediate.
[0023] In some embodiments, combining the 3-nitro[1,5]naphthyridin-4-ol with phosphorous oxychloride involves using at least one equivalent of phosphorous oxychloride. Generally, the phosphorous oxychloride is added to the 3-nitro-[1,5]naphthyridin-4-ol, Preferably, this addition occurs relatively slowly (e.g., over a period of at least 30 minutes).
[0024] In some embodiments, the conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine include a temperature of at least 15°C. In some embodiments, the temperature is at least 20 °C. In some embodiments, the conditions effective to form 4-chloro-3-nitro[1,5]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.
[0025] This method then involves forming solid (i.e., precipitating) 4-chloro-3-nitro[1,5]naphthyridine using water. Typically, the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine is added to the water. In some embodiments, 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 °C. Generally, the water is pre-cooled, and during the addition, the mixture is maintained at a temperature of less than 20 °C. In certain embodiments, the temperature is at least 5 °C.
[0026] In some embodiments, separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine involves filtering the solid 4-chloro-3-nitro[1,5]naphthyridine from the mixture that includes the water. One skilled in the art will appreciate, however, that 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.
[0027] In some embodiments, separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine occurs less than 30 minutes after combining the mixture that includes the 4-chloro-3-nitro[1,5]naphthyridine with water.
[0028] In some embodiments, the solid 4-chloro-3-nitro[1,5]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.
[0029] Referring to Scheme 1 (step 2), the present invention provides a method for preparing N4-(2-methylpzopyl)-3-nitro[1,5]naphthyridin-4-amine. This method includes: providing 4-chloro-3-nitro[1,5]naphthyridine in a carrier that includes a water-miscible organic liquid; combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture including N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; combining the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water; and separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture that includes the water.
[0030] In some embodiments, 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.
[0031] In some embodiments, the 4-chloro-3-nitro[1,5]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[1,5]naphthyridine. In some embodiments, at least 2.05 equivalents are used, and in some embodiments up to 2.4 equivalents are used if desired.
[0032] Generally, the isobutylamine is added to the 4-chloro-3-mtro[1,5]naphthyridine in the water-miscible organic liquid. This addition preferably occurs relatively slowly (e.g., over a period of at least 30 minutes).
[0033] In some embodiments, the conditions effective to form N4-(2-methylpropyl)-3-nitro[1,5]naphthyAdin-4-amlre include a temperature of at least 15°C. In some embodiments, the temperature is at least 20 °C. In some embodiments, the temperature is at most 30 °C. In some embodiments, this temperature is maintained for at least 30 minutes, and in some embodiments for at least 3 hours.
[0034] Water is then typically used to precipitate solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine, although solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine can form before the reaction mixture is added to water or water is added to the reaction mixture.
[0035] In some embodiments, separating at least a portion of the solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine involves filtering the solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine. One skilled in the art will appreciate, however, that there are many other ways to separate the solid (i.e., a precipitate) from the mixture, such as decanting and centrifugation.
[0036] The method can further include washing and drying this solid if desired. For example, after separation, the precipitate may optionally be washed with water to remove impurities. One skilled in the art will appreciate that 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. In one embodiment, drying the precipitate occurs at a temperature range of 45 °C to 55 °C while under at least a partial vacuum. In another method, at least partially drying the precipitate occurs under at least a partial vacuum.
[0037] Referring to Scheme 1 (step 3), the present invention provides a method for preparing N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine. This method involves: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier that includes a non-chlorinated solvent; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyI)[l,5]naphthyridine-3,4-diamine; and removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine.
[0038] In some embodiments, 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.
[0039] In some embodiments, combining the N4-(2-methylpropyl)-3-natro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst includes combining the N4-(2-methylpropyl)-3-nitro[1,5]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.
[0040] In some embodiments, the hydrogenation catalyst includes platinum, although it is believed that palladium may also work. Preferably 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.
[0041] In some embodiments, the conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine include a temperature of at least 15 °C. In some embodiments, this temperature is at least 18°C. In some embodiments, the conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine include a temperature of no greater than 30 °C. In some embodiments, this temperature is no greater than 25°C.
[0042] In some embodiments, the conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine include a hydrogen pressure of 1 x 105 Pa to 3 x 105 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.
[0043] In some embodiments, the conditions effective to form N4-(2-methylpropyl)[1,5]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.
[0044] In some embodiments, the method involves subsequently removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier that includes toluene and isopropanol.
[0045] Generally, the hydrogenation catalyst is removed and, in some embodiments, the N4-(2-methylpropyl)[1,5]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.
