Trimethyl orthoformate → 2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidine

HRID 1805797Notes

Reaction equation

HRID 1805797 reaction equation
[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[Cl-].[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C([O-])(=O)C.[Na+].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1

Participants

9

Reactant 6

HCID 9005Trimethyl orthoformateHCID 517045Sodium AcetateHCID 5049666Sodium triacetoxyborohydrideHCID 162656121-Methanesulfonylpiperazine hydrochlorideHCID 568338442-Chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehydeHCID 68731830HCID 68731830, compound

Product 1

HCID 568339462-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidineYield 80%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19 (90.8 g, 0.320 mol, 1.0 equiv.), 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 92.3 g, 0.460 mol, 1.45 equiv.) and sodium acetate (anhydrous powder, 37.7 g, 0.460 mol, 1.45 equiv.) in 1,2-dichloroethane (anhydrous, 1.8 L) was added trimethyl orthoformate (340 g, 3.20 mol, 10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours. Sodium triacetoxyborohydride (assay>90%, 101.3 g, 0.430 mol, 1.35 equiv.) was added and the reaction was stirred for 24 hours. LC/MS indicated that the reaction was complete. The reaction was quenched with water (4.4 L) and methylene chloride (4.4 L). The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated to give a yellow solid. The crude solid was then stirred in ethyl acetate (2.0 L) at 80° C. for 2 hours. The slurry was cooled to 30-40° C., filtered and rinsed with ethyl acetate (50 ml). The cake was dried in vacuum oven at 45° C. to give 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 as an off-white solid (110.2 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.52-2.55 (m, 4H), 2.89 (s, 3H), 3.12-3.14 (m, 4H), 3.73 (t, J=4.4 Hz, 4H), 3.81 (s, 2H), 3.86 (t, J=4.8 Hz, 4H), 7.59 (s, 1H). LCMS (ESI pos) m/e 432 (M+1).

Workup

  1. stirringthe reaction was stirred for 24 hours
  2. customThe reaction was quenched with water (4.4 L) and methylene chloride (4.4 L)
  3. customThe phases were separated
  4. dry with materialthe organic phase was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give a yellow solid
  8. temperatureThe slurry was cooled to 30-40° C.
  9. filtrationfiltered
  10. washrinsed with ethyl acetate (50 ml)
  11. customThe cake was dried in vacuum oven at 45° C.

Sources & evidence

ORD record
ord-e2e8acea9198470794d141ab570a3643
Source dataset
uspto-grants-2013_01
Patent number
US08354528B2

Reaction notes

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