ChemicalBook CAS DataBase List 1H-CyclopentapyriMidine-1-acetic acid, 2-[[(4-fluorophenyl)Methyl]thio]-4,5,6,7-tetrahydro-4-oxo-

1H-CyclopentapyriMidine-1-acetic acid, 2-[[(4