[0046] Referring to Scheme 1 (step 4), the present invention provides a method for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,3-c][1,5]naphthyridine. The method includes: providing N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier including a non-chlorinated solvent at a temperature of at least 18 °C (and typically no more than 30 °C); combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with an organic acid to form a mixture; combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate at a temperature of at least 70 °C (and typically no more than 100 °C, and preferably no more than 90 °C); and maintaining the temperature at at least 70 °C (and typically no more than 100 °C) for a sufficient time to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphhyridine.
[0047] In some embodiments, 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.
[0048] In some embodiments, the organic acid is selected from the group consisting of p-toluenesulfonic acid, trifluoroacetic acid, ethanesulfonic acid, and mixtures thereof. In some embodiments, the organic acid is p-toluenesulfonic acid.
[0049] In some embodiments, 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.
[0050] Generally, the organic acid is added to the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier including a non-chlorinated solvent (e.g., the material from step (3) of Scheme I).
[0051] In some embodiments, the trialkyl orthoacetate can be triethyl orthoacetate or trimethyl orthoacetate. In some embodiments, the trialkyl orthoacetate is triethyl orthoacetate.
[0052] In some embodiments, at least one equivalent of the trialkyl orthoacetate is used. In some embodiments, 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.
[0053] In some embodiments, combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate occurs by heating the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid to a temperature of 70 °C to 100 °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).
[0054] In some embodiments, maintaining the temperature at 70 °C to 100 °C for a period time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine involves maintaining the temperature at 70 °C to 100 °C for at least 30 minutes. In some embodiments, the temperature is maintained at 70 °C to 100 °C for at least 2 hours. In some embodiments, the temperature is maintained at 70 °C to 100 °C for up to 6 hours.
[0055] In some embodiments, the method further includes a step of cooling the mixture that includes 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of no greater than 70 °C, preferably no greater than 55 °C. Topically, this temperature is at least 25 °C, preferably at least 40 °C, and more preferably at least 45 °C.
[0056] In some embodiments, the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]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.
[0057] Referring to Scheme 1 (step 5), the present invention provides a method for preparing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. This method includes: providing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier that includes a non-chlorinated solvent at a temperature of at least 25°C (and typically up to 70 °C); combining the 2-methyl-1-(2-methylpropyl)-1H-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 °C (and typically up to 70 °C) for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
[0058] In some embodiments, 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.
[0059] In some embodiments, the temperature of the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin,e 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-1-(2-methylpropyl)-1H imidazo[4,5-c][1,5]naphthyridine in a carrier that includes a non-chlorinated solvent is a temperature of at most 55 °C.
[0060] In some embodiments, 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.
[0061] Generally, the oxidizing agent is added to the 2-methyl-1-(2-methylpropyl)-1H imidazo[4,5-c][1,5]naphthyridine.
[0062] The oxidizing agent addition is generally exothermic. With peracetic acid, there is a theoretical adiabatic temperature rise of 29 °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.
[0063] In some embodiments, the mixture of 2-methyl-1-(2-methylpzvpyl)-1H imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent is maintained at a temperature of at least 40 °C. In some embodiments, the mixture of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent is maintained at a temperature of at least 45 °C. In some embodiments, the mixture of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent is maintained at a temperature of at most 55 °C.
[0064] In some embodiments, the period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine includes a period of time sufficient to react at least 80% of the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine. In some embodiments, the period of time sufficient to react at least 80% of the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridnne is at least 5 hours (and often up to 7 hours).
[0065] In some embodiments, isolating the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyndine includes: combining the mixture that includes the 2-methyl-1-(2-methylpropyl)-5-oxado-1H-imidazo[4,5-c][1,5]naphthyridine with an aqueous solution of a reducing agent followed by an aqueous base; cooling the mixture to form solid 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and separating at least a portion of the solid 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine from at least a portion of the mixture.
[0066] In some embodiments, the reducing agent is selected from the group consisting of sodium metabisulfite, sodium sulfite, ferrous sulfate, and combinations thereof. In some embodiments, the reducing agent is sodium metabisulfite.
[0067] In some embodiments, 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.
[0068] In some embodiments, a sufficient amount of aqueous base is used to adjust the mixture to a pH of greater than 10. Typically, 4 to 4.5 equivalents of sodium hydroxide are used to reach the targeted pH.
[0069] In some embodiments, six to ten milliliters of water per gram of 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine are combined with a mixture of eight to twelve milliliters of toluene per gram of 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. Preferably, the volume ratio of water to toluene is 0.8:1.
[0070] In some embodiments, 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 °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°C.
[0071] In some embodiments, separating at least a portion of the solid 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine involves separating by centrifugation. One skilled in the art will appreciate, however, that there are many other ways to separate the solid (i.e., a precipitate) from the mixture, such as decanting and filtering.
