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

HRID 2046768Notes

Reaction equation

HRID 2046768 reaction equation
[CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:12]([CH2:27][CH2:28][CH2:29][CH3:30])[C:11](=[O:31])[C:10]=2[CH:32]=1.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:27][CH2:28][CH2:29][CH3:30])[C:11](=[O:31])[C:10]=2[CH:32]=1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 58147941(E)-3-{1'-tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester2×

Product 1

HCID 66932349(E)-3-{3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester hydrochlorideYield 99%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (182 mg, 0.397 mmol, Intermediate 7) was treated with 4 M HCl in dioxane following the procedure described in Example 1 STEP C, to give (E)-3-{3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride (157 mg, 99%). Reaction with acetaldehyde (24 μl, 0.42 mmol) and NaCN(BH3) (26 mg, 0.42 mmol) following the procedure described in Example 71, Step A, gave (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (123 mg, 80%). The ester was hydrolyzed as described in Example 71, Step B, giving (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid. The resulting acid was treated with NH2OTHP following the procedure described in Example 71, Step C, giving (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of THP protecting group following the procedure described in Example 71, STEP C gave (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide that was purified by preparative LC-MS and obtained as trifluoroacetate salt (18 mg).

Sources & evidence

ORD record
ord-fb8c9cc242d14961bee0ce53bab044bf
Source dataset
uspto-grants-2013_11
Patent number
US08592444B2

Reaction notes

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