2-(Ethylamino)ethanol → Defosbarasertib

HRID 1864481Notes

Reaction equation

HRID 1864481 reaction equation
Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[CH2:33]([NH:35][CH2:36][CH2:37][OH:38])[CH3:34].CN(C)C(=O)C>O>[CH2:33]([N:35]([CH2:36][CH2:37][OH:38])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH2:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)=[O:24])[NH:19][N:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:34]

Participants

5

Reactant 3

HCID 80722-(Ethylamino)ethanolHCID 31374DimethylacetamideHCID 162214542-(3-((7-(3-chloropropoxy)quinazolin-4-yl)amino)-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide

Product 1

HCID 16007391DefosbarasertibYield 85%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

2-(3-{[7-(3-Chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-5-yl)-N-(3-fluorophenyl)acetamide and 2-(ethylamino)ethanol (ideally 12 molar equivalents) were added to N,N-dimethylacetamide under an inert atmosphere (such as provided by nitrogen) and the mixture heated to 90° C. with stirring. After a period of 12-16 hours (ideally 12 hours) the reaction is cooled back to about 85° C. and water added in a controlled manner to maintain the temperature between 80-85° C. The batch is adjusted to 80° C. and seeded with crystals of the preferred form of the product (ideally an amount of about 1% of the expected yield). The mixture was cooled to 20° C. in a carefully controlled manner over a period of about 20 hours so as to crystallise the product in the required form and of a size sufficient to afford a good filtration rate. The product is then filtered and washed with a mixture of water/N,N-dimethylacetamide and acetonitrile and suitably deliquored to afford a hydrated form of the product. Following this, the cake is slurried in situ for a period (ideally 2 hours) with warm acetonitrile (ideally at a temperature of 40° C.) then filtered, washed with more acetonitrile and then dried (in vacuo or under a stream of nitrogen) to afford the almost anhydrous 2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}-quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide as an off-white solid in a yield of 85-90%.

Workup

  1. temperatureAfter a period of 12-16 hours (ideally 12 hours) the reaction is cooled back to about 85° C.
  2. temperatureto maintain the temperature between 80-85° C
  3. customis adjusted to 80° C.
  4. customexpected yield)
  5. temperatureThe mixture was cooled to 20° C. in a carefully controlled manner over a period of about 20 hours so as
  6. customto crystallise the product in the required form
  7. customof a size sufficient to afford a good filtration rate
  8. filtrationThe product is then filtered
  9. washwashed with a mixture of water/N,N-dimethylacetamide and acetonitrile
  10. customto afford a hydrated form of the product
  11. waitis slurried in situ for a period
  12. filtration(ideally 2 hours) with warm acetonitrile (ideally at a temperature of 40° C.) then filtered
  13. washwashed with more acetonitrile
  14. customdried (in vacuo

Sources & evidence

ORD record
ord-4798754af0094a49bf57c8430368df8f
Source dataset
uspto-grants-2009_12
Patent number
US07625910B2

Reaction notes

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