[0072] Referring to Scheme 1 (step 6), the present invention provides a method for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine. The method includes providing 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in a carrier that includes methanol or ethanol; combining the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with ammonium hydroxide in water and an benzenesulfonyl chloride or p-toluenesulfonyl chloride to form a mixture; allowing the components of the mixture to react for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
[0073] Generally, this method is carried out under nitrogen, although other inert gases can be used (e.g., argon) if desired.
[0074] In some embodiments, the step of providing 2-methyl-1-(2-methylpropyl)-5-oxido, 1H-imidazo[4,5-c][1,5]naphthyridine in a carrier that includes methanol or ethanol occurs at a temperature of at least 20 °C. In some embodiments, this temperature is no greater than 30 °C.
[0075] In some embodiments of this method, the ammonium hydroxide in water is preferably added prior to the benzenesulfonyl chloride or p-toluenesulfonyl chloride.
[0076] In The ammonia- or ammonium-containing reagent is ammonium hydroxide in water. In some embodiments, the ammonia- or ammonium-containing reagent includes less than ten equivalents of ammonium hydroxide.
[0077] In some embodiments, combining the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with ammonium hydroxide in water is carried out at a temperature of at least 20 °C. In some embodiments, this temperature is no greater than 30 °C.
[0078] In some embodiments, the ammonium hydroxide in water is added to the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. This addition preferably occurs relatively quickly with continuous agitation. One skilled in the art will appreciate that there are many means for agitating a mixture such as stirring, shaking, and sonicating.
[0080] In some embodiments, combining benzenesulfonyl chloride or p-toluenesulfonyl chloride (typically after the ammonium hydroxide in water is added) is carried out at a temperature of at least 20 °C. In some embodiments, this temperature is no greater than 30 °C.
[0081] In some embodiments, allowing the components of the mixture to react for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,3-c][1,5]naphthyridin-4-arnine is carried out at a temperature of at least 20°C. In some embodiments, this temperature is no greater than 30 °C.
[0082] In some embodiments, the period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine is at least 45 minutes. In some embodiments, this period of time is no greater than 75 minutes.
[0083] In some embodiments, 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,
[0084] In some embodiments of this method, 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.
[0085] In some embodiments, the method further includes a step of cooling the mixture to a temperature of no greater than 15°C. In some embodiments, this temperature is at least 15 °C.
[0086] In some embodiment this method can further include separating at least a portion of the resultant 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]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-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin4-amine.
[0087] One skilled in the art will appreciate that there are many ways to separate 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 °C to 60 °C under at least a partial vacuum.
EXAMPLES
[0088] Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.
Example 1
Preparation of N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amine
Part A
[0089] Under a nitrogen atmosphere, a suspension of 3-nitro[1,5]naphthyridine-4-ol (12.00 kg, 67-78 mol) in DMF (49 L) was stirred for 30 minutes at a temperature of 20 °C to 24 °C. Phosphorous oxychloride (10.6 kg, 69.1 mol) was added slowly over a period of 53 minutes while maintaining the temperature at 20.6 °C to 25.6 °C. Additional DMF (5 L) was used to rinse the addition vessel and added to the reaction. The reaction was stirred for 19 hours and 17 minutes at a temperature of 20 °C to 24 °C and then added quickly, over a period of four minutes, to purified water (275 L) that had been cooled to 8.4 °C. During the addition, the temperature of the mixture did not exceed 18 °C. Additional water (80 L) was used to rinse the original vessel and added quickly to the resulting mixture, which ranged in temperature from 16.6 °C to 17.2 °C during this addition. The mixture resulting from the additions was stirred for 30 minutes while cooling to a temperature of approximately 10 °C. A solid formed and was isolated by filtration and washed with cold water (6 x 33 L at 10 °C) to provide 20.55 kg of 4-chloro-3-nitro[1,5]naphthyridine, which contained some water and was used in Part B within 2.75 hours of filtration.
Part B
[0090] 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 °C to 27 °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 °C to 24°C, and then water (288 L) was added over a period of about one hour while maintaining the reaction temperature at 21.4 °C to 23.8 °C. The resulting mixture was stirred at 20 °C to 24 °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 °C to 55 °C to provide 13.7 kg of N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine.
Example 2
Preparation of N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amine
Part A
[0091] Under a nitrogen atmosphere, a suspension of 3-nitro[1,5]naphthyridin-4-ol (1.00 kg, 5.23 mol) in DMF (4.5 L) was cooled in an ice bath. Phosphorous oxychloride (882.5 g, 5.75 mol) was added slowly over a period of one hour while maintaining the temperature at 16°C to 20 °C. After the addition was complete, the reaction was stirred for three hours at a temperature of 20 °C to 24 °C and then added quickly to two portions of demineralized water (12.5 L each) at 20 °C to 24 °C. During the addition, the temperature of the mixtures was allowed to reach 29.5 °C to 30.5 °C. The resulting mixtures were cooled to a temperature of approximately 10 °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. The tan solid product, 4-chloro-3-nitro[1,5]naphthyridine, contained water and was used in Part B within one hour.
