1-Butanol → HCID 178522431, compound

HRID 1946286Notes

Reaction equation

HRID 1946286 reaction equation
[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)CCC.[C:30](#[N:34])[CH2:31][CH2:32]C.C1(N)CC1>C1(C)C=CC=CC=1>[CH:30]1([NH:34][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:32][CH2:31]1

Participants

6

Reactant 4

HCID 2631-ButanolHCID 8008ButyronitrileHCID 69828CyclopropylamineHCID 178518660HCID 178518660, compound

Product 1

HCID 178522431HCID 178522431, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
60 °C

Procedure

7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[α]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66A) and a solvent such as n-butanol, butyronitrile, glycol or toluene (3.0 vol) can be charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) can be added at temperature such as 15 to 30° C. under an inert atmosphere e.g. nitrogen. The contents can be heated to 40 to 105° C., in particular 40-80° C. and stirred at this temperature for 16 to 24 hours. Reaction completion can be determined by 1H NMR analysis. The reaction mixture can then be cooled to 10 to 20° C. The product can then be isolated by organic-aqueous extraction method as outlined above in Example 66A, or an alternative method of isolation may be employed such as the addition of an anti-solvent, for example n-heptanes, to the reaction mixture. This could allow the reaction product to precipitate with subsequent isolation by filtration. The solid can then be dried under vacuum at 35 to 45° C. to yield 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea. At this stage the solid can be purified by recrystallisation from an appropriate solvent, preferably a Class 2 or 3 solvent1. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. 1 Class 3 and Class 2 solvents are as outlined Q3C—Tables and List in Guidance for Industry Q3C Impurities: Residual Solvents (November 2003, CDER, CBER, FDA, ICH) and as further outlined in Impurities: Guideline for Residual Solvents (1997, ICH).

Workup

  1. customequipped with a mechanical stirrer, condenser
  2. customReaction completion
  3. temperatureThe reaction mixture can then be cooled to 10 to 20° C
  4. customThe product can then be isolated by organic-aqueous extraction method
  5. customto precipitate with subsequent isolation by filtration
  6. customThe solid can then be dried under vacuum at 35 to 45° C.

Sources & evidence

ORD record
ord-2df57b8f0f85485c853594fe3adcb8ec
Source dataset
uspto-grants-2013_03
Patent number
US08399442B2

Reaction notes

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