Dichloromethane → (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid

HRID 879487Notes

Reaction equation

HRID 879487 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[CH:12]1[CH2:14][CH2:13]1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:24]1[S:25][C:26]2[C:32]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[C:31]([C@H:40]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]([O:43]CC)=[O:42])[C:30]([CH3:51])=[CH:29][C:27]=2[N:28]=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:47]([O:46][C@@H:40]([C:31]1[C:30]([CH3:51])=[CH:29][C:27]2[N:28]=[C:24]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH3:11])[N:6]=[C:5]4[CH:12]3[CH2:14][CH2:13]3)[S:25][C:26]=2[C:32]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:41]([OH:43])=[O:42])([CH3:50])([CH3:48])[CH3:49]

Participants

11

Reactant 6

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 517044Potassium AcetateHCID 547590345-Bromo-3-cyclopropyl-1-methyl-1H-indazoleHCID 86700141(S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate

Product 1

HCID 86700303(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-5-methylbenzo[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-3-cyclopropyl-1-methyl-1H-indazole (49 mg, 0.19 mmol), bis-pinacolatodiboron (53 mg, 0.21 mmol), PdCl2(dppf).DCM (15 mg, 19 μmol), KOAc (62 mg, 0.62 mmol), and dioxane (1.6 mL). The reaction was sealed and heated to 100° C. for 2 h. (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (94 mg, 0.190 mmol), Pd(PPh3)4 (22 mg, 19 μmol), and 2 M aq K2CO3 (400 μL) were added; the reaction was heated at 100° C. for 1.5 h. The reaction was treated with absolute EtOH (2 mL) and 10 M aq NaOH (2 mL). After heating to 100° C. for 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 C31H30ClN3O3S: 560.2, 562.2 (M+H+); Found: 560.2, 562.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.37 (s, 1H), 7.99 (dd, J=8.8, 1.3 Hz, 1H), 7.77 (s, 1H), 7.72-7.66 (m, 1H), 7.58 (d, J=3.2 Hz, 3H), 7.49 (d, J=8.9 Hz, 1H), 5.25 (s, 1H), 3.93 (s, 3H), 2.59 (s, 3H), 2.26 (ddd, J=13.1, 8.3, 5.2 Hz, 1H), 1.16-0.98 (m, 4H), 0.97 (s, 9H).

Workup

  1. customThe reaction was sealed
  2. additionwere added
  3. temperatureAfter heating to 100° C. for 1 h
  4. temperaturethe reaction was cooled to 23° C.
  5. filtrationfiltered
  6. filtration(0.45 micron teflon syringe filter)
  7. customThe filtrate was purified by reverse phase HPLC
  8. washeluting by 5-100% acetonitrile in H2O with 0.1% TFA

Sources & evidence

ORD record
ord-c6f47120c1fc4802941faeeaf49bd354
Source dataset
uspto-grants-2015_03
Patent number
US08987250B2

Reaction notes

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