Part B
[0092] 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 °C to 27°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 °C to 22.5 °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 N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid.
Example 3
Preparation of 2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide
Part A
[0093] A hydrogenation vessel was charged with N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (7.50 kg, 30.5 mol) and toluene (125.0 kg). A suspension of 3% platinum on carbon (0.44 kg, approximately 33% by weight (w/w) in water) in isopropanol (7.0 kg) was added to the vessel followed by a rinse with toluene (10.0 kg). The reaction mixture was then placed under hydrogen pressure (2.4 x 105 Pa, 2.4 bars) for six hours while stirring and maintaining the temperature at 22 °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 (1x104 Pa, 0.1 bar) at approximately 50 °C to provide a solution of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in toluene (75 L, approximately 10 mL/g).
Part B
[0094] The solution from Part A (75 L) was heated to a temperature of 50 °C, and p-toluenesulfonic acid monohydrate (0.35 kg, 1.8 mol) was added. The reaction was heated to a temperature of 80 °C, and triethyl orthoacetate (5.70 kg, 35.1 mol) was slowly added with stirring over a period of 40 minutes. The reaction was stirred at 80 °C for two hours and then cooled to 50 °C to provide a solution of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in toluene.
Part C
[0095] Peracetic acid (7.15 kg of 40% w/w) was added over a period of 60 minutes to the 50°C solution from Part B. The reaction was stirred for six hours at 50 °C, and then cooled to 5°C. Aqueous sodium metabisulfite (46.2 kg of 2.5 % w/w), and aqueous sodium hydroxide (19.50 kg of 25% w/w, to achieve pH 13) were carefully added sequentially. The resulting suspension was stirred at 5 °C for one hour and then separated by centrifugation. A solid was collected and dried under vacuum (2x103 Pa, 0.02 bar) at 30°C for 24 hours to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide as a yellow solid.
Example 4
Preparation of 2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
[0096] Under a nitrogen atmosphere, aqueous ammonium hydroxide (four equivalents) was quickly added witch continuous stirring to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide in methanol (6 mL/g) while maintaining the reaction temperature at 20 °C to 24 °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 °C to 30°C. Methanol was used to rinse the addition vessel and added to the reaction. The reaction was stirred for 45 to 75 minutes at 20°C to 24°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 °C and 25 °C. Water (10 L), used to rinse the addition vessel, was added to the reaction mixture. The resulting mixture was cooled to 10°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. The solid was dried at 50 °C under vacuum to provide 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an off-white solid.
Example 5
Preparation of 2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
[0097] Aqueous ammonium hydroxide (5.07 kg of 30% w/w) was added over a period of ten minutes to a suspension of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-5-oxide (6.00 kg, 23.4 mol) in ethanol (23.2 kg) at 22°C. The reaction was stirred for five minutes. Benzenesulfonyl chloride (8.80 kg, 49.8 mol) was added over a period of 30 minutes. The reaction was stirred for one hour at 22°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 °C to adjust the mixture to pH 13. The resulting mixture was cooled to 11°C and stirred at that temperature for three hours and then separated by centrifugation. A solid was collected, washed with demineralized water (105.0 kg) at 22 °C until the filtrate was pH 7, and dried under vacuum (2 x 103 Pa, 0.02 bar) at 45°C for 24 hours to provide 2-ethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.
combining the mixture comprising the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine with an aqueous solution of a reducing agent followed by an aqueous base;
cooling the mixture to form solid 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and
separating at least a portion of the solid 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine from at least a portion of the mixture.
providing N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier comprising a non-chlorinated solvent at a temperature of 18°C to 30°C;
combining the N4-(2-methylpropyl)[1,5]napthyridine-3,4-diamine in the carrier with an organic acid to form a mixture;
combining the mixture comprising the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and organic acid with a trialkyl orthoacetate at a temperature of 70°C to 100°C; and
maintaining the temperature at 70 °C to 100°C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine.
providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier comprising a non-chlorinated solvent;
combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst to form a mixture;
subjecting the mixture comprising the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; and
removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine.
providing 4-chloro-3-nitro[1,5]naphthyridine in a carrier comprising a water-miscible organic liquid;
combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N4-(2-methylpropyl)-3-nitro [1,5]naphthyridine-4-amine;
combining the mixture comprising the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and
separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water.
providing 3-nitro[1,5]naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;
combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;
combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine; and
separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water.
