Acetic Acid → p-Toluenesulfonic acid monohydrate

HRID 68202Notes

Reaction equation

Cl.[CH3:2][S:3]([CH2:6][CH2:7][NH2:8])(=[O:5])=[O:4].[C:9]([OH:12])(=O)[CH3:10].[CH:13](N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH2:36].[CH3:37]C1C=CC(S(O)(=O)=O)=CC=1.[Cl:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]2[C:74]3[C:69](=[CH:70][CH:71]=[C:72]([C:75]4OC(CNCCS(C)(=O)=O)=[CH:78][CH:79]=4)[CH:73]=3)[N:68]=[CH:67][N:66]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=1.[OH2:88].S([C:93]1C=CC(C)=C[CH:94]=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.ClC1C=C(NC2C3C(=CC=C(C4OC(CNCCS(C)(=O)=O)=CC=4)C=3)N=CN=2)C=CC=1OCC1C=CC=C(F)C=1>O1CCCC1.O>[OH2:4].[C:9]1([CH3:10])[CH:37]=[CH:7][C:6]([S:3]([OH:5])(=[O:88])=[O:36])=[CH:54][CH:49]=1.[OH2:4].[CH3:13][C:9]1[CH:10]=[CH:7][C:6]([S:3]([OH:5])(=[O:88])=[O:36])=[CH:94][CH:93]=1.[Cl:48][C:49]1[CH:50]=[C:51]([NH:64][C:65]2[C:74]3[C:69](=[CH:70][CH:71]=[C:72]([C:75]4[O:12][C:9]([CH2:10][NH:8][CH2:7][CH2:6][S:3]([CH3:2])(=[O:5])=[O:4])=[CH:78][CH:79]=4)[CH:73]=3)[N:68]=[CH:67][N:66]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=1

Participants

Conditions

Temperature: 22 °C

Procedure

Stage 3—5-{4-[(3-Chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)amino]-6-quinazolinyl}-2-furancarbaldehyde 4-methylbenzenesulfonate (1 wt) and 2-(methylsulfonyl)ethylamine hydrochloride (0.4 wt, 1.60 equiv.) are suspended in THF (10 vols). Sequentially, acetic acid (0.354 vol., 4.00 equiv.) and di-isopropylethylamine (DIPEA, 1.08 vols, 4.00 equiv.) are added. The resulting solution is stirred at 30°-35° C. for ca. 1 hour then cooled to ca. 22° C. Sodium tri-acetoxyborohydride (0.66 wt, 2.00 equiv.) is then added. The resulting mixture is stirred at ca. 22° C. for 2-4 hours then sampled for HPLC analysis. The reaction is quenched by addition of aqueous sodium hydroxide (25% w/w, 3 vols.) followed by water (2 vols.). The aqueous phase is then separated, extracted with THF (2 vols) and the combined THF extracts are then washed twice with 25% w/v aqueous ammonium chloride solution (2×5 vols). A solution of p-toluenesulfonic acid monohydrate (p-TSA, 0.74 wt, 2.5 equiv.) in water (1 vol) is prepared, warmed to ca. 60° C., and N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4-methylbenzenesulfonate hydrate seeds are added. The THF solution of the free base is added to the p-TSA solution over at least 1 hr, maintaining the batch temperature at 60±3° C. The resulting suspension is stirred at ca. 60° C. for 1-2 hours, cooled to 20-25° C. over an hour and aged at this temperature for ca. 1 hr. The solid is collected by filtration, washed with 95:5 THF: Water (3×2 vols) and dried in vacuum at ca. 35° C. to give N-(3-chloro-4-{[(3-fluorophenyl)methyl]oxy}phenyl)-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furanyl]-4-quinazolinamine 4-methylbenzenesulfonate hydrate as a bright yellow crystalline solid.

Workup

stirringThe resulting mixture is stirred at ca. 22° C. for 2-4 hours
aliquotthen sampled for HPLC analysis
customThe reaction is quenched by addition of aqueous sodium hydroxide (25% w/w, 3 vols.)
customThe aqueous phase is then separated
extractionextracted with THF (2 vols)
washthe combined THF extracts are then washed twice with 25% w/v aqueous ammonium chloride solution (2×5 vols)
temperaturewarmed to ca. 60° C.
temperaturemaintaining the batch temperature at 60±3° C
stirringThe resulting suspension is stirred at ca. 60° C. for 1-2 hours
temperaturecooled to 20-25° C. over an hour
waitaged at this temperature for ca. 1 hr
filtrationThe solid is collected by filtration
washwashed with 95:5 THF
dry with materialWater (3×2 vols) and dried in vacuum at ca. 35° C.

Sources & evidence

ORD record: ord-71171d54ed63400eab8b112ec375d866
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08821927B2

Reaction notes

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