Methane → 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile citrate

HRID 1676906Notes

Reaction equation

HRID 1676906 reaction equation
[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]#[N:25])=[CH:6][CH:5]=2.[C:26]([OH:38])(=[O:37])[CH2:27][C:28]([CH2:33][C:34]([OH:36])=[O:35])([C:30]([OH:32])=[O:31])[OH:29].C>C(O)C.O>[C:26]([OH:38])(=[O:37])[CH2:27][C:28]([CH2:33][C:34]([OH:36])=[O:35])([C:30]([OH:32])=[O:31])[OH:29].[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][N:12]=1)=[CH:8][C:7]([C:24]#[N:25])=[CH:6][CH:5]=2

Participants

6

Reactant 3

HCID 297MethaneHCID 311Citric AcidHCID 135564570AZD 1080

Product 1

HCID 1358027732-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile citrateYield 82.2%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile (5.14 kg, 15.4 mol) was suspended in ethanol (54 L) at room temperature. The suspension was heated to an inner temperature of 70° C. and a solution of citric acid (3.424 kg, 17.82 mol) in water (103 L) was added keeping the inner temperature above 65° C. The mixture was heated to reflux. After this the resulting solution was mixed with activated charcoal (0.412 kg) and reflux continued for 3.5 h after which the reaction mixture was clear filtered at 83° C. followed by cooling to room temperature over 20 h. After filtration the precipitate was washed twice with a cold mixture of ethanol/water (6.9 L/13.7 L). Drying under vacuum at 50° C. gave 6.648 kg, 82.2% yield of 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile citrate having a purity of at least 98%. The palladium content was less than 1 ppm and the zinc content was lower than 10 ppm. 1H NMR (d6-DMSO, 400 MHz) δ 14.8 (br s, 1 H), 10.98 (s, 1H), 8.1 (s 1H), 7.55 (m, 3H), 7.31 (d, 1 H), 7.02 (d, 1H), 3.6 (s, 4H), 3.45 (m, 2H), 2.75 (ap d, 2H), 2.65 (ap d, 2H), 2.47 (s, 4H) ppm; 13C NMR (d6-DMSO, 400 MHz) δ 174.9, 171.3, 168.7, 148.4, 142.1, 137.1, 136.4, 125.2, 124.1, 121.1, 121.0, 118.8, 118.4, 101.4, 84.6, 72.3, 65.7, 58.0, 52.5, 42.9 ppm; MS (ES) m/z [M++1] 335.

Workup

  1. customthe inner temperature above 65° C
  2. temperatureThe mixture was heated to reflux
  3. temperaturereflux
  4. filtrationafter which the reaction mixture was clear filtered at 83° C.
  5. temperatureby cooling to room temperature over 20 h
  6. filtrationAfter filtration the precipitate
  7. washwas washed twice with a cold mixture of ethanol/water (6.9 L/13.7 L)
  8. customDrying under vacuum at 50° C.

Sources & evidence

ORD record
ord-bb57d497087843a2b3ea1687755686b5
Source dataset
uspto-grants-2011_08
Patent number
US08008294B2

Reaction notes

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