Triethylamine → (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate

HRID 921148Notes

Reaction equation

HRID 921148 reaction equation
[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([C:53](O)=[O:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:56])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH2:53][OH:54])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 4311764Sodium borohydrideHCID 86621139Isopropyl chloroformate tolueneHCID 1317349096-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid

Product 1

HCID 131734910(S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetateYield 65.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (900 mg, 1.143 mmol) and Et3N (0.207 mL, 1.487 mmol) in THF (20 mL) was added 1M isopropyl chloroformate/toluene (1.487 mL, 1.487 mmol) at 0° C. After 1 h, a solution of NaBH4 (216 mg, 5.72 mmol) in cold water (20 mL) was added at once and stirred for additional 1 h at 0° C. Then the reaction was quenched with MeOH (1 mL), diluted with Et2O (100 mL), washed with water (2×50 mL) and brine (25 mL). The organic layer dried (Na2SO4), filtered and concentrate. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (580 mg, 0.750 mmol, 65.6% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.74-7.70 (m, 4H), 7.46-7.35 (m, 6H), 6.48 (s, 1H), 5.90 (br. s., 1H), 4.91-4.83 (m, 2H), 4.29-4.11 (m, 2H), 3.94-3.84 (m, 1H), 3.41-3.29 (m, 3H), 2.61 (s, 3H), 2.17 (q, J=5.8 Hz, 1H), 1.94-1.87 (m, 2H), 1.87 (br. s., 1H), 1.66 (br. s., 1H), 1.59 (s, 3H), 1.58-1.40 (m, 5H), 1.33-1.26 (m, 3H), 1.26-1.21 (m, 12H), 1.09 (d, J=6.1 Hz, 3H), 1.07 (s, 9H). LCMS (M+H)=773.4.

Workup

  1. customThen the reaction was quenched with MeOH (1 mL)
  2. additiondiluted with Et2O (100 mL)
  3. washwashed with water (2×50 mL) and brine (25 mL)
  4. dry with materialThe organic layer dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrate
  7. customThe residue was then purified by Biotage (5-30% EtOAc/hexane)

Sources & evidence

ORD record
ord-c27aeb49c06349f58397acf17103b3b8
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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