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

HRID 63021Notes

Reaction equation

HRID 63021 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-].[K+].C([O-])([O-])=O.[K+].[K+].[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 11430Potassium CarbonateHCID 14797Potassium 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 96.5%

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 (30.0 g, 1.0 eq) was slurried in a mixture of water (162 mL) and isopropyl alcohol (30 mL). KOH solution (50% aqueous, 28.3 g, 1.90 eq) was added followed by a water line wash (15 mL) resulting in a solution. Then K2CO3 (2.75 g, 0.15 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (18.2 g, 0.95 eq) was added, followed by a line wash of isopropyl alcohol (18 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 (3.1 g, 0.5 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (10.4 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 (48 mL) and isopropyl alcohol (12 mL), then with isopropyl alcohol (60 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (40.6 g, 92%). 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 (15 mL)
  2. customresulting in a solution
  3. washwash of isopropyl alcohol (18 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 (48 mL) and isopropyl alcohol (12 mL)
  12. dry with materialwith isopropyl alcohol (60 mL) and dried in vacuo at 50° C.

Sources & evidence

ORD record
ord-58269fc1c6f843cb933b7c64e58a42a2
Source dataset
uspto-grants-2016_09
Patent number
US09447052B2

Reaction notes

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