Formic Acid → 2-(2-((4-fluorobenzyl)thio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid

HRID 63023Notes

Reaction equation

HRID 63023 reaction equation
[O:1]=[C:2]1[NH:7][C:6](=[S:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]2[CH2:13][CH2:14][CH2:15][C:3]1=2.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(O)=O>O.C(O)(C)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:8][C:6]2[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]3[CH2:13][CH2:14][CH2:15][C:3]=3[C:2](=[O:1])[N:7]=2)=[CH:27][CH:26]=1

Participants

8

Reactant 5

HCID 284Formic Acid2×HCID 96024-Fluorobenzyl chlorideHCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 546754002-(4-Oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid

Product 1

HCID 98807792-(2-((4-fluorobenzyl)thio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acidYield 97%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 3776IsopropanolSolvent

Conditions

Temperature
40 °C

Procedure

(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid (20.0 g, 1.0 eq) was slurried in a mixture of water (112 mL) and isopropyl alcohol (20 mL). NaOH solution (50.9% aqueous, 13.82 g, 1.99 eq) was added followed by a water line wash (10 mL) resulting in a solution. Then Na2CO3 (1.50 g, 0.16 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (13.4 g, 1.05 eq) was added, followed by a line wash of isopropyl alcohol (12 mL) and the reaction mixture was stirred at 40±3° C. until the reaction was deemed complete (˜2.5 hours). The reaction mixture was cooled to 20±3° C. and formic acid (2.4 g, 0.6 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (6.9 g, 1.7 eq) was added over 1 hour and the slurry was stirred at 20±3° C. for at least one hour. The slurry was filtered to isolate the product, which was washed twice with a mixture of water (32 mL) and isopropyl alcohol (8 mL), then with isopropyl alcohol (40 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (28.6 g, 97% th). 1H NMR (d6 DMSO) δ 1.95 (2H, m), 2.57 (2H, t), 2.85 (2H, t), 4.4 (2H, s), 4.7 (2H, s), 7.15 (2H, dd), 7.45 (2H, dd), ˜13.6 (1H, vbrs).

Workup

  1. washwash (10 mL)
  2. customresulting in a solution
  3. washwash of isopropyl alcohol (12 mL)
  4. custom(˜2.5 hours)
  5. temperatureThe reaction mixture was cooled to 20±3° C.
  6. customresulting in crystallisation of the product within 30 minutes
  7. additionwas added over 1 hour
  8. stirringthe slurry was stirred at 20±3° C. for at least one hour
  9. filtrationThe slurry was filtered
  10. customto isolate the product, which
  11. washwas washed twice with a mixture of water (32 mL) and isopropyl alcohol (8 mL)
  12. dry with materialwith isopropyl alcohol (40 mL) and dried in vacuo at 50° C.

Sources & evidence

ORD record
ord-bbd2624d37dd4c1fbe9039fc2b7c2317
Source dataset
uspto-grants-2016_09
Patent number
US09447052B2

Reaction notes

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