4-Methylmorpholine → (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one

HRID 341316Notes

Reaction equation

HRID 341316 reaction equation
[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C(O)(=O)C(O)=O.[OH:26][C@@H:27]([CH3:36])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29].CN1CCOCC1.COC(OC)OC.B.C(C1C=CC(C)=NC=1)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@@H:27]([OH:26])[CH3:36])[CH2:35][CH2:34]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 9005Trimethyl orthoformateHCID 566485822-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehydeHCID 73603469(S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalateHCID 178419175HCID 178419175, compound

Product 1

HCID 86623526(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-oneYield 81%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
57.5 °C

Procedure

2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (15.0 g, 50 mmol) was charged to a suitably sized reactor, followed by methanol (306 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate V (18.8 g, 75 mmol), N-methyl morpholine (10.2 g, 100 mmol) and trimethylorthoformate (53.1 g, 500 mmol). The slurry was heated to 55-60° C. and stirred for 4 hrs. 5-Ethyl-2-methylpyridine borane (8.7 g, 60.0 mmol) were slowly added and the solution was stirred for 2 h. The reaction mixture was partially concentrated under reduced pressure. Me-THF (350 mL) was added and the reaction mixture was concentrated under reduced pressure to an end volume of 300 mL. The mixture was cooled to 5° C. 3.3% Sulfuric acid in water (401 g) was added and pH 1.6 was reached. The organic phase was removed. The pH of the aqueous phase was adjusted to 7.9 with 10% aqueous sodium carbonate solution (300 g) at 0-5° C. The mixture was warmed to 25° C. and the organic phase was separated. The organic phase was concentrated under reduced pressure to 75 mL. The solution was warmed to 35° C. and seeded with 41 mg (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II. The suspension was cooled to 0° C. and n-heptane (200 g) was added. The resulting slurry was aged at −5° C., filtered and washed with n-heptane. The cake was dried at 70° C. under reduced pressure to afford (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (17.8 g, 81% yield)

Workup

  1. stirringthe solution was stirred for 2 h
  2. concentrationThe reaction mixture was partially concentrated under reduced pressure
  3. additionMe-THF (350 mL) was added
  4. concentrationthe reaction mixture was concentrated under reduced pressure to an end volume of 300 mL
  5. temperatureThe mixture was cooled to 5° C
  6. addition3.3% Sulfuric acid in water (401 g) was added
  7. customThe organic phase was removed
  8. customwas adjusted to 7.9 with 10% aqueous sodium carbonate solution (300 g) at 0-5° C
  9. temperatureThe mixture was warmed to 25° C.
  10. customthe organic phase was separated
  11. concentrationThe organic phase was concentrated under reduced pressure to 75 mL
  12. temperatureThe solution was warmed to 35° C.
  13. temperatureThe suspension was cooled to 0° C.
  14. additionn-heptane (200 g) was added
  15. customwas aged at −5° C.
  16. filtrationfiltered
  17. washwashed with n-heptane
  18. customThe cake was dried at 70° C. under reduced pressure

Sources & evidence

ORD record
ord-9d607b75087849a78676465652858b0c
Source dataset
uspto-grants-2014_11
Patent number
US08895729B2

Reaction notes

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