Hydrochloric Acid → (E)-3-{1'-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid

HRID 518232Notes

Reaction equation

HRID 518232 reaction equation
C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11](=[O:27])[C:10]=2[CH:28]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CC(O)=O>[CH2:30]([N:16]1[CH2:17][CH2:18][C:13]2([N:12]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:19]2)[CH2:14][CH2:15]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 7498Benzyl BromideHCID 58147954(E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester2×

Product 1

HCID 66932371(E)-3-{1'-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acidYield 95%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

(E)-3-{1′-Benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester was obtained by reacting (E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (485 mg, 1.13 mmol, Intermediate 6) with benzyl bromide, according to the procedure described in Example 2, Step A, giving a white solid (544 mg, quantitative). The methyl ester (500 mg, 1.03 mmol) was hydrolyzed with HCl 20% and AcOH following the procedure described Example 55, Step B, giving (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid as a white solid (500 mg, 95%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (228 mg, 40%). Finally, removal of the THP protecting group (177 mg, 0.312 mmol) following the procedure described in Example 1, Step C gave (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide (150 mg, trifluoroacetate salt) after purification by preparative HPLC.

Workup

  1. customgiving a white solid (544 mg, quantitative)

Sources & evidence

ORD record
ord-a2bb4f93dd384cbfaccc7871cb367703
Source dataset
uspto-grants-2015_08
Patent number
US09115148B2

Reaction notes

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