providing 3-nitro-1,5-naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;
combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;
combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine;
separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water;
combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier comprising a water-miscible organic liquid;
combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine;
combining the mixture comprising the N4-(2-methylpropyl)-3-nitzo[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro [1,5]naphthyridin-4-amine;
separating at least a portion of solid N4(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water; and
converting the solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine to 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,3-c][1,5]naphthyridine.
providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier comprising toluene;
combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture;
subjecting the mixture comprising the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpmpyl)[1,5]naphthyridine-3,4-diamine;
removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine;
removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier comprising toluene and isopropanol;
heating the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20°C to 55 °C;
combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture;
combining the mixture comprising the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70 °C to 100 °C;
maintaining the temperature at 70 °C to 100 °C for a period time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine;
cooling the mixture comprising 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45 °C to 55 °C;
combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent comprising peracetic acid to form a mixture;
maintaining the mixture comprising the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45 °C to 55 °C for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and
isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-inaidazo[4,5-c][1,5]naphthyridine.
providing 3-nitro[1,5]naphthyridin-4-ol in a carrier comprising N,N-dimethylformamide;
combining the 3-nitro[1,5]naphthyridin-4-ol in the carrier with phosphorous oxychloride under conditions effective to form 4-chloro-3-nitro[1,5]naphthyridine;
combining the mixture comprising the 4-chloro-3-nitro[1,5]naphthyridine with water under conditions effective to form solid 4-chloro-3-nitro[1,5]naphthyridine;
separating at least a portion of the solid 4-chloro-3-nitro[1,5]naphthyridine from at least a portion of the mixture comprising the water,
combining the separated solid 4-chloro-3-nitro[1,5]naphthyridine with a carrier comprising tetrahydrofuran;
combining the 4-chloro-3-nitro[1,5]naphthyridine in the carrier with isobutylamine under conditions effective to form a mixture comprising N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine;
combining the mixture comprising the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine with water to form solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine; and
separating at least a portion of solid N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine from at least a portion of the mixture comprising the water.
2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin in einem Träger, der Methanol oder Ethanol umfaßt, bereitstellt;
das 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo-[4,5-c][1,5]naphthyridin in dem Träger mit Ammoniumhydroxid in Wasser und Benzolsulfonylchlorid oder p-Toluolsulfonylchlorid zu einer Mischung vereinigt; und
die Komponenten der Mischung über einen zur Bildung von 2-Methyl-1(2-methylpropyl)-1H-imidazo-[4,5-c][1,5]naphthyridin-4-amin ausreichenden Zeitraum reagieren läßt.
das 2-Methyl-1(2-methylpropyl)-1H-imidazo[4,5-c]-[1,5]naphthyridin in dem Träger mit einem Oxidationsmittel zu einer Mischung vereinigt und die Mischung über einen zur Bildung von 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]-naphthyridin ausreichenden Zeitraum bei einer Temperatur von 25°C bis 70°C hält und
zumindest einen Teil des 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]-naphthyridins isoliert.
die das 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin umfassende Mischung mit einer wäßrigen Lösung eines Reduktionsmittels gefolgt von einer wäßrigen Base vereinigt;
die Mischung zur Bildung von festem 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]-naphthyridin abkühlt und
zumindest einen Teil des festen 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]-naphthyridins von zumindest einem Teil der Mischung abtrennt.
N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin in einem Träger, der ein nichtchloriertes Lösungsmittel umfaßt, bei einer Temperatur von 18°C bis 30°C bereitstellt;
das N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin in dem Träger mit einer organischen Säure zu einer Mischung vereinigt;
die das N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin und organische Säure umfassende Mischung bei einer Temperatur von 70°C bis 100°C mit einem Orthoessigsäuretrialkylester vereinigt und
die Temperatur über einen zur Bildung von 2-Methyl-1(2-methylpropyl)-1H-imidazo[4,5-c][1,5]-naphthyridin ausreichenden Zeitraum bei 70°C bis 100°C hält.
N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amin in einem Träger, der ein nichtchloriertes Lösungsmittel umfaßt, bereitstellt;
das N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amin in dem Träger mit einem Hydrierkatalysator zu einer Mischung vereinigt;
die das N4-(2-Methylpropyl)-3-nitro[1,5]-naphthyridin-4-amin und den Hydrierkatalysator umfassende Mischung unter zur Bildung von N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin wirksamen Bedingungen einer Wasserstoffatmosphäre aussetzt und
zumindest einen Teil des Hydrierkatalysators von dem N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin entfernt.
