【结 构 式】 |
【药物名称】FK-453, FR-453, FR-113453 【化学名称】(+)-2(R)-(2-Hydroxyethyl)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]piperidine 【CA登记号】121524-18-3, 122742-02-3 ((Z)-isomer), 121491-21-2 (E-isomer; non-specified stereoch.), 121491-38-1 (racemate), 121524-22-9 (S-i 【 分 子 式 】C23H25N3O2 【 分 子 量 】375.4746 |
【开发单位】Fujisawa (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, Diuretics, Heart Failure Therapy, HEMATOLOGIC DRUGS, Hypertension, Treatment of, METABOLIC DRUGS, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Disorders of Purine and Pyrimidine Metabolism, Treatment of Gout, Treatment of Renal Diseases, Uricosurics, Adenosine A1 Antagonists |
合成路线1
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.
【1】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpds. and their production method. JP 91141222 . |
【2】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpds. and processes for preparation thereof. AU 8817602; EP 0299209; JP 1989045385; US 4925849; US 4994453; US 5087629; US 5102878; US 5179103; US 5296490 . |
【3】 Castaner, J.; Prous, J.; FK-453. Drugs Fut 1992, 17, 11, 991. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 13271 | 2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde | C14H10N2O | 详情 | 详情 | |
(II) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
(III) | 13273 | methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C17H14N2O2 | 详情 | 详情 | |
(IV) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
(V) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
(VI) | 13276 | 2-[(2R)Piperidinyl]-1-ethanol | C7H15NO | 详情 | 详情 |
合成路线2
A new synthesis of FK-453 has been published: The cyclization of 1-aminopyridinium iodide (I) with 3-phenylpropynoic acid ethyl ester (II) by means of KOH in DMF gives 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (III), which is decarboxylated with 47% aqueous HBr yielding 2-phenylpyrazolo[1,5-a]pyridine (IV). The Vilsmayer formylation of (IV) with POCl3 and DMF affords 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (V), which by a Horner-Emmonds condensation with 2-(diethoxyphosphoryl)acetic acid ethyl ester and NaH in THF is converted into 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (VII). The hydrolysis of (VII) with NaOH in methanol gives the free acid (VIII), which by reaction with SOCl2 in dichloromethane yields the corresponding acyl chloride (IX). The condensation of (IX) with 2-(2-hydroxyethyl)piperidine (X) by means of triethylamine in dichloromethane affords FK-453 as a racemic mixture (XI), which is finally submitted to optical resolution.
【1】 Kita, Y.; Akahane, A.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y.; Mitsunaga, T.; Katayama, H.; Discovery of FK453, a novel non-xanthine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1996, 6, 17, 2059. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
(II) | 13278 | ethyl phenylpropiolate; ethyl 3-phenyl-2-propynoate | 2216-94-6 | C11H10O2 | 详情 | 详情 |
(III) | 13279 | ethyl 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate | C16H14N2O2 | 详情 | 详情 | |
(IV) | 13280 | 2-Phenylpyrazolo[1,5-a]pyridine | C13H10N2 | 详情 | 详情 | |
(V) | 13271 | 2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde | C14H10N2O | 详情 | 详情 | |
(VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(VII) | 13283 | ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C18H16N2O2 | 详情 | 详情 | |
(VIII) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
(IX) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
(X) | 17614 | 2-(2-piperidinyl)-1-ethanol; 2-Piperidineethanol | 1484-84-0 | C7H15NO | 详情 | 详情 |
(XI) | 13287 | (E)-1-[2-(2-Hydroxyethyl)-1-piperidinyl]-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propen-1-one | C23H25N3O2 | 详情 | 详情 |
合成路线3
A new practical synthesis of FK-453, suitable for large scale manufacture is described: Bromination of cinnamic aldehyde (I) with Br2 in HOAc gives the dibromoderivative (II), which is treated with NaHSO3 and triethylamine yielding alpha-bromocinnamic aldehyde (III). The reaction of (III) with triethyl orthoformate affords the corresponding acetal (IV), which is treated with KOH in hot ethanol to give the acetylenic acetal (V). Acidic hydrolysis of the acetal (V) with sulfuric acid in refluxing water affords phenylpropargyl aldehyde (VI), which by a Horner-Emmons condensation with the phosphonate (VII) by means of KOH in DMSO gives 5-phenylpent-2(E)-en-4-ynoic acid ethyl ester (VIII). The 1,3-dipolar cycloaddition of (VIII) with 1-aminopyridinium iodide (IX) by means of KOH and K2CO3 in the same solvent yields 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (X), which is hydrolyzed with NaOH in hot methanol affording the corresponding free acid (XI). Reaction of (XI) with SOCl2 and DMF gives the activated acyl chloride (XII), which is condensed with the silylated chiral piperidineethanol (XIII) [obtained by silylation of the chiral piperidineethanol (XIV) with N,N'-bis(trimethylsilyl)urea (BSU)] by means of Et3N and DMAP in CH2Cl2, yielding the silylated target compound (XV). Finally, this compound is desilylated by means of K2CO3 in methanol.
【1】 Morinaga, Y.; Zanka, A.; Uematsu, R.; Yamazaki, H.; Yasuda, H.; Process development of a novel-xanthine adenosine A1 receptor antagonist. Org Process Res Dev 1999, 3, 6, 389. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
(II) | 41735 | 2,3-dibromo-3-phenylpropanal | C9H8Br2O | 详情 | 详情 | |
(III) | 41736 | (Z)-2-bromo-3-phenyl-2-propenal | 5443-49-2 | C9H7BrO | 详情 | 详情 |
(IV) | 41737 | (Z)-2-bromo-1-ethoxy-3-phenyl-2-propenyl ethyl ether; 1-[(Z)-2-bromo-3,3-diethoxy-1-propenyl]benzene | C13H17BrO2 | 详情 | 详情 | |
(V) | 41738 | 1-(3,3-diethoxy-1-propynyl)benzene; 1-ethoxy-3-phenyl-2-propynyl ethyl ether | 6142-95-6 | C13H16O2 | 详情 | 详情 |
(VI) | 41739 | 3-phenyl-2-propynal | 2579-22-8 | C9H6O | 详情 | 详情 |
(VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(VIII) | 41740 | ethyl (E)-5-phenyl-2-penten-4-ynoate | C13H12O2 | 详情 | 详情 | |
(IX) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
(X) | 13273 | methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C17H14N2O2 | 详情 | 详情 | |
(XI) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
(XII) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
(XIII) | 41741 | (2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidine; 2-[(2R)piperidinyl]ethyl trimethylsilyl ether | C10H23NOSi | 详情 | 详情 | |
(XIV) | 13276 | 2-[(2R)Piperidinyl]-1-ethanol | C7H15NO | 详情 | 详情 | |
(XV) | 41742 | (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1-((2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidinyl)-2-propen-1-one | C26H33N3O2Si | 详情 | 详情 |