Dichloromethane → (S)-2-(2-([1,1'-biphenyl]-3-yl)-7-((1R,5 S)-8-azabicyclo[3.2.1]octan-8-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid

HRID 574350

反応式

HRID 574350 の反応式
Br[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]C)=[O:19])=[C:15](Cl)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:30]12[NH:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32][CH2:31]2.CCN(C(C)C)C(C)C.N1C=CC=NC=1N.[C:54]1(B(O)O)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.O[Li].O>CN(C=O)C.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].O.CO>[C:2]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:7]=[CH:6][CH:5]=[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]([CH3:24])([CH3:26])[CH3:25])[C:18]([OH:20])=[O:19])=[C:15]([N:37]4[C@@H:34]5[CH2:35][CH2:36][C@H:30]4[CH2:31][CH2:32][CH2:33]5)[N:10]3[N:9]=2)[CH:3]=1

参加物

13

反応物 8

HCID 6344DichloromethaneHCID 79782-AminopyrimidineHCID 62657Potassium Phosphate, TribasicHCID 66827Phenylboronic AcidHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 5222728-Azabicyclo[3.2.1]octane hydrochlorideHCID 86710775(S)-Methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

生成物 1

HCID 89780871(S)-2-(2-([1,1'-biphenyl]-3-yl)-7-((1R,5 S)-8-azabicyclo[3.2.1]octan-8-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid収率 17%

試薬・触媒・溶媒 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 887Methanol溶媒HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
85 °C

実験手順

To a solution of (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.107 mmol, 1 equiv) in DMF (0.54 mL) was added 8-azabicyclo[3.2.1]octane hydrochloride (31 mg, 0.214 mmol, 2 equiv) and DIPEA (0.075 mL, 0.428 mmol, 4 equiv). The resulting solution was stirred at 85° C. for 18 h. Complete conversion to pyrimidyl amine was observed. To this solution was then added phenyl boronic acid (30 mg, 0.250 mmol, 2.5 equiv), potassium phosphate, tribasic (0.25 mL of a 2 M aqueous solution, 0.500 mmol, 4.7 equiv), and PdCl2(dppf).CH2Cl2 adduct (8 mg, 0.010 mmol, 0.09 equiv). The mixture was heated at 85° C. for 2 h. Upon completion of the Suzuki reaction, the reaction temperature was lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (24 mg, 1.00 mmol, 9 equiv) added and heating was continued for 2 h. Upon completion of hydrolysis, reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×200 mm, 5-μμm particles Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B, to provide (S)-2-(2-([1,1′-biphenyl]-3-yl)-7-((1R,5 S)-8-azabicyclo[3.2.1]octan-8-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (8.9 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.44-7.38 (m, 1H), 7.00 (s, 1H), 5.45 (br. s., 1H), 5.15 (br. s., 1H), 4.37 (br. s., 1H), 2.86 (br. s., 1H), 2.46 (s, 3H), 2.29 (br. s., 1H), 1.92 (d, J=13.7 Hz, 3H), 1.78 (d, J=12.8 Hz, 2H), 1.69 (d, J=14.0 Hz, 3H), 1.14 (s, 9H). LCMS (ESI, M+1): 525.4.

後処理

  1. temperatureThe mixture was heated at 85° C. for 2 h
  2. customUpon completion of the Suzuki reaction
  3. customwas lowered to 60° C
  4. temperatureheating
  5. waitwas continued for 2 h
  6. customUpon completion of hydrolysis, reaction
  7. customwas removed
  8. temperaturefrom heat
  9. filtrationfiltered through a syringe
  10. filtrationfilter
  11. customThe crude reaction mixture
  12. customwas purified via preparative LC/MS with the following conditions
  13. waitGradient: 40-80% B over 20 minutes

出典と根拠

ORDレコード
ord-3d18bf86d8a84d97966f6e590fe4a8cb
出典データセット
uspto-grants-2015_05
特許番号
US09034882B2

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