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  • Pirodomast, Sch-37224,108310-20-9,C18-H17-N3-O2,1-(4-Hydroxy--药物合成数据库
  • 发布时间:2004-10-25 来源:本站整理
  • 【药物名称】
    Pirodomast, Sch-37224
    【化学名】
    1-(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridin-3-yl)pyrrolidine; 4-Hydroxy-1-phenyl-3-(1-pyrrolidinyl)-1,8-naphthyridin-2(1H)-one; 1-(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydro-1,8-naphthyridin-3-yl)pyrrolidinium hydroxide inner salt
    【CAS登记号】
    108310-20-9
    【结构式】
    Pirodomast, Sch-37224,108310-20-9,C18-H17-N3-O2,1-(4-Hydroxy--药物合成数据库
    【分子式】
    C18-H17-N3-O2
    【分子量】
    307.355
    【原研厂家】
    Schering-Plough (Originator)
    【作用类别】
    Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Leukotriene Antagonists, Leukotriene Synthesis Inhibitors
    【研发状态】
    Phase II
    【合成情况】
     
    〖来源〗
    Drugs Fut
    〖合成路线〗
    〖标题〗
    Pirodomast < Prop INN >
    〖合成方法〗
    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.
    〖作者〗
    Blythin, D.J.; Gala, D.
    〖参考〗
    Blythin, D.J.; Gala, D.; Pirodomast Prop INN >. Drugs Fut 1991, 16, 12, 1099
    〖出处〗
    Drugs Fut1991,16,(12):1099
    〖备注〗
    Synthesis The first synthesis of Sch 37224 (1, 2) (Scheme 13301001a) began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b) (3, 4). 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 these problems, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research towards this goal led to the new synthesis of (I) outlined in Scheme 13301002a. Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult (6), 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 (7). 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, which is outlined in Scheme 133010031. Here, the high yielding synthesis (4) 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 (8). Description White crystalline solid, m.p. 290?(discolors); 325-6?(decomp.). References 1. Blythin, D.J., Shue, H.-J. (Schering Corp.). Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cytoprotective agents. EP 232328, JP 88500453, US 4684727, WO 8700752. 2. Bythin, D.J., Carlon, F.E., Kreutner, W., Rizzo, C., Sherwood, J., Shue, H.-J., Spitler, J.M. Anti-allergy agents. 2. Zwitterionic 1,8-naphthyridin-2(1H)-ones. Potent, orally active inhibitors of the release of leukotrienes and other bronchospastic agents. Med Chem Res 1991, 1(2): 151-4. 3. Kanji, N., Nakagawa, A., Miyata, S., Ide, H. (Hisamitsu Pharm. Co., Inc.). Naphthyridine derivatives. JP 77116495; C.A. 1978, 88: 105298y. 4. Sherlock, M. (Schering Corp.). 1-Phenyl-1,8-naphthyridin-2(1H)-ones. EP 092786, US 4492702. 5. Under refluxing conditions dimethylamine, generated from DMF, reacted with (IV) to form (V). The structure of (V) was verified by synthesizing pure (V) by reacting 4 with dimethylamine in an autoclave. 6. Andresen, O.R., Pedersen, E.B. Phosphorus pentoxide in organic synthesis, III. New synthesis of pyrido[2,3-d]pyrimidin-4(3H)-ones. Liebigs Ann Chem 1982: 1012-5. 7. Nyce, P.L., Gala, D., Steinman, M. An efficient synthesis of 1,8-napthyridin-2(1H)-ones: Synthesis of leukotriene inhibitor Sch 37224. Synthesis 1991: 571-4. 8. Duelfer, T., Gala, D. A short synthesis and its application to the preparation of radiolabelled leukotriene inhibitor Sch 37224. J Label Compound Radiopharm 1991: 651-6.
    〖来源〗
    Med Chem Res
    〖合成路线〗
    〖标题〗
    Anti-allergy agents. 2. Zwitterionic 1,8-naphthyridin-2(1H)-ones. Potent, orally active inhibitors of the release of leukotrienes and other bronchospastic agents
    〖合成方法〗
    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.
    〖作者〗
    Shue, H.-J.; Spitler, J.M.; Carlon, F.E.; Kreutner, W.; Sherwood, J.; Bythin, D.J.; Rizzo, C.
    〖参考〗
    Shue, H.-J.; Spitler, J.M.; Carlon, F.E.; Kreutner, W.; Sherwood, J.; Bythin, D.J.; Rizzo, C.; Anti-allergy agents. 2. Zwitterionic 1,8-naphthyridin-2(1H)-ones. Potent, orally active inhibitors of the release of leukotrienes and other bronchospastic agent BI-RM-270,147432-77-7,N-[2-Cyclo
    〖出处〗
    Med Chem Res1991,1,(2):151-4
    〖备注〗
    〖来源〗
    Synthesis
    〖合成路线〗
    〖标题〗
    An efficient synthesis of 1,8-napthyridin-2(1H)-ones: Synthesis of leukotriene inhibitor Sch 37224
    〖合成方法〗
    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).
