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【结 构 式】 
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【分子编号】11789 【品名】(E)-3-(Dimethylamino)-2-propenal 【CA登记号】692-32-0 |
【 分 子 式 】C5H9NO 【 分 子 量 】99.1326 【元素组成】C 60.58% H 9.15% N 14.13% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of 4-fluorophenacyl chloride (I) with N-isopropylaniline gives N-(4-fluorobenzoylmethyl)-N-isopropylaniline (II), which is cyclized in a conventional way to 3-(4-fluorophenyl)-1-isopropyl-indole (III) and condensed with 3-(dimethylamino)acrolein (IV) by means of POCl3 in refluxing acetonitrile, yielding 3-[3-(4-fluorophenyl)-1-isopropyl-indol-2-yl]acrolein (V). The condensation of (V) with methylacetoacetate (VI) by means of NaH and butyl-lithium in THF affords methyl 7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate (VII), which is reduced with triethylborane and NaBH4 in THF, giving the dihydroxy ester (VIII). Finally, this compound is hydrolyzed with NaOH in ethanol.
| 【1】 Kathawala, F. (Novartis AG); Analogs of mevalolactone and derivs. thereof, processes for their production, pharmaceutical compsns. containing them and their use as pharmaceuticals. JP 1991047167; US 4739073; WO 8402131 . |
| 【2】 Kapa, P.K. (Novartis AG); 6-Substituted-4-hydroxy-tetrahydropyran-2-ones. US 4571428 . |
| 【3】 Chen, K.-M.; Hardtmann, G.E.; Lee, G.T.; Linder, J.; Wattanasin, S. (Novartis AG; Novartis Deutschland GmbH); Preparation of olefinic cpds. EP 0244364 . |
| 【4】 Castaner, J.; Prous, J.; Fluvastatin Sodium. Drugs Fut 1991, 16, 9, 804. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27905 | N-isopropyl-N-phenylamine | 768-52-5 | C9H13N | 详情 | 详情 | |
| (I) | 11786 | 2-Chloro-1-(4-fluorophenyl)-1-ethanone; 2-Chloro-4'-fluoroacetophenone | 456-04-2 | C8H6ClFO | 详情 | 详情 |
| (II) | 11787 | 1-(4-Fluorophenyl)-2-(isopropylanilino)-1-ethanone | C17H18FNO | 详情 | 详情 | |
| (III) | 11788 | 3-(4-Fluorophenyl)-1-isopropyl-1H-indole | 93957-49-4 | C17H16FN | 详情 | 详情 |
| (IV) | 11789 | (E)-3-(Dimethylamino)-2-propenal | 692-32-0 | C5H9NO | 详情 | 详情 |
| (V) | 11790 | (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal | C20H18FNO | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VII) | 11792 | methyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate | C25H26FNO4 | 详情 | 详情 | |
| (VIII) | 11793 | methyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate | C25H28FNO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The condensation between 2-fluorobenzylhydrazine (I) and the sodium enolate of ethyl cyanopyruvate (II) in the presence of trifluoroacetic acid produced the pyrazole derivative (III). Subsequent cyclization of aminopyrazole (III) with (dimethylamino)acrolein (IV) gave the pyrazolopyridine (V). Amonolysis of the ethyl ester group of (V) afforded amide (VI), which was further dehydrated to nitrile (VII) by means of trifluoroacetic anhydride and pyridine. Addition of sodium methoxide to nitrile (VII) furnished imidate (VIII). This was converted to the corresponding amidine (IX) upon treatment with ammonium chloride and HOAc. Finally, the title diamino pyrimidine compound was obtained by heating a mixture of amidine (IX) and morpholinomalononitrile (X).
| 【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. |
| 【2】 Hutter, J.; Stasch, J.-P.; Dembowsky, K.; Perzborn, E.; Straub, A.; Feurer, A.; Alonso-Alija, C.; Stahl, E. (Bayer AG); Substd. pyrazolo derivs. condensed with six-membered heterocyclic rings. DE 19834044; EP 1102768; WO 0006569 . |
| 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) | 50471 | 1-(2-fluorobenzyl)hydrazine | 51859-98-4 | C7H9FN2 | 详情 | 详情 |
| (II) | 52079 | sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate | 627076-29-3 | C6H6NNaO3 | 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 |
| (X) | 52080 | 2-(4-morpholinyl)malononitrile | C7H9N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)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4
该中间体在本合成路线中的序号：(II)The reaction of octaethylporphyrin (I) with 3-(dimethylamino)acrolein (II) by means of POCl3 gives the 10-(2-formylvinyl)octaethylporphyrin (III), which is treated with decylmagnesium bromide (IV) in THF to yield the corresponding alcohol (V). The cyclization of (V) in concentrated H2SO4 affords the decylbenzochlorin (VI), which is finally treated with zinc acetate in methanol/dichloromethane to provide the target zinc complex.
