2-amino-6-isopropyl-4-pyrimidinol -Drug Synthesis Database

【结构式】

【分子编号】30387

【品名】2-amino-6-isopropyl-4-pyrimidinol

【CA登记号】

【分子式】C₇H₁₁N₃O

【分子量】153.18396

【元素组成】C 54.89% H 7.24% N 27.43% O 10.44%

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：(III)

Cyclization of ethyl 4-methyl-3-oxopentanoate (I) with guanidine carbonate (II) in boiling EtOH gave 2-amino-4-hydroxy-6-isopropylpyrimidine (III), which was converted to the corresponding chloropyrimidine (IV) by means of POCl3. Boronic ester (VI) was prepared by lithiation of 1-bromo-4-fluoronaphthalene (V) with n-butyllithium, followed by reaction with trimethyl borate. Subsequent coupling of chloropyrimidine (IV) with boronic ester (VI) in the presence of tetrakis(triphenylphosphine)palladium yielded the target naphthylpyrimidine.

参考文献中间体

合成目标

【1】 Berger, J.; Flippin, L.A.; Greenhouse, R.; Jaime-Figueroa, S.; Liu, Y.; Miller, A.K.; Putman, D.G.; Weinhardt, K.K.; Zhao, S.-H. (F. Hoffmann-La Roche AG); Aryl pyrimidine derivs.. EP 0901474; US 5863924; WO 9744326 .

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)	19408	ethyl 4-methyl-3-oxopentanoate	7152-15-0	C₈H₁₄O₃	详情	详情
(II)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(III)	30387	2-amino-6-isopropyl-4-pyrimidinol		C₇H₁₁N₃O	详情	详情
(IV)	30388	4-chloro-6-isopropyl-2-pyrimidinylamine; 4-chloro-6-isopropyl-2-pyrimidinamine		C₇H₁₀ClN₃	详情	详情
(V)	30389	1-bromo-4-fluoronaphthalene	341-41-3	C₁₀H₆BrF	详情	详情
(VI)	30390	dimethyl 4-fluoro-1-naphthylboronate		C₁₂H₁₂BFO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The reduction of 1-indanone (I) with NaBH4 in methanol gives 1-indanol (II), which is brominated with Tms-Br in chloroform to yield 1-bromoindane (III) (1). The condensation of (III) with triethyl phosphonoacetate (IV) and NaH in DMF affords 2-(diethoxyphosphoryl)-2-(1-indanyl)acetic acid ethyl ester (V), which is treated with paraformaldehyde and K2CO3 in refluxing THF to provide 2-(1-indanyl)acrylic acid ethyl ester (VI). The hydrolysis of (VI) with NaOH in acetone/water gives the corresponding acrylic acid (VII), which is condensed with thioacetic acid (VIII) in refluxing chloroform to yield 3-(acetylsulfanyl)-2-(1-indanyl)propionic acid ethyl ester (IX) as a mixture of the two (R,R)+(S,S) and (R,S)+(S,R) racemates. These two racemates are easily separated by HPLC affording the desired (R,R)+(S,S)-(X) racemate. The condensation of (X) with L-tryptophan methyl ester (XI) by means of EDC and HOBT in THF/chloroform to provide a diastereomeric mixture (R,R,S)+(S,S,S) of compounds that is separated by HPLC to provide the desired (R,R,S) diastereomer (XII). Finally, this compound is hydrolyzed with NaOH in methanol/water to furnish the target tryptophan derivative.

参考文献中间体

合成目标

【1】 Inguimbert, N.; Roques, B.P.; Meudal, H.; Teffot, F.; Poras, H.; Fournié-Zaluski, M.-C.; Coric, P.; Toward an optimal joint recognition of the S1' subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). J Med Chem 2002, 45, 7, 1477.
【2】 Roques, B.P.; Renard, P.; Scalbert, E.; Bennejean, C.; Fournie-Lazuski, M.-C.; Inguimbert, N.; Poras, H. (ADIR et Cie.; INSERM (Institut National de la Sante et de la Recherche Medicale)); Amino acid derivs. and use thereof as NEP, ACE and ECE inhibitors. FR 2805259; WO 0160822 .

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)	23857	1-indanone	83-33-0	C₉H₈O	详情	详情
(II)	53590	1-Hydroxyhydrindene; 1-Hydroxyindan; 1-Indanol	6351-10-6	C₉H₁₀O	详情	详情
(III)	53591	1-bromoindane	n/a	C₉H₉Br	详情	详情
(IV)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(V)	53592	ethyl 2-(diethoxyphosphoryl)-2-(2,3-dihydro-1H-inden-1-yl)acetate	n/a	C₁₇H₂₅O₅P	详情	详情
(VI)	53593	ethyl 2-(2,3-dihydro-1H-inden-1-yl)acrylate	n/a	C₁₄H₁₆O₂	详情	详情
(VII)	53594	2-(2,3-dihydro-1H-inden-1-yl)acrylic acid	n/a	C₁₂H₁₂O₂	详情	详情
(VIII)	12893	Ethanethioic S-acid		C₂H₄OS	详情	详情
(IX)	53595	3-(acetylsulfanyl)-2-(2,3-dihydro-1H-inden-1-yl)propanoic acid	n/a	C₁₄H₁₆O₃S	详情	详情
(X)	53596	(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoic acid	n/a	C₁₄H₁₆O₃S	详情	详情
(XI)	30387	2-amino-6-isopropyl-4-pyrimidinol		C₇H₁₁N₃O	详情	详情
(XII)	53597	methyl (2S)-2-({(2R)-3-(acetylsulfanyl)-2-[(1R)-2,3-dihydro-1H-inden-1-yl]propanoyl}amino)-3-(1H-indol-3-yl)propanoate	n/a	C₂₆H₂₈N₂O₄S	详情	详情

Extended Information