formamidine acetate -Drug Synthesis Database

【结构式】

【分子编号】67709

【品名】formamidine acetate

【CA登记号】3473-63-0

【分子式】CH₄N₂.C₂H₄O₂

【分子量】104.1088

【元素组成】C 34.61% H 7.75% N 26.91% O 30.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

Condensation of ethyl(ethoxymethylene)cyanoacetate (I) with diethyl aminomalonate hydrochloride (II) in the presence of NaOMe in refluxing MeOH gives the pyrrole derivative (III), which is cyclized with formamidine acetate (IV) in refluxing EtOH to yield methyl 4-hydroxy-pyrrolo[3,2-d]pyrimidine-7-carboxylate (V). Decarbomethoxylation of ester (V) by means of aqueous KOH at reflux provides 4-hydroxy-pyrrolo[3,2-d]pyrimidine (VI), which by chlorination with POCl3 at reflux and subsequent chloride displacement with NaOBn in refluxing benzyl alcohol leads to 4-(benzyloxy)pyrrolo[3,2-d]pyrimidine (VII). Mannich reaction of deazapurine derivative (VII) with 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol (VIII) [obtained by debenzylation of compound (IX) with H2 and Pd/C in EtOH at 58 °C and formaldehyde in H2O at 58 °C yields the O-benzyl ulodesine derivative (X), which is finally deprotected by hydrogenolysis over Pd/C in aqueous ammonia .
In a related procedure, Mannich reaction of 4-hydroxypyrrolo-[3,2-d]pyrimidine (VI) with 4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol hydrochloride (XI) [obtained by N-deprotection of 1-Boc-4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol (XII) using HCl in MeOH (4)] and formaldehyde in the presence of NaOAc in H2O at 95 °C provides ulodesine as the corresponding acetate salt .
Alternatively, ulodesine can be obtained by deprotection of precursor (XIII) with H2 and Pd(OH)2/C in EtOH/AcOH .

参考文献中间体

合成目标

【1】 Bradley, P.A., de Koning, P.D., Johnson, P.S., Lecouturier, Y.C., McManus, D.J., Robin, A., Underwood, T.J. Development of a practical synthesis of the progesterone receptor antagonist 4-[[3-cyclopropyl-1(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy]-2,6-dimethylbenzonitrile. Org Process Res Dev 2009, 13(5): 848.
【2】 Evans, G.B., Furneaux, R.H., Tyler, P.C., Schramm, V.L. Synthesis of a transition state analogue inhibitor of purine nucleoside phosphorylate via the Mannich reaction. Org Lett 2003, 5(20): 3639-40.
【3】 Evans, G.B., Tyler, P.C. (Callaghan Innovation Research, Ltd.; Albert Einstein College of Medicine). Process for preparing inhibitors of nucleoside phosphorylase and nucleosidases. JP 2006516615, US 7655795, US 2010094003, WO 2004069856.
【4】 Furneaux, R.H., Schramm, V.L., Lenz, D.H., Evans, G.B., Tyler, P.C., Zubkova, O.V. (Albert Einstein College of Medicine; Callaghan Innovation Research, Ltd.). Inhibitors of nucleoside phosphorylases and nucleosidases. CA 2496698, EP 1539783, JP 2006501239, US 2006160765, US 2009239885, US 8173662, WO 2004018496.

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)	43041	ethyl (Z)-2-cyano-3-ethoxy-2-propenoate	94-05-3	C₈H₁₁NO₃	详情	详情
(II)	67707	diethyl aminomalonate hydrochloride	13433-00-6	C₇H₁₃NO₄.HCl	详情	详情
(III)	67708	dimethyl 3-amino-1H-pyrrole-2,4-dicarboxylate	180059-04-5	C₈H₁₀N₂O₄	详情	详情
(IV)	67709	formamidine acetate	3473-63-0	CH₄N₂.C₂H₄O₂	详情	详情
(V)	67710	methyl 4-hydroxy-pyrrolo[3,2-d]pyrimidine-7-carboxylate		C₈H₇N₃O₃	详情	详情
(VI)	67711	4-hydroxy-pyrrolo[3,2-d]pyrimidine		C₆H₅N₃O	详情	详情
(VII)	67712	4-(benzyloxy)pyrrolo[3,2-d]pyrimidine		C₁₃H₁₁N₃O	详情	详情
(VIII)	67713	4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol		C₅H₁₁NO₂	详情	详情
(IX)	67714	(3R,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidin-3-ol	253129-03-2	C₁₂H₁₇NO₂	详情	详情
(X)	67715	(3R,4R)-1-((4-(benzyloxy)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-(hydroxymethyl)pyrrolidin-3-ol		C₁₉H₂₂N₄O₃	详情	详情
(XI)	67716	4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol hydrochloride		C₅H₁₁NO₂.HCl	详情	详情
(XII)	67718	1-Boc-4(R)-(hydroxymethyl)pyrrolidin-3(R)-ol		C₁₀H₁₉NO₄	详情	详情
(XIII)	67717	7-(((3R,4R)-3-(benzyloxy)-4-((benzyloxy)methyl)pyrrolidin-1-yl)methyl)-5-((benzyloxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol		C₃₄H₃₆N₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The 7-methoxy-6-nitroquinazoline derivative (I) can be prepared by cyclization of 2-amino-4-fluorobenzoic acid (XIV) with formamidine acetate (XV) in 2-methoxyethanol to yield 7-fluoroquinazolin-4(3H)-one (XVI), which is then nitrated with HNO3 and H2SO4 to give 7-fluoro-6-nitroquinazolin-4(3H)-one (XVII) (1). Chlorination of quinazolinone (XVII) with SOCl2 at reflux provides 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) , which is then coupled with 3-chloro-4-fluoroaniline (XIX) by means of Et3N or PhNMe2 in i-PrOH to produce the diarylamine (XX). Finally, fluoroquinazoline (XX) is treated with MeOH and NaH in .

参考文献中间体

合成目标

【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758.
【3】 Bridges, A.J., Klohs, W.D., Driscoll, D. (Pfizer, Inc.). N-[4-(3-Chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, an irreversible inhibitor of tyrosine kinases. EP 1131304, JP 2002530386, US 6344455, WO 2000031048.
【4】 Smaill, J.B., Rewcastle, G.W., Loo, J.A. et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino) quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solublizing functions. J Med Chem 2000, 43(7): 1380-97.
【2】 Bridges, A.J., Horne, N.M., Jacks, T.E. et al. (Pfizer, Inc.). Preparation of substituted quinazolines. JP 2006517959, US 2004158065, WO 2004069791.

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)	68469	N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine		C₁₅H₁₀ClFN₄O₃	详情	详情
(XIV)	10805	2-Amino-4-fluorobenzoic acid	446-32-2	C₇H₆FNO₂	详情	详情
(XV)	67709	formamidine acetate	3473-63-0	CH₄N₂.C₂H₄O₂	详情	详情
(XVI)	19140	7-fluoro-4(3H)-quinazolinone		C₈H₅FN₂O	详情	详情
(XVII)	19141	7-fluoro-6-nitro-4(3H)-quinazolinone		C₈H₄FN₃O₃	详情	详情
(XVIII)	19142	4-chloro-7-fluoro-6-nitroquinazoline		C₈H₃ClFN₃O₂	详情	详情
(XIX)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(XX)	54956	N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine; N-(3-chloro-4-fluorophenyl)-N-(7-fluoro-6-nitro-4-quinazolinyl)amine	162012-67-1	C₁₄H₇ClF₂N₄O₂	详情	详情

Extended Information