| 【1】 Li, G.; et al.; A simple and efficient approach for the synthesis of fluorinated and nonfluorinated octaethylporphyrin-based benzochlorins with variable lipophilicity. Their in vivo tumor uptake, and the preliminary in vitro photosensitizing. J Org Chem 2001, 66, 4, 1316. |
合成路线5
该中间体在本合成路线中的序号：(VI)Treatment of 2-fluorobenzyl bromide (I) with hydrazine hydrate in refluxing EtOH gives 2-fluorobenzyl hydrazine (II) (1), which by cyclocondensation with the sodium salt of ethyl cyanopyruvate (III) — prepared by reaction of diethyl oxalate (IV) with acetonitrile mediated by NaOEt (2) — by means of TFA in refluxing dioxane yields the 5-aminopyrazole derivative (V). Condensation of intermediate (V) with 3-dimethylaminoacrolein (VI) in the presence of TFA in refluxing dioxane provides the pyrazolo[3,4-b]pyridine derivative (VII), which is amidated with methanolic ammonia, affording amide (VIII). Treatment of amide (VIII) with pyridine and trifluoroacetic anhydride in THF followed by methanolysis of the resulting nitrile (IX) by means of NaOMe in MeOH generates the methyl imidoate (X), which, without isolation, undergoes amination with NH4Cl in the presence of glacial acetic acid in refluxing MeOH to give the carboxamidine (XI). Coupling of amidine (XI) with phenylazomalononitrile (XII) by means of NaOMe in DMF at 110 °C affords diamine (XIII), which upon reduction with H2 over Raney-Ni in H2O/DMF at 62 °C provides triamine (XIV). Acylation of amine (XIV) with methyl chloroformate (XV) in pyridine affords carbamate (XVI), which is finally N-methylated by means of MeI and NaH in DMF (3) or LiHMDS in THF (4). Scheme 1.
| 【1】 Kelley, J.L., Davis, R.G., McLean, E.W., Glen, R.C., Soroko, F.E., Cooper, B.R. Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: Imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine. J Med Chem 1995, 38(19): 3884-8. |
| 【2】 Von Borsche, W., Manteuffel, R. Substituted pyrazole derivatives condensed with six-membered heterocyclic rings. Justus Liebigs Ann Chem 1934, 512: 97. |
| 【3】 Alonso-Alija, C., Bischoff, E., Muenter, K., Feurer, A., Stahl, E., Weigand, S., Stasch, J.-P. (Bayer Healthcare AG). Carbamate-substituted pyrazolopyridines. CA 2485143, DE 10220570, EP 1506193, JP 2005531553, US 2006052397, US 7173037, WO 2003095451. |
| 【4】 Mittendorf, J., Weigand, S., Alonso-Alija, C. et al. Discovery of riociguat (BAY 63-2521): A potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009, 4(5): 853-65. |
| 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) | 38775 | 1-(bromomethyl)-2-fluorobenzene | 446-48-0 | C7H6BrF | 详情 | 详情 |
| (II) | 50471 | 1-(2-fluorobenzyl)hydrazine | 51859-98-4 | C7H9FN2 | 详情 | 详情 |
| (III) | 52079 | sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate | 627076-29-3 | C6H6NNaO3 | 详情 | 详情 |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 50472 | ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate | 256504-39-9 | C13H14FN3O2 | 详情 | 详情 |
| (VI) | 11789 | (E)-3-(Dimethylamino)-2-propenal | 692-32-0 | C5H9NO | 详情 | 详情 |
| (VII) | 50473 | ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate | 256376-59-7 | C16H14FN3O2 | 详情 | 详情 |
| (VIII) | 50474 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide | 256376-62-2 | C14H11FN4O | 详情 | 详情 |
| (IX) | 50475 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile | 256376-65-5 | C14H9FN4 | 详情 | 详情 |
| (X) | 50476 | methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidoate | 304874-06-4 | C15H13FN4O | 详情 | 详情 |
| (XI) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (XII) | 63162 | 2-[(E)-2-phenyldiazenyl]malononitrile | 6017-21-6 | C9H6N4 | 详情 | 详情 |
| (XIII) | 63163 | 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine | 428854-23-3 | C23H18FN9 | 详情 | 详情 |
| (XIV) | 63164 | 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylamine; 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine | 428854-24-4 | C17H15FN8 | 详情 | 详情 |
| (XV) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XVI) | 65980 | Methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate | 625115-52-8 | C19H17FN8O2 | 详情 | 详情 |