4-Chlor-3-nitro[1,5]naphthyridin in einem Träger,
der eine mit Wasser mischbare organische Flüssigkeit umfaßt, bereitstellt;
das 4-Chlor-3-nitro[1,5]naphthyridin in dem Träger unter zur Bildung einer N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amin umfassenden Mischung wirksamen Bedingungen mit Isobutylamin vereinigt;
die das N4-(2-Methylpropyl)-3-nitro[1,5]-naphthyridin-4-amin umfassende Mischung zur Bildung von festem N4-(2-Methylpropyl)-3-nitro-[1,5]naphthyridin-4-amin mit Wasser vereinigt und
zumindest einen Teil des festen N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amins von zumindest einem Teil der das Wasser umfassenden Mischung abtrennt.
3-Nitro[1,5]naphthyridin-4-ol in einem Träger, der N,N-Dimethylformamid umfaßt, bereitstellt;
das 3-Nitro[1,5]naphthyridin-4-ol in dem Träger unter zur Bildung von 4-Chlor-3-nitro[1,5]-naphthyridin wirksamen Bedingungen mit Phosphoroxidchlorid vereinigt;
die das 4-Chlor-3-nitro[1,5]naphthyridin umfassende Mischung unter zur Bildung von festem 4-Chlor-3-nitro[1,5]naphthyridin wirksamen Bedingungen mit Wasser vereinigt und
zumindest einen Teil des festen 4-Chlor-3-nitro-[1,5]naphthyridins von zumindest einem Teil der das Wasser umfassenden Mischung abtrennt.
3-Nitro-1,5-naphthyridin-4-ol in einem Träger, der N,N-Dimethylformamid umfaßt, bereitstellt;
das 3-Nitro[1,5]naphthyridin-4-ol in dem Träger unter zur Bildung von 4-Chlor-3-nitro[1,5]-naphthyridin wirksamen Bedingungen mit Phosphoroxidchlorid vereinigt;
die das 4-Chlor-3-nitro[1,5]naphthyridin umfassende Mischung unter zur Bildung von festem 4-Chlor-3-nitro[1,5]naphthyridin wirksamen Bedingungen mit Wasser vereinigt;
zumindest einen Teil des festen 4-Chlor-3-nitro-[1,5]naphthyridins von zumindest einem Teil der das Wasser umfassenden Mischung abtrennt;
das abgetrennte feste 4-Chlor-3-nitro[1,5]-naphthyridin mit einem Träger, der eine mit Wasser mischbare organische Flüssigkeit umfaßt, vereinigt;
das 4-Chlor-3-nitro[1,5]naphthyridin in dem Träger unter zur Bildung einer N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amin umfassenden Mischung wirksamen Bedingungen mit Isobutylamin vereinigt;
die das N4-(2-Methylpropyl)-3-nitro[1,5]-naphthyridin-4-amin umfassende Mischung zur Bildung von festem N4-(2-Methylpropyl)-3-nitro-[1,5]naphthyridin-4-amin mit Wasser vereinigt;
zumindest einen Teil des festen N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amins von zumindest einem Teil der das Wasser umfassenden Mischung abtrennt und
das feste N4-(2-Methylpropyl)-3-nitro[1,5]-naphthyridin-4-amin in 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin umwandelt.
N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin in einem Träger, der Toluol umfaßt, bereitstellt;
das N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amin in dem Träger mit einem Hydrierkatalysator und Isopropanol zu einer Mischung vereinigt;
die das N4-(2-Methylpropyl)-3-nitro[1,5]-naphthyridin-4-amin und den Hydrierkatalysator umfassende Mischung unter zur Bildung von N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin wirksamen Bedingungen einer Wasserstoffatmosphäre aussetzt;
zumindest einen Teil des Hydrierkatalysators von dem N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin entfernt;
aus der Mischung von N4-(2-Methylpropyl)[1,5]-naphthyridin-3,4-diamin in einem Träger, der Toluol und Isopropanol umfaßt, zumindest einen Teil des Isopropanols entfernt;
das N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin in dem Träger auf eine Temperatur von 20°C bis 55°C erhitzt;
das N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin in dem Träger mit p-Toluolsulfonsäure zu einer Mischung vereinigt;
die das N4-(2-Methylpropyl)[1,5]naphthyridin-3,4-diamin und p-Toluolsulfonsäure umfassende Mischung bei einer Temperatur von 70°C bis 100°C mit einem Orthoessigsäuretrialkylester vereinigt;
die Temperatur über einen zur Bildung von 2-Methyl-1(2-methylpropyl)-1H-imidazo[4,5-c][1,5]-naphthyridin ausreichenden Zeitraum bei 70°C bis 100°C hält;
die 2-Methyl-1(2-methylpropyl)-1H-imidazo[4,5-c]-[1,5]naphthyridin umfassende Mischung auf eine Temperatur von 45°C bis 55°C abkühlt;
das 2-Methyl-1(2-methylpropyl)-1H-imidazo[4,5-c]-[1,5]naphthyridin in dem Träger mit einem Peressigsäure umfassenden Oxidationsmittel zu einer Mischung vereinigt;
die das 2-Methyl-1(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin und Peressigsäure umfassende Mischung über einen zur Bildung von 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]-naphthyridin ausreichenden Zeitraum bei einer Temperatur von 45°C bis 55°C hält und
zumindest einen Teil des 2-Methyl-1(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]-naphthyridins isoliert.
