(1R)-1-(6-oxo-1,6-dihydro-2-pyrimidinyl)ethyl butyrate -Drug Synthesis Database

【结构式】

【分子编号】64066

【品名】(1R)-1-(6-oxo-1,6-dihydro-2-pyrimidinyl)ethyl butyrate

【CA登记号】

【分子式】C₁₀H₁₄N₂O₃

【分子量】210.23284

【元素组成】C 57.13% H 6.71% N 13.32% O 22.83%

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：(X)

The chiral intermediate (X) is prepared by two methods. Treatment of lactonitrile (I) with HCl/EtOH affords imidate (II), which is further reacted with ethanolic ammonia to produce amidine (III). Claisen condensation between ethyl acetate (IV) and ethyl formate (V) in the presence of NaH provides the sodium salt of ethyl 3-hydroxyacrylate (VI). Cyclization of (VI) with amidine (III) then furnishes the racemic pyrimidinone (VII). Kinetic resolution of (VII) is accomplished by acylation with vinyl butyrate (VIII) in the presence of lipase P30 to yield a mixture of unreacted (S)-alcohol (IX) and the desired (R)-butyrate ester (X), which can be separated by partition between CH2Cl2 and H2O.

参考文献中间体

合成目标

【1】 Mylari, B.L.; Zembrowski, W.J.; Murry, J.A.; Chu-Moyer, M.Y. (Pfizer Products Inc.); Aminopyrimidines as sorbitol dehydrogenase inhibitors. EP 1185275; US 6414149; WO 0059510 .

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)	64060	2-hydroxypropanenitrile		C₃H₅NO	详情	详情
(II)	64061	ethyl 2-hydroxypropanimidoate		C₅H₁₁NO₂	详情	详情
(III)	64062	2-hydroxypropanimidamide		C₃H₈N₂O	详情	详情
(IV)	17491	ethyl acetate	141-78-6	C₄H₈O₂	详情	详情
(V)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(VI)	64063	sodium (E)-3-ethoxy-3-oxo-1-propen-1-olate		C₅H₇NaO₃	详情	详情
(VII)	64064	2-(1-hydroxyethyl)-4(3H)-pyrimidinone		C₆H₈N₂O₂	详情	详情
(VIII)	53263	n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate	123-20-6	C₆H₁₀O₂	详情	详情
(IX)	64065	2-[(1S)-1-hydroxyethyl]-4(3H)-pyrimidinone		C₆H₈N₂O₂	详情	详情
(X)	64066	(1R)-1-(6-oxo-1,6-dihydro-2-pyrimidinyl)ethyl butyrate		C₁₀H₁₄N₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

In an alternative synthesis of (X), treatment of (R)-2-hydroxypropionamide (XI) with triethyloxonium fluoborate affords the chiral imidate (XII), which is further converted to amidine (XIII) with ammonia in MeOH. Condensation of (XIII) with the sodium salt of ethyl 3-hydroxyacrylate (VI) leads to the (R)-2-(1-hydroxyethyl)pyrimidinone (XIV). This is then esterified with butyric anhydride to give intermediate (X).

参考文献中间体

合成目标

【1】 Mylari, B.L.; Zembrowski, W.J.; Murry, J.A.; Chu-Moyer, M.Y. (Pfizer Products Inc.); Aminopyrimidines as sorbitol dehydrogenase inhibitors. EP 1185275; US 6414149; WO 0059510 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	64063	sodium (E)-3-ethoxy-3-oxo-1-propen-1-olate	C₅H₇NaO₃	详情	详情
(X)	64066	(1R)-1-(6-oxo-1,6-dihydro-2-pyrimidinyl)ethyl butyrate	C₁₀H₁₄N₂O₃	详情	详情
(XI)	64067	(2R)-2-hydroxypropanamide	C₃H₇NO₂	详情	详情
(XII)	64068	ethyl (2R)-2-hydroxypropanimidoate	C₅H₁₁NO₂	详情	详情
(XIII)	64069	(2R)-2-hydroxypropanimidamide	C₃H₈N₂O	详情	详情
(XIV)	64070	2-[(1R)-1-hydroxyethyl]-4(3H)-pyrimidinone	C₆H₈N₂O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

Pyrimidinone (X) is treated with trifluoromethanesulfonic anhydride and Et3N to provide the pyrimidinyl triflate (XV). The triflate group of (XV) is subsequently displaced with cis-1-benzyl-3,5-dimethylpiperazine (XVI) to generate the pyrimidinyl piperazine adduct as a diastereomeric mixture, from which isomer (XVII) can be isolated as the corresponding L-dibenzoyltartrate salt. Removal of the N-benzyl protecting group of (XVII) by transfer hydrogenolysis leads to piperazine (XVIII) (1). This is then coupled with 2-methyl-4,6-bis(trichloromethyl)-[1,3,5]triazine (XIX) to furnish (XX). Finally, dechlorination of (XX) by hydrogenation over Pd/C, followed by acidic ester hydrolysis gives rise to the title compound (1,2).

参考文献中间体

合成目标

【1】 Mylari, B.L.; Oates, P.J.; Zembrowski, W.J.; Beebe, D.A.; Conn, E.L.; Coutcher, J.B.; O'Gorman, M.T.; Linhares, M.C,; Withbroe, G.J.; A sorbitol dehydrogenase inhibitor of exceptional in vivo potency with a long duration of action: 1-(R)-[4-[4-(4,6-Dimethyl[1,3,5]triazin-2-yl)-2R,6S-dimethylpiperazin-1-yl]pyrimidin-2-yl]ethanol. J Med Chem 2002, 45, 20, 4398.
【2】 Mylari, B.L.; Zembrowski, W.J.; Murry, J.A.; Chu-Moyer, M.Y. (Pfizer Products Inc.); Aminopyrimidines as sorbitol dehydrogenase inhibitors. EP 1185275; US 6414149; WO 0059510 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	64066	(1R)-1-(6-oxo-1,6-dihydro-2-pyrimidinyl)ethyl butyrate	C₁₀H₁₄N₂O₃	详情	详情
(XV)	64071	(1R)-1-(4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyrimidinyl)ethyl butyrate	C₁₁H₁₃F₃N₂O₅S	详情	详情
(XVI)	64072	(3R,5S)-1-benzyl-3,5-dimethylpiperazine	C₁₃H₂₀N₂	详情	详情
(XVII)	64073		C₄₁H₄₆N₄O₁₀	详情	详情
(XVIII)	64074		C₃₄H₄₀N₄O₁₀	详情	详情
(XIX)	64075	2-methyl-4,6-bis(trichloromethyl)-1,3,5-triazine	C₆H₃Cl₆N₃	详情	详情
(XX)	64076	(1R)-1-(4-{(2R,6S)-2,6-dimethyl-4-[4-methyl-6-(trichloromethyl)-1,3,5-triazin-2-yl]piperazinyl}-2-pyrimidinyl)ethyl butyrate	C₂₁H₂₈Cl₃N₇O₂	详情	详情

Extended Information