The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.

The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.

The optical resolution of (?-tetrahydropapaverine (I) with N-acetyl-L-leucine yields (R)-tetrahydropapaverine (II), which is condensed with 1,5-pentamethylene diacrylate (III) (obtained by esterification of 1,5-pentanediol (IV) with 3-bromopropionic acid by means of p-toluenesulfonic acid followed by dehydromination with triethylamine) in hot glacial acetic acid and treated with oxalic acid to afford the bis-tetrahydropapaverine derivative (VI). Finally, this compound is treated with aqueous Na2CO3 to eliminate the oxalic acid and then treated with methyl benezenesulfonate (VII) at room temperature. The resulting product is a 58:34:6 mixture of the (1R-cis, 1'R-cis)- (1R-cis, 1'R-trans)- and (1R-trans, 1'R-trans)-isomers, which is resolved by column chromatography over silica gel using an 80:20:5 mixture of dichloromethane methanol and methanesulfonic acid.

The preparation of radiolabeled (I), needed for biological and pharmacological studies, was accomplished by yet another synthesis. Here, the high yielding synthesis of (IIa) was utilized to prepare labeled (IIa) from chloronicotinic acid and U-14C aniline. This was then condensed with (VIII) to produce radiolabeled (I). This process minimized the handling and workup of radiolabeled materials. The mechanistic aspects for the development of this synthesis have been described recently.

To overcome problems for the previous synthesis, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research toward this goal led to the new synthesis of (I). Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult, a novel, mild, high yielding N-acylation procedure, utilizing propylene oxide as a neutral, irreversible acid scavenger during the N-acylation step, was developed for the conversion of (II) to (VI). The displacement of chlorine from (VI) led to (VII), which proved to be moderately unstable. Hence, mild conditions were developed for an efficient conversion of crude (VII) to (I). The merits of this synthesis are discussed in the literature. This synthesis was used successfully to prepare tens of kilos of (I).

The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.

To overcome problems for the previous synthesis, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research toward this goal led to the new synthesis of (I). Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult, a novel, mild, high yielding N-acylation procedure, utilizing propylene oxide as a neutral, irreversible acid scavenger during the N-acylation step, was developed for the conversion of (II) to (VI). The displacement of chlorine from (VI) led to (VII), which proved to be moderately unstable. Hence, mild conditions were developed for an efficient conversion of crude (VII) to (I). The merits of this synthesis are discussed in the literature. This synthesis was used successfully to prepare tens of kilos of (I).

The preparation of radiolabeled (I), needed for biological and pharmacological studies, was accomplished by yet another synthesis. Here, the high yielding synthesis of (IIa) was utilized to prepare labeled (IIa) from chloronicotinic acid and U-14C aniline. This was then condensed with (VIII) to produce radiolabeled (I). This process minimized the handling and workup of radiolabeled materials. The mechanistic aspects for the development of this synthesis have been described recently.

The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.

To overcome problems for the previous synthesis, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research toward this goal led to the new synthesis of (I). Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult, a novel, mild, high yielding N-acylation procedure, utilizing propylene oxide as a neutral, irreversible acid scavenger during the N-acylation step, was developed for the conversion of (II) to (VI). The displacement of chlorine from (VI) led to (VII), which proved to be moderately unstable. Hence, mild conditions were developed for an efficient conversion of crude (VII) to (I). The merits of this synthesis are discussed in the literature. This synthesis was used successfully to prepare tens of kilos of (I).

The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.