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FK-352B, FK-352

(2R)-1-(2E)-1-氧代-3-(2-苯基吡拉唑1,5-阿立啶-3-基)-2-丙烯-1-基-2-哌啶醋酸Chemical Name: 2-[1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoyl]piperidin-2(R)-yl]acetic acid
CAS No. 143881-08-7, 147977-49-9 (cis-isomer), 143955-46-8 (racemate)
项目整合开发状态: Phase II
项目研究机构: Fujisawa (Originator)
合成路线:The Grignard reaction of the protected epoxide (I) with 4-(dimethylamino)phenylmagnesium bromide (II) gives the 11-substituted compound (III),which is submitted to an Oppenhauer oxidation with cyclohexanone and aluminum isopropoxide yielding the 17-keto derivative (IV).The photochemical epimerization of the 13beta-methyl of (IV) with a high pressure mercury lamp in dioxane affords the epimer (V),which is condensed with 1-tetrahydropyranyloxy-2-propyne (VI) by means of butyllithium in THF to give the acetylenic alcohol (VII).Finally,this compound is reduced with hydrogen over Pd/C in ethanol and deprotected and dehydrated by treatment with hot aqueous acetic acid.

合成路线:The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carboxaldehyde (I) with trimethylphosphonoacetic acid methyl ester (II) by means of NaH in hot toluene gives 3(E)-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid methyl ester (III),which is hydrolyzed with NaOH in methanol - water yielding the corresponding free acid (IV).The reaction of (IV) with SOCl2 in DMF affords the acyl chloride (V),which is finally condensed with 2(R)-(2-hydroxyethyl)piperidine (VI) by means of bis(trimethylsilyl)acetamide and triethylamine in dichloromethane.

合成路线:FK-352 can be obtained by two related ways:1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III),which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1).The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V),which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII).Finally,this compound is hydrolyzed with NaOH in refluxing methanol.2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X),which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.
📌 参考资料/链接：
参考文献标题:Pyrazolopyridine cpds.and processes for preparation thereof
文献作者:Shiokawa,Y.; Akahane,A.; Katayama,H.; Mitsunaga,T.(Fujisawa Pharmaceutical Co.,Ltd.)
参考来源:AU 8817602; EP 0299209; JP 1989045385; US 4925849; US 4994453; US 5087629; US 5102878; US 5179103; US 5296490

📄 详细内容


合成路线:This compound can be obtained by three different ways:1) The methylation of androsta-1,4-diene-3,17-dione (I) with methyllithium and Cu2I2,followed by acetylation with acetic anhydride gives 3-acetoxy-1alpha-methylandrosta-2,4-dien-17-one (II),which is treated with 1,3-dibromo-5,5-dimethylhydantoin (DBDH) in dioxane - water yielding 2alpha(beta)-bromo-1alpha-methylandrost-4-ene-3,17-dione (III).Finally,this compound is dehydrobrominated with MgO in hot DMF.2) By oxidation of 17beta-hydroxy-1-methylandrosta-1,4-dien-3-one (IV) with chromium trioxide and H2SO4 in acetone.3) By oxidation of 17beta-hydroxy-1-methylandrost-1-en-3-one (V) with iodoxybenzene and diphenyldiselenide in hot toluene.

合成路线:FK-352 can be obtained by two related ways:1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III),which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1).The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V),which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII).Finally,this compound is hydrolyzed with NaOH in refluxing methanol.2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X),which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.

参考文献标题:Use of adenosine antagonists in the prevention and treatment of pancreatitis and ulcer
文献作者:Shiokawa,Y.; Akahane,A.; Katayama,H.; Mitsunaga,T.(Fujisawa Pharmaceutical Co.,Ltd.)
参考来源:EP 0497258; JP 1992244084; JP 1993058913; US 5338743


合成路线:FK-352 can be obtained by two related ways:1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III),which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1).The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V),which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII).Finally,this compound is hydrolyzed with NaOH in refluxing methanol.2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X),which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.

参考文献标题:Pyrazolopyridine cpd.and process for preparation thereof
文献作者:Shiokawa,Y.; Akahane,A.; Katayama,H.; Mitsunaga,T.(Fujisawa Pharmaceutical Co.,Ltd.)
参考来源:EP 0516941; JP 1993112566; JP 1996208650; US 5234930


合成路线:FK-352 can be obtained by two related ways:1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III),which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1).The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V),which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII).Finally,this compound is hydrolyzed with NaOH in refluxing methanol.2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X),which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.

参考文献标题:Pyrazolopyridine cpds.for the treatment of anemia
文献作者:Kohno,Y.; Nagatomi,I.; Hanaoka,K.(Fujisawa Pharmaceutical Co.,Ltd.)
参考来源:EP 0644762; WO 9325205


合成路线:FK-352 can be obtained by two related ways:1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III),which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1).The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V),which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII).Finally,this compound is hydrolyzed with NaOH in refluxing methanol.2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X),which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.
参考文献标题:FK-352
文献作者:Ireland,C.; Castar,J.
参考来源:Drugs Fut 1997,22(4),350


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