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

HRID 512115Notes

Reaction equation

HRID 512115 reaction equation
[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]

Participants

10

Reactant 5

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

Product 1

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

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

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.

Workup

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

Sources & evidence

ORD record
ord-7aeee6a0c4ba4c34add08535d63e23e9
Source dataset
uspto-grants-2015_08
Patent number
US09102631B2

Reaction notes

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