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【结 构 式】 
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【药物名称】BAY-41-2272 【化学名称】5-Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-amine 【CA登记号】256376-24-6, 256376-86-0 (hydrochloride) 【 分 子 式 】C20H17FN6 【 分 子 量 】360.39709 |
【开发单位】Bayer (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Vasodilators, Guanylate Cyclase Activators |
合成路线1
The condensation of ethyl cyanopyruvate (I) with 2-fluorobenzyl hydrazine (II) in the presence of trifluoroacetic acid produced the aminopyrazole (III). This was further condensed with (dimethylamino)acrolein (IV) under acidic conditions to furnish the pyrazolopyridine (V). The ethyl ester group of (V) was then converted to nitrile (VII) via formation of the corresponding amide (VI), followed by dehydration with trifluoroacetic anhydride. Addition of methoxide to the cyano group of (VII) produced imidate (VIII), which was treated with ammonium chloride to yield the amidine (IX).
| 【1】 Starub, A.; et al.; NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 2001, 11, 6, 781. |
| 【2】 Feurer, A.; Stahl, E.; Stasch, J.-P.; Straub, A.; Dembowsky, K.; Alonso-Alija, C.; Perzborn, E.; Hutter, J. (Bayer AG); Substd. pyrazole derivs.. DE 19834047; EP 1102767; WO 0006568 . |
| 【3】 Straub, A.; Alonso-Alija, C.; Preiss, M.; Janichen, J. (Bayer AG); Method for the production of substd. pyrimidine derivs.. DE 19942809; WO 0117998 . |
| 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) | 50470 | ethyl 3-cyano-2-oxopropanoate | C6H7NO3 | 详情 | 详情 | |
| (II) | 50471 | 1-(2-fluorobenzyl)hydrazine | 51859-98-4 | C7H9FN2 | 详情 | 详情 |
| (III) | 50472 | ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate | 256504-39-9 | C13H14FN3O2 | 详情 | 详情 |
| (IV) | 11789 | (E)-3-(Dimethylamino)-2-propenal | 692-32-0 | C5H9NO | 详情 | 详情 |
| (V) | 50473 | ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate | 256376-59-7 | C16H14FN3O2 | 详情 | 详情 |
| (VI) | 50474 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide | 256376-62-2 | C14H11FN4O | 详情 | 详情 |
| (VII) | 50475 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile | 256376-65-5 | C14H9FN4 | 详情 | 详情 |
| (VIII) | 50476 | methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidoate | 304874-06-4 | C15H13FN4O | 详情 | 详情 |
| (IX) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
合成路线2
Condensation of cyclopropaneacetonitrile (X) with bis(dimethylamino)-tert-butoxymethane gave rise to the enamino nitrile (XI). This was then cyclized with amidine (IX) to produce the target pyrimidine derivative.
| 【1】 Starub, A.; et al.; NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 2001, 11, 6, 781. |
| 【2】 Feurer, A.; Stahl, E.; Stasch, J.-P.; Straub, A.; Dembowsky, K.; Alonso-Alija, C.; Perzborn, E.; Hutter, J. (Bayer AG); Substd. pyrazole derivs.. DE 19834047; EP 1102767; WO 0006568 . |
合成路线3
In a related method, Claisen condensation of ethyl formate with cyclopropaneacetonitrile (X), followed by acetylation of the intermediate potassium enolate (XII) with Ac2O, furnished the (acetoxy)acrylonitrile (XIII). This was finally cyclized with amidine (IX) in the presence of Et3N in refluxing toluene.
| 【1】 Straub, A.; Alonso-Alija, C.; Preiss, M.; Janichen, J. (Bayer AG); Method for the production of substd. pyrimidine derivs.. DE 19942809; WO 0117998 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (X) | 16824 | 2-cyclopropylacetonitrile; Cyclopropylacetonitrile | 6542-60-5 | C5H7N | 详情 | 详情 |
| (XII) | 50479 | potassium (E)-2-cyano-2-cyclopropyl-1-ethenolate | C6H6KNO | 详情 | 详情 | |
| (XIII) | 50480 | (E)-2-cyano-2-cyclopropylethenyl acetate | C8H9NO2 | 详情 | 详情 |
合成路线4
The reaction of 2-cyclopropylacetonitrile (I) with ethyl formate (II) by means of t-BuOK in THF gives the hydroxymethylene derivative (III), which is cyclized with 1-(2-fluorobenzyl)pyrazolo[3,4-b]pyridine-3-carboxamidine (IV)(see scheme no. 28591301a, intermediate (IX)) by heating at 105 C to afford the target aminopyrimidine derivative.
| 【1】 Feurer, A.; et al.; 3-(2-Pyrimidinyl)pyrazolo[3,4-b]pyridines: A novel class of orally active NO-independent stimulators of soluble guanylate cyclase. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 205. |
| 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) | 16824 | 2-cyclopropylacetonitrile; Cyclopropylacetonitrile | 6542-60-5 | C5H7N | 详情 | 详情 |
| (II) | 45474 | methyl formate | 107-31-3 | C2H4O2 | 详情 | 详情 |
| (III) | 63160 | (Z)-2-cyclopropyl-3-hydroxy-2-propenenitrile | C6H7NO | 详情 | 详情 | |
| (IV) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |