Hydrochloric Acid → (+/-)-4-[Amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester

HRID 1424255Notes

Reaction equation

[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14]2)=O)=[CH:7][CH:6]=1)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].Cl.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:26])[CH:13]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]

Participants

Conditions

Temperature: 60 °C

Procedure

4-(3,3-dimethyl-cyclobutanecarbonyl)-benzoic acid ethyl ester (Intermediate 23) (235 mg, 0.903 mmol) was dissolved in methanol (5 mL). Ammonium acetate (710 mg, 9.03 mmol) was added followed by sodium cyanoborohydride (89.6 mg, 1.36 mmol). This was heated to 60° C. for 17 h before cooling and adding 1 N HCl (3 mL). This was stirred for 15 min and then 1N NaOH (10 mL) was added. The material was extracted into two portions of ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave (+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (137 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 2H) 7.37 (d, J=8.2 Hz, 2H) 4.38 (q, J=7.0 Hz, 2H) 3.82 (d, J=9.2 Hz, 1H) 2.39 (sxt, J=8.7 Hz, 1H) 1.90-2.02 (m, 1H) 1.60-1.70 (m, 1H) 1.46-1.57 (m, 2H) 1.40 (t, J=7.1 Hz, 3H) 1.11 (s, 3H) 1.06 (s, 3H); GCMS (M): 261.

Workup

temperaturebefore cooling
extractionThe material was extracted into two portions of ethyl acetate
dry with materialthe combined organics dried over MgSO4
customPurification by silica gel flash chromatography (methanol/ethyl acetate)

Sources & evidence

ORD record: ord-be70c8f819454e218bc5779f12f6e065
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08927577B2

Reaction notes

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