Acetyl chloride → 2-[5-(6-Methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride

HRID 1913457Notes

Reaction equation

HRID 1913457 reaction equation
C([Cl:4])(=O)C.C(OC([N:12]1[CH2:36][CH2:35][C:15]2([CH2:18][N:17]([C@H:19]3[C:27]4[C:22](=[CH:23][C:24]([C:28]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:16]2)[CH2:14][CH2:13]1)=O)(C)(C)C>CO>[ClH:4].[ClH:4].[CH3:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[CH:19]([N:17]2[CH2:18][C:15]4([CH2:35][CH2:36][NH:12][CH2:13][CH2:14]4)[CH2:16]2)[CH2:20][CH2:21]3)[CH:33]=1

Participants

4

Reactant 2

HCID 6367Acetyl chlorideHCID 674086712-[(R)-5-(6-Methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester

Product 1

HCID 674060892-[5-(6-Methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochlorideYield 102.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
0 °C

Procedure

A flask containing methanol (100 mL) was cooled to 0° C. The solution was then charged dropwise with acetyl chloride (16.38 mL, 230.11 mmol) over 1 h maintaining a temperature of 10° C. The resulting mixture was charged with 2-[(R)-5-(6-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1f, 10.0 g, 23.01 mmol) in methanol (50 mL). The resulting mixture was stirred while warming to 20° C. for 18 h. HPLC after 18 h indicated disappearance of starting material. The resulting slurry was concentrated under reduced pressure removing approximately half the total volume. Isopropylacetate (50 mL) was then added and the resulting slurry was stirred for 1 h at 20° C. The solid was filtered and washed with isopropyl acetate (20 mL) under nitrogen. The solids were dried using a filter press with a nitrogen stream followed by drying under vacuum at 45° C. to afford 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 9.6 g, 98%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).

Workup

  1. temperaturemaintaining a temperature of 10° C
  2. temperaturewhile warming to 20° C. for 18 h
  3. concentrationThe resulting slurry was concentrated under reduced pressure
  4. customremoving approximately half the total volume
  5. additionIsopropylacetate (50 mL) was then added
  6. stirringthe resulting slurry was stirred for 1 h at 20° C
  7. filtrationThe solid was filtered
  8. washwashed with isopropyl acetate (20 mL) under nitrogen
  9. customThe solids were dried
  10. customby drying under vacuum at 45° C.

Sources & evidence

ORD record
ord-db11fc641ec547f1b3f95671749d2c14
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

Loading…