    〖作者〗
    Nyce, P.L.; Steinman, M.; Gala, D.
    〖参考〗
    Nyce, P.L.; Steinman, M.; Gala, D.; An efficient synthesis of 1,8-napthyridin-2(1H)-ones: Synthesis of leukotriene inhibitor Sch 37224. Synthesis 1991, 7, 571-4
    〖出处〗
    Synthesis1991,,(7):571-4
    〖备注〗
    〖来源〗
    Drugs Fut
    〖合成路线〗
    〖标题〗
    Pirodomast < Prop INN >
    〖合成方法〗
    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).
    〖作者〗
    Blythin, D.J.; Gala, D.
    〖参考〗
    Blythin, D.J.; Gala, D.; Pirodomast Prop INN >. Drugs Fut 1991, 16, 12, 1099
    〖出处〗
    Drugs Fut1991,16,(12):1099
    〖备注〗
    Synthesis The first synthesis of Sch 37224 (1, 2) (Scheme 13301001a) began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b) (3, 4). 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 these problems, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research towards this goal led to the new synthesis of (I) outlined in Scheme 13301002a. Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult (6), 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 (7). 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, which is outlined in Scheme 133010031. Here, the high yielding synthesis (4) 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 (8). Description White crystalline solid, m.p. 290?(discolors); 325-6?(decomp.). References 1. Blythin, D.J., Shue, H.-J. (Schering Corp.). Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cytoprotective agents. EP 232328, JP 88500453, US 4684727, WO 8700752. 2. Bythin, D.J., Carlon, F.E., Kreutner, W., Rizzo, C., Sherwood, J., Shue, H.-J., Spitler, J.M. Anti-allergy agents. 2. Zwitterionic 1,8-naphthyridin-2(1H)-ones. Potent, orally active inhibitors of the release of leukotrienes and other bronchospastic agents. Med Chem Res 1991, 1(2): 151-4. 3. Kanji, N., Nakagawa, A., Miyata, S., Ide, H. (Hisamitsu Pharm. Co., Inc.). Naphthyridine derivatives. JP 77116495; C.A. 1978, 88: 105298y. 4. Sherlock, M. (Schering Corp.). 1-Phenyl-1,8-naphthyridin-2(1H)-ones. EP 092786, US 4492702. 5. Under refluxing conditions dimethylamine, generated from DMF, reacted with (IV) to form (V). The structure of (V) was verified by synthesizing pure (V) by reacting 4 with dimethylamine in an autoclave. 6. Andresen, O.R., Pedersen, E.B. Phosphorus pentoxide in organic synthesis, III. New synthesis of pyrido[2,3-d]pyrimidin-4(3H)-ones. Liebigs Ann Chem 1982: 1012-5. 7. Nyce, P.L., Gala, D., Steinman, M. An efficient synthesis of 1,8-napthyridin-2(1H)-ones: Synthesis of leukotriene inhibitor Sch 37224. Synthesis 1991: 571-4. 8. Duelfer, T., Gala, D. A short synthesis and its application to the preparation of radiolabelled leukotriene inhibitor Sch 37224. J Label Compound Radiopharm 1991: 651-6.
    〖来源〗
    Liebigs Ann Chem
    〖合成路线〗
    〖标题〗
    Phosphorus pentoxide in organic synthesis, III. New synthesis of pyrido[2,3-d]pyrimidin-4(3H)-ones
    〖合成方法〗
    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).
    〖作者〗
    Andresen, O.R.; Pedersen, E.B.
    〖参考〗
    Andresen, O.R.; Pedersen, E.B.; Phosphorus pentoxide in organic synthesis, III. New synthesis of pyrido[2,3-d]pyrimidin-4(3H)-ones. Liebigs Ann Chem 1982, 1012
    〖出处〗
    Liebigs Ann Chem1982,,():1012
    〖备注〗
    〖来源〗
    J Label Compd Radiopharm
    〖合成路线〗
    〖标题〗
    A short synthesis and its application to the preparation of radiolabelled leukotriene inhibitor Sch 37224
    〖合成方法〗
    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.
    〖作者〗
    Gala, D.; Duelfer, T.
    〖参考〗
    Gala, D.; Duelfer, T.; A short synthesis and its application to the preparation of radiolabelled leukotriene inhibitor Sch 37224. J Label Compd Radiopharm 1991, 29, 6, 651-6
    〖出处〗
    J Label Compd Radiopharm1991,29,(6):651-6
    〖备注〗
    〖来源〗
    Drugs Fut
    〖合成路线〗
    〖标题〗
    Pirodomast < Prop INN >
    〖合成方法〗
    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.
