5,6-diamino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione -Drug Synthesis Database

【结构式】

【分子编号】44185

【品名】5,6-diamino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione

【CA登记号】

【分子式】C₁₁H₁₂N₄O₂

【分子量】232.24204

【元素组成】C 56.89% H 5.21% N 24.12% O 13.78%

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：(VI)

Acylation of urea derivative (I) with cyanoacetic acid (II) in HOAc in the presence of Ac2O yields derivative (III), which is then cyclized by treatment with NaOH to provide (IV). Nitrosation of (IV) with NaNO2 and HCl affords nitroso derivative (V), which is then hydrogenated over Pd/C in EtOH to furnish substituted pyrimidinedione (VI). Finally, (VI) is coupled to Trolox (VII) with N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt) in DMF or with 4-(dimethylamino)pyridine (DMAP) and N-dicyclohexylcarbodiimide (DCC) in CH2Cl2 to yield the target compound.

参考文献中间体

合成目标

【2】 Isobe, Y.; Goto, Y.; Tobe, M.; Takahashi, O. (Japan Energy Corp.); Hydroquinone derivs. and their medicinal use. JP 1998147575; US 5821247 .
【1】 Matsui, J.; Tsuchiya, M.; Hayashi, H.; Goto, Y.; Hirota, K.; Obara, f.; Isobe, Y.; Tobe, M.; Synthesis and biological evaluation of CX-659S and its related compounds for their inhibitory effects on the delayed-type hypersensitivity reaction. Bioorg Med Chem 2000, 8, 8, 2037.

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)	44181	N-methyl-N'-phenylurea	1007-36-9	C₈H₁₀N₂O	详情	详情
(II)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情
(III)	44182	N-(2-cyanoacetyl)-N-methyl-N'-phenylurea		C₁₁H₁₁N₃O₂	详情	详情
(IV)	44183	6-amino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₁N₃O₂	详情	详情
(V)	44184	6-amino-3-methyl-5-nitro-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₀N₄O₄	详情	详情
(VI)	44185	5,6-diamino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₂N₄O₂	详情	详情
(VII)	34833	(2S)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromene-2-carboxylic acid		C₁₄H₁₈O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIIa)

(S)-7-Hydroxy-1,2,3,4-tetrahydroqinoline-3-carboxylic acid (I) is N-protected by means of di-tert-butyldicarbonate (Boc2O) and Na2CO3 in H2O/dioxane and then converted into methyl ester derivative (II) by treatment with trimethylsilyl diazomethane (TMSCNH2). Reaction of (II) with triflic anhydride (Tf2O) and Et3N in CH2Cl2 yields triflate (III), which is then coupled to boronic acid (IV) by Suzuki cross-coupling reaction in the presence of Pd(PPh3)4 and Na2CO3 in toluene/EtOH, providing derivative (V). Boc removal in (V) by treatment with HCl/HOAc followed by coupling with N-Boc-2,6-dimethyl-D/L-tyrosine (VIa-b) by means of EDC, HOBt, DIEA and DMAP in DMF furnishes protected compound (VIIa-b). Compound (VIIa-b) is hydrolyzed with LiOH and N-deprotected by means of HCl/HOAc to afford a mixture of diastereomers (VIIIa-b) from which the target compound is separated by reverse-phase HPLC.

参考文献中间体

合成目标

【1】 Brown, W.; Mischki, T.; Butterworth, J.; Schmidt, R.; McGlory, A.; Payza, K.; St-Onge, S.; Labarre, M.; Pagé, D.; Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists. Bioorg Med Chem Lett 2000, 10, 2, 167.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIa)	44185	5,6-diamino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₂N₄O₂	详情	详情
(VIa)	44813	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)propionic acid		C₁₆H₂₃NO₅	详情	详情
(VIb)	44814	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)propionic acid		C₁₆H₂₃NO₅	详情	详情
(VIIb)	44816	methyl (3S)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate		C₃₃H₃₇FN₂O₆	详情	详情
(VIIIa)	44817	(3S)-2-[(2R)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid		C₂₇H₂₇FN₂O₄	详情	详情
(VIIIb)	44818	(3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid		C₂₇H₂₇FN₂O₄	详情	详情
(I)	44809	(3S)-7-hydroxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid	128502-56-7	C₁₀H₁₁NO₃	详情	详情
(II)	44810	2-(tert-butyl) 3-methyl (3S)-7-hydroxy-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate		C₁₆H₂₁NO₅	详情	详情
(III)	44811	2-(tert-butyl) 3-methyl (3S)-7-[[(trifluoromethyl)sulfonyl]oxy]-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate		C₁₇H₂₀F₃NO₇S	详情	详情
(IV)	38403	4-fluorophenylboronic acid	1765-93-1	C₆H₆BFO₂	详情	详情
(V)	44812	2-(tert-butyl) 3-methyl (3S)-7-(4-fluorophenyl)-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate		C₂₂H₂₄FNO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Nitrosation of pyrimidinedione (I) with NaNO2/HCl affords (II), which is further reduced to the diaminopyrimidine (III) by catalytic hydrogenation over Pd/C. Subsequent coupling of (III) with 2,6-di-tert-butyl-4-hydroxycinnamic acid (IV) employing DPP-Cl furnishes the title amide

参考文献中间体

合成目标

【1】 Isobe, Y.; Tobe, M.; Inoue, Y.; Goto, Y.; Obara, F.; Isobe, M.; Hayashi, H.; Inhibitory activities of novel pyrimidine derivatives on the contact hypersensitivity reaction. Chem Pharm Bull 2003, 51, 3, 309.

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)	44183	6-amino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₁N₃O₂	详情	详情
(II)	63475	6-amino-3-methyl-5-nitroso-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₀N₄O₃	详情	详情
(III)	44185	5,6-diamino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione		C₁₁H₁₂N₄O₂	详情	详情
(IV)	43375	(E)-3-[3,5-di(tert-butyl)-4-hydroxyphenyl]-2-propenoic acid	22014-01-3	C₁₇H₂₄O₃	详情	详情

Extended Information