3-Nitro-1,5-naphthyridin-4-ol in einem Träger, der N,N-Dimethylformamid umfaßt, bereitstellt;
das 3-Nitro[1,5]naphthyridin-4-ol in dem Träger unter zur Bildung von 9-Chlor-3-nitro[1,5]-naphthyridin wirksamen Bedingungen mit Phosphoroxidchlorid vereinigt;
die das 4-Chlor-3-nitro[1,5]naphthyridin umfassende Mischung unter zur Bildung von festem 4-Chlor-3-nitro[1,5]naphthyridin wirksamen Bedingungen mit Wasser vereinigt;
zumindest einen Teil des festen 4-Chlor-3-nitro-[1,5]naphthyridins von zumindest einem Teil der das Wasser umfassenden Mischung abtrennt;
das abgetrennte feste 4-Chlor-3-nitro[1,5]-naphthyridin mit einem Träger, der Tetrahydrofuran umfaßt, vereinigt;
das 4-Chlor-3-nitro[1,5]naphthyridin in dem Träger unter zur Bildung einer N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amin umfassenden Mischung wirksamen Bedingungen mit Isobutylamin vereinigt;
die das N4-(2-Methylpropyl)-3-nitro[1,5]-naphthyridin-4-amin umfassende Mischung zur Bildung von festem N4-(2-Methylpropyl)-3-nitro-[1,5]naphthyridin-4-amin mit Wasser vereinigt und
zumindest einen Teil des festen N4-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amins von zumindest einem Teil der das Wasser umfassenden Mischung abtrennt.
se procurer de la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine dans un véhicule comprenant du méthanol ou de l'éthanol ;
combiner la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine dans le véhicule avec de l'hydroxyde d'ammonium dans de l'eau et du chlorure de benzènesulfonyle ou du chlorure de p-toluènesulfonyle pour former un mélange ; et
faire réagir les constituants du mélange pendant une durée suffisante pour former la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridin-4-amine.
se procurer de la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine dans un véhicule comprenant un solvant non chloré à une température de 25 °C à 70 °C ;
combiner la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine dans le véhicule avec un agent oxydant pour former un mélange et maintenir le mélange à une température de 25 °C à 70 °C pendant une durée suffisante pour former la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine ; et
isoler au moins une partie de la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine.
la combinaison du mélange comprenant la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine avec une solution aqueuse d'un agent réducteur suivie d'une base aqueuse ;
le refroidissement du mélange pour former de la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]-naphtyridine solide ; et
la séparation d'au moins une partie de la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine solide d'avec au moins une partie du mélange.
se procurer de la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine dans un véhicule comprenant un solvant non chloré à une température de 18°C à 30 °C ;
combiner la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine dans le véhicule avec un acide organique pour former un mélange ;
combiner le mélange comprenant la N4-(2-méthylpropyl)-[1,5]naphtyridine-3,4-diamine et l'acide organique avec un orthoacétate de trialkyle à une température de 70 °C à 100 °C ; et
maintenir la température à 70 °C à 100 °C pendant une durée suffisante pour former la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine.
se procurer la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine dans un véhicule comprenant un solvant non chloré ;
combiner la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine dans le véhicule avec un catalyseur d'hydrogénation pour former un mélange ;
soumettre le mélange comprenant la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine et le catalyseur d'hydrogénation à une atmosphère d'hydrogène dans des conditions efficaces pour former de la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine ; et
éliminer de la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine au moins une partie du catalyseur d'hydrogénation.
se procurer de la 4-chloro-3-nitro[1,5]naphtyridine dans un véhicule comprenant un liquide organique miscible avec l'eau ;
combiner la 4-chloro-3-nitro[1,5]naphtyridine dans le véhicule avec de l'isobutylamine dans des conditions efficaces pour former un mélange comprenant de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridine-4-amine ;
combiner le mélange comprenant la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine avec de l'eau pour former de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide ; et
séparer au moins une partie de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide d'au moins une partie du mélange comprenant l'eau.
se procurer du 3-nitro[1,5]naphtyridin-4-ol dans un véhicule comprenant du N,N-diméthylformamide ;
combiner le 3-nitro[1,5]naphtyridin-4-ol dans le véhicule avec de l'oxychlorure de phosphore dans des conditions efficaces pour former de la 4-chloro-3-nitro-[1,5]naphtyridine ;
combiner le mélange comprenant la 4-chloro-3-nitro-[1,5]naphtyridine avec de l'eau dans des conditions efficaces pour former de la 4-chloro-3-nitro[1,5]naphtyridine solide ; et
séparer au moins une partie de la 4-chloro-3-nitro-[1,5]naphtyridine solide d'au moins une partie du mélange comprenant l'eau.