    〖作者〗
    Blythin, D.J.; Gala, D.
    〖参考〗
    Blythin, D.J.; Gala, D.; Pirodomast Prop INN >. Drugs Fut 1991, 16, 12, 1099
    〖出处〗
    Drugs Fut1991,16,(12):1099
    〖备注〗
    Synthesis The first synthesis of Sch 37224 (1, 2) (Scheme 13301001a) began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b) (3, 4). 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 these problems, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research towards this goal led to the new synthesis of (I) outlined in Scheme 13301002a. Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult (6), 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 (7). 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, which is outlined in Scheme 133010031. Here, the high yielding synthesis (4) 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 (8). Description White crystalline solid, m.p. 290?(discolors); 325-6?(decomp.). References 1. Blythin, D.J., Shue, H.-J. (Schering Corp.). Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cytoprotective agents. EP 232328, JP 88500453, US 4684727, WO 8700752. 2. Bythin, D.J., Carlon, F.E., Kreutner, W., Rizzo, C., Sherwood, J., Shue, H.-J., Spitler, J.M. Anti-allergy agents. 2. Zwitterionic 1,8-naphthyridin-2(1H)-ones. Potent, orally active inhibitors of the release of leukotrienes and other bronchospastic agents. Med Chem Res 1991, 1(2): 151-4. 3. Kanji, N., Nakagawa, A., Miyata, S., Ide, H. (Hisamitsu Pharm. Co., Inc.). Naphthyridine derivatives. JP 77116495; C.A. 1978, 88: 105298y. 4. Sherlock, M. (Schering Corp.). 1-Phenyl-1,8-naphthyridin-2(1H)-ones. EP 092786, US 4492702. 5. Under refluxing conditions dimethylamine, generated from DMF, reacted with (IV) to form (V). The structure of (V) was verified by synthesizing pure (V) by reacting 4 with dimethylamine in an autoclave. 6. Andresen, O.R., Pedersen, E.B. Phosphorus pentoxide in organic synthesis, III. New synthesis of pyrido[2,3-d]pyrimidin-4(3H)-ones. Liebigs Ann Chem 1982: 1012-5. 7. Nyce, P.L., Gala, D., Steinman, M. An efficient synthesis of 1,8-napthyridin-2(1H)-ones: Synthesis of leukotriene inhibitor Sch 37224. Synthesis 1991: 571-4. 8. Duelfer, T., Gala, D. A short synthesis and its application to the preparation of radiolabelled leukotriene inhibitor Sch 37224. J Label Compound Radiopharm 1991: 651-6.
    〖来源〗
    EP 0232328; JP 1988500453; US 4684727; WO 8700752
    〖合成路线〗
    〖标题〗
    Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cytoprotective agents
    〖合成方法〗
    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.
    〖作者〗
    Blythin, D.J.; Shue, H. (Schering Corp.)
    〖参考〗
    Blythin, D.J.; Shue, H. (Schering Corp.); Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cytoprotective agents. EP 0232328; JP 1988500453; US 4684727; WO 8700752
    〖出处〗
    EP 0232328; JP 1988500453; US 4684727; WO 8700752,,():
    〖备注〗
    〖来源〗
    CH 683427; EP 0539470; FR 2665791; GB 2260763; JP 1993508648; JP 1998139763; US 5453510; WO 9200965
    〖合成路线〗
    〖标题〗
    Neuromuscular blocking agents
    〖合成方法〗
    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.
    〖作者〗
    Hill, D.A.; Turner, G.L. (Glaxo Wellcome plc)
    〖参考〗
    Hill, D.A.; Turner, G.L. (Glaxo Wellcome plc); Neuromuscular blocking agents. CH 683427; EP 0539470; FR 2665791; GB 2260763; JP 1993508648; JP 1998139763; US 5453510; WO 9200965
    〖出处〗
    CH 683427; EP 0539470; FR 2665791; GB 2260763; JP 1993508648; JP 1998139763; US 5453510; WO 9200965,,():
    〖备注〗
    〖来源〗
    JP 77116495
    〖合成路线〗
    〖标题〗
    Naphthyridine derivatives
    〖合成方法〗
    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.
    〖作者〗
    Kanji, N.; Nakagawa, A.; Miyata, S.; Ide, H. (Hisamitsu Pharmaceutical Co., Ltd.)
    〖参考〗
    Kanji, N.; Nakagawa, A.; Miyata, S.; Ide, H. (Hisamitsu Pharmaceutical Co., Ltd.); Naphthyridine derivatives. JP 77116495
    〖出处〗
    JP 77116495,,():
    〖备注〗
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