Acetic Acid → (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetic acid

HRID 879483Notes

Reaction equation

HRID 879483 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.C(Cl)Cl.CC(O)=O.CC([O-])=O.[K+].Br[C:32]1[S:33][C:34]2[C:40]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)=[C:39]([C@H:48]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:49]([O:51]CC)=[O:50])[C:38]([CH3:59])=[CH:37][C:35]=2[N:36]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.CCO.O1CCOCC1>[C:55]([O:54][C@@H:48]([C:39]1[C:38]([CH3:59])=[CH:37][C:35]2[N:36]=[C:32]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[N:6]=[C:5]4[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[S:33][C:34]=2[C:40]=1[C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:49]([OH:51])=[O:50])([CH3:58])([CH3:56])[CH3:57]

Participants

12

Reactant 7

HCID 176Acetic AcidHCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 517044Potassium AcetateHCID 858434475-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazoleHCID 86700141(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate

Product 1

HCID 72196116(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetic acid

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A vial was charged with 5-bromo-1-methyl-3-(4-methylpiperazin-1-yl)-1H-indazole (64.0 mg, 0.208 mmol), bis-pinacolatodiboron (58 mg, 0.23 mmol), PdCl2(dppf).DCM (17 mg, 21 μmol), glacial AcOH (13 μL, 0.23 mmol), KOAc (67 mg, 0.69 mmol), and dioxane (1.6 mL). The reaction was heated to 100° C. for 2 h. To this reaction was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (103 mg, 0.208 mmol), KHCO3 (23 mg, 0.23 mmol), 2 M aq K2CO3 (400 μL), and Pd(PPh3)4 (24 mg, 21 μmol). The reaction was heated for another 1 h at 100° C. Finally, EtOH (absolute, 800 μL) and 10 M aq NaOH (500 μL) were added. The reaction was heated to 100° C. for another 1 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C33H36ClN5O3S: 618.2, 620.2 (M+H+); Found: 618.4, 620.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J=9.1 Hz, 1H), 7.62-7.47 (m, 4H), 5.24 (s, 1H), 4.31-4.01 (m, 2H), 3.94 (s, 3H), 3.74-3.54 (m, 2H), 3.54-3.35 (m, 2H), 3.32-3.16 (m, 2H), 3.00 (s, 3H), 2.61 (s, 3H), 0.97 (s, 9H).

Workup

  1. temperatureThe reaction was heated for another 1 h at 100° C
  2. temperatureThe reaction was heated to 100° C. for another 1 h
  3. temperatureThe reaction was cooled to 23° C.
  4. filtrationfiltered
  5. filtration(0.45 micron teflon syringe filter)
  6. customThe filtrate was purified by reverse phase HPLC
  7. washeluting by 5-100% acetonitrile in H2O with 0.1% TFA

Sources & evidence

ORD record
ord-9c6b9e6e772244128656462af94f3bc9
Source dataset
uspto-grants-2015_03
Patent number
US08987250B2

Reaction notes

Loading…