se procurer du 3-nitro-1,5-naphtyridin-4-ol dans un véhicule comprenant du N,N-diméthylformamide ;
combiner le 3-nitro[1,5]naphtyridin-4-ol dans le véhicule avec de l'oxychlorure de phosphore dans des conditions efficaces pour former de la 4-chloro-3-nitro-[1,5]naphtyridine ;
combiner le mélange comprenant la 4-chloro-3-nitro-[1,5]naphtyridine avec de l'eau dans des conditions efficaces pour former de la 4-chloro-3-nitro[1,5]-naphtyridine solide ;
séparer au moins une partie de la 4-chloro-3-nitro-[1,5]naphtyridine solide d'avec au moins une partie du mélange comprenant l'eau ;
combiner la 4-chloro-3-nitro[1,5]naphtyridine solide séparée avec un véhicule comprenant un liquide organique miscible avec l'eau ;
combiner la 4-chloro-3-nitro[1,5]naphtyridine dans le véhicule avec de l'isobutylamine dans des conditions efficaces pour former un mélange comprenant de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine ;
combiner le mélange comprenant la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine avec de l'eau pour former de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide ;
séparer au moins une partie de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide d'avec au moins une partie du mélange comprenant l'eau ; et
convertir la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide en 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine.
se procurer de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine dans un véhicule comprenant du toluène ;
combiner la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine dans le véhicule avec un catalyseur d'hydrogénation et de l'isopropanol pour former un mélange ;
soumettre le mélange comprenant la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine et le catalyseur d'hydrogénation à une atmosphère d'hydrogène dans des conditions efficaces pour former de la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine ;
éliminer de la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine au moins une partie du catalyseur d'hydrogénation ;
éliminer au moins une partie de l'isopropanol du mélange de N4-(2-méthylpropyl) [1,5]naphtyridine-3,4-diamine dans un véhicule comprenant du toluène et de l'isopropanol ;
chauffer la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine dans le véhicule à une température de 20 °C à 55 °C ;
combiner la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine dans le véhicule avec de l'acide p-toluènesulfonique pour former un mélange ;
combiner le mélange comprenant la N4-(2-méthylpropyl)[1,5]naphtyridine-3,4-diamine et l'acide p-toluènesulfonique avec un orthoacétate de trialkyle à une température de 70 °C à 100 °C ;
maintenir la température à 70 °C jusqu'à 100 °C pendant une durée suffisante pour former de la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine ;
refroidir le mélange comprenant la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine à une température de 45 °C à 55 °C ;
combiner la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine dans le véhicule avec un agent oxydant comprenant de l'acide peracétique pour former un mélange ;
maintenir le mélange comprenant la 2-méthyl-1-(2-méthylpropyl)-1H-imidazo[4,5-c][1,5]naphtyridine et
l'acide peracétique à une température de 45 °C à 55 °C pendant une durée suffisante pour former de la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]-naphtyridine ; et
isoler au moins une partie de la 2-méthyl-1-(2-méthylpropyl)-5-oxydo-1H-imidazo[4,5-c][1,5]naphtyridine.
se procurer du 3-nitro[1,5]naphtyzidin-4-ol dans un véhicule comprenant du N,N-diméthylformamide ;
combiner le 3-nitro[1,5]naphtyridin-4-ol dans le véhicule avec de l'oxychlorure de phosphore dans des conditions efficaces pour former de la 4-chloro-3-nitro-[1,5]naphtyridine ;
combiner le mélange comprenant la 4-chloro-3-nitro-[1,5]naphtyridine avec de l'eau dans des conditions efficaces pour former de la 4-chloro-3-nitro[1,5]-naphtyridine solide ;
séparer au moins une partie de la 4-chloro-3-nitro-[1,5]naphtyridine solide d'avec au moins une partie du mélange comprenant l'eau ;
combiner la 4-chloro-3-nitro[1,5]naphtyridine solide séparée avec un véhicule comprenant du tétrahydrofurane ;
combiner la 4-chloro-3-nitro[1,5]naphtyridine dans le véhicule avec de l'isobutylamine dans des conditions efficaces pour former un mélange comprenant de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine ;
combiner le mélange comprenant la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine avec de l'eau pour former de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide ; et
séparer au moins une partie de la N4-(2-méthylpropyl)-3-nitro[1,5]naphtyridin-4-amine solide d'avec au moins une partie du mélange comprenant l'eau.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description