Sodium Hydroxide → (2S)-2-(32-chloro-4-methyl-20,28-dioxa-5,7,8,25-tetrazaheptacyclo[23.6.2.16,9.110,14.115,19.02,7.029,33]hexatriaconta-1(32),2,4,6(36),8,10,12,14(35),15(34),16,18,22,29(33),30-tetradecaen-3-yl)-2-[(2-methylpropan-2-yl)oxy]acetic acid

HRID 1400697Notes

Reaction equation

HRID 1400697 reaction equation
[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH:38]=C)[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:40])[C:16]=3[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44]C)=[O:43])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=C.[OH-].[Na+]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl.CO>[C:47]([O:46][C@@H:41]([C:16]1[C:17]([CH3:40])=[N:18][C:19]2=[CH:23][C:22]3=[N:21][N:20]2[C:15]=1[C:12]1[C:13]([Cl:14])=[C:5]2[C:6]([O:7][CH2:8][CH2:9][N:4]2[CH2:1][CH:2]=[CH:38][CH2:37][O:36][C:32]2[CH:31]=[C:30]([C:26]4[CH:25]=[C:24]3[CH:29]=[CH:28][CH:27]=4)[CH:35]=[CH:34][CH:33]=2)=[CH:10][CH:11]=1)[C:42]([OH:44])=[O:43])([CH3:50])([CH3:48])[CH3:49]

Participants

6

Reactant 2

HCID 14798Sodium HydroxideHCID 86710747(2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3'-(allyloxy)-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 86710749(2S)-2-(32-chloro-4-methyl-20,28-dioxa-5,7,8,25-tetrazaheptacyclo[23.6.2.16,9.110,14.115,19.02,7.029,33]hexatriaconta-1(32),2,4,6(36),8,10,12,14(35),15(34),16,18,22,29(33),30-tetradecaen-3-yl)-2-[(2-methylpropan-2-yl)oxy]acetic acidYield 26.6%

Reagents, catalysts & solvents 3

HCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(allyloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (40 mg, 0.058 mmol) and Hoveyda-Grubbs 2nd generation catalyst (4.90 mg, 5.77 μmol) catalyst in DCE (2 mL) was heated at 50° C. for 5 h. Mixture was then cooled to room temp and concentrated under reduced pressure. Mixture was then treated with 1N NaOH (0.173 mL, 0.173 mmol) in MeOH (2.0 mL) at 50° C. for 3 h. Mixture was then cooled to room temp and purified by prep-HPLC to afford desired product (10 mg, 0.015 mmol, 26.6% yield) as inseparable mixture of cis and trans isomers. Used as is in the next step without further purification. LCMS (M+H)=651.3.

Workup

  1. temperatureMixture was then cooled to room temp
  2. concentrationconcentrated under reduced pressure
  3. temperatureMixture was then cooled to room temp
  4. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-d746e91629494ce2b2feae98f6644dc7
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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