sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate -Drug Synthesis Database

【结构式】

【分子编号】52079

【品名】sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate

【CA登记号】627076-29-3

【分子式】C₆H₆NNaO₃

【分子量】163.108348

【元素组成】C 44.18% H 3.71% N 8.59% Na 14.09% O 29.43%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

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).

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(III)

Intermediates (III) and (XII) are prepared as follows:
Trimethyl orthooctanoate (XII) is prepared by Pinner reaction of octanonitrile (XXXVII) with MeOH in the presence of HCl in MeOAc followed by treatment of the resulting methyl octanimidate hydrochloride (XXXVIII) with MeOH in methylcyclohexane (3). Scheme 5.
Intermediate (III) can be prepared by consecutive N-protection of the amidine nitrogens in pyrazole-1-carboxamidine (XIV), first by treatment with Boc2O by means of DIEA in DMF, and then reaction of the resulting monoprotected intermediate (XXXIX) with Boc2O in the presence of NaH in THF (3). Scheme 5.

参考文献中间体

合成目标

【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	52079	sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate	627076-29-3	C₆H₆NNaO₃	详情	详情
(XII)	66000	trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane	161838-87-5	C₁₁H₂₄O₃	详情	详情
(XIV)	15983	1H-pyrazole-1-carboximidamide	4023-00-1	C₄H₆N₄	详情	详情
(XXXVII)	59081	octanenitrile	124-12-9	C₈H₁₅N	详情	详情
(XXXVIII)	66024			C₉H₁₉NO.HCl	详情	详情
(XXXIX)	66025	N-(tert-Butoxycarbonyl)-1H-pyrazole-1-carboxamidine; N-Boc-1H-pyrazole-1-carboxamidine	152120-61-1	C₉H₁₄N₄O₂	详情	详情

Extended Information