Sulfuric Acid → 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione

HRID 512115ノート

反応式

HRID 512115 の反応式
[NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[NH:3][C:2]1=[O:12].C[Si](C)(C)N[Si](C)(C)C.S(=O)(=O)(O)O.C[Si](C)(C)OC1N=C(O[Si](C)(C)C)C2CCCCC=2N=1.Br[CH2:48][C:49]1[CH:50]=[C:51]([CH:56]=[CH:57][CH:58]=1)[C:52]([O:54][CH3:55])=[O:53]>C1(C)C=CC=CC=1.CN(C=O)C.CO.O1CCOCC1>[CH3:55][O:54][C:52]([C:51]1[CH:50]=[C:49]([CH:58]=[CH:57][CH:56]=1)[CH2:48][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[NH:3][C:2]1=[O:12])=[O:53]

参加物

10

反応物 5

HCID 1118Sulfuric AcidHCID 13838HexamethyldisilazaneHCID 4718725,6,7,8-Tetrahydroquinazoline-2,4(1H,3H)-dioneHCID 517981Methyl 3-(bromomethyl)benzoateHCID 12514465HCID 12514465、化合物

生成物 1

HCID 895453961-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione

試薬・触媒・溶媒 4

HCID 887Methanol溶媒HCID 1140Toluene溶媒HCID 6228Dimethylformamide溶媒HCID 312751,4-Dioxane溶媒

実験手順

The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formula I, II or III can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of cyclohexanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclohexanecarboxy late. Reaction of ethyl 2-oxocyclohexanecarboxylate with urea at 175-185° C. produced 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione. Reaction of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazol. Reaction of 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazoline with methyl 3-(bromomethyl)benzoate in DMF , followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H )-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione.

後処理

  1. customproduced the intermediate 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazol

出典と根拠

ORDレコード
ord-7aeee6a0c4ba4c34add08535d63e23e9
出典データセット
uspto-grants-2015_08
特許番号
US09102631B2

反応ノート

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