Sodium Carbonate → (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

HRID 1400721Notes

Reaction equation

HRID 1400721 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:11]3[N:12]=[C:13]([CH3:27])[C:14]([C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:15](I)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[C:41]([Cl:42])[C:33]1=2)[CH:30]=[CH2:31].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][C:34]2[CH:38]=[CH:39][C:40]([C:15]3[N:10]4[N:9]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=5)[CH:28]=[C:11]4[N:12]=[C:13]([CH3:27])[C:14]=3[C@H:17]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19])=[C:41]([Cl:42])[C:33]1=2)[CH:30]=[CH2:31]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 86710746(S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateHCID 867107714-Allyl-5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

Product 1

HCID 86710751(2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateYield 49.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A solution of (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.160 g, 0.287 mmol) and 4-allyl-5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.096 g, 0.287 mmol) in DMF (3 mL) was treated with 2.0 M aq. Na2CO3 (0.358 mL, 0.717 mmol), sparged with N2 for 10 min, treated with Pd(Ph3P)4 (0.033 g, 0.029 mmol), sparged for 5 min, then sealed and heated (90° C.) for 16 h. The reaction was cooled, diluted with EtOAc (20 mL) and washed with 1:1 water/brine (2×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by biotage column chromatography (4 g Isco SiO2, 0% (5 CV), 0%-80% (15 CV), EtOAc/hexanes) to afford semi-purified product (0.122 g, 0.143 mmol, 49.9% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.98 (t, J=1.7 Hz, 1H), 7.76 (dt, J=7.8, 1.2 Hz, 1H), 7.44 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 6.99-7.03 (m, 1H), 6.93-6.97 (m, 1H), 6.85 (s, 1H), 5.99-6.10 (m, 1H), 5.36 (dd, J=17.2, 1.6 Hz, 1H), 5.26 (dd, J=10.2, 1.5 Hz, 1H), 5.05 (s, 1H), 4.23-4.32 (m, 2H), 3.69 (dd, J=12.1, 6.0 Hz, 2H), 3.65 (s, 3H), 3.17-3.29 (m, 2H), 2.84 (s, 3H), 1.17 (s, 9H). LCMS (M+H)=641.2.

Workup

  1. customsparged with N2 for 10 min
  2. customsparged for 5 min
  3. customsealed
  4. temperatureThe reaction was cooled
  5. additiondiluted with EtOAc (20 mL)
  6. washwashed with 1:1 water/brine (2×10 mL)
  7. dry with materialThe organic layer was dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe residue was purified by biotage column chromatography (4 g Isco SiO2, 0% (5 CV), 0%-80% (15 CV), EtOAc/hexanes)

Sources & evidence

ORD record
ord-209a6906bc314d9ca9c06ca8734d2e21
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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