Benzoic acid, 3-(chlorosulfonyl)- → 3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-N-[(6-fluoro-3'-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]benzamide

HRID 564644Notes

Reaction equation

[NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.Cl[S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=O)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:78][CH2:79][C:80]1[CH:81]=[CH:82][C:83]([F:107])=[C:84]([C:86]2[CH:91]=[CH:90][CH:89]=[C:88]([CH2:92][N:93]3[CH2:98][CH2:97][N:96](C(OC(C)(C)C)=O)[C@@H:95]([CH3:106])[CH2:94]3)[CH:87]=2)[CH:85]=1>ClCCl.O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][S:24]([C:27]3[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=3)[C:30]([NH:78][CH2:79][C:80]3[CH:85]=[C:84]([C:86]4[CH:91]=[CH:90][CH:89]=[C:88]([CH2:92][N:93]5[CH2:98][CH2:97][NH:96][C@@H:95]([CH3:106])[CH2:94]5)[CH:87]=4)[C:83]([F:107])=[CH:82][CH:81]=3)=[O:32])(=[O:25])=[O:26])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]

Participants

Conditions

Temperature: 0 °C

Procedure

A cooled solution (0° C.) of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine, (80 mg, 0.26 mmol) in dichloromethane (10 mL) was treated with 3-(chlorosulfonyl)benzoic acid (30 mg, 0.36 mmol) and diisopropylethylamine (0.09 mL, 0.52 mmol) and the mixture was stirred at 0° C. for 20 min. The mixture was then treated with PyBOP (100 mg, 0.31 mmol), diisopropylethylamine (0.15 mL, 0.86 mmol) and 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (107 mg, 0.26 mmol) and stirred at ambient temperature for 16 h. The mixture was treated with water (40 mL) and extracted with dichloromethane (25 mL) and the organic phase was then concentrated to dryness and the intermediate Boc-protected material purified by mass-directed automated preparative HPLC. Product-containing fractions were passed though a 5 g SCX solid-phase extraction cartridge and the product eluted off with a 10% solution of ammonia in methanol, product containing fractions were concentrated to dryness. The residue was dissolved in methanol, treated with aqueous hydrochloric acid (2M, 2 mL) and stirred at ambient temperature for 16 h. The mixture was then dried (hydrophobic frit), evaporated to dryness and the product purified by mass-directed automated preparative HPLC. Product-containing fractions were passed though a 2 g SCX solid-phase extraction cartridge and the product eluted off with a 10% solution of ammonia in methanol, product-containing fractions were concentrated to dryness to afford 16 mg of the title compound. LC-MS m/z 783 (M+H)+, 0.92 min (ret time).

Workup

stirringstirred at ambient temperature for 16 h
extractionextracted with dichloromethane (25 mL)
concentrationthe organic phase was then concentrated to dryness
custompurified
extractionProduct-containing fractions were passed though a 5 g SCX solid-phase extraction cartridge
washthe product eluted off with a 10% solution of ammonia in methanol, product
additioncontaining fractions
concentrationwere concentrated to dryness
dissolutionThe residue was dissolved in methanol
additiontreated with aqueous hydrochloric acid (2M, 2 mL)
stirringstirred at ambient temperature for 16 h
customThe mixture was then dried (hydrophobic frit)
customevaporated to dryness
customthe product purified
extractionProduct-containing fractions were passed though a 2 g SCX solid-phase extraction cartridge
washthe product eluted off with a 10% solution of ammonia in methanol
additionproduct-containing fractions
concentrationwere concentrated to dryness

Sources & evidence

ORD record: ord-adff33bad5724b0bb4a7e318754ed19e
Source dataset: uspto-grants-2011_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08067408B2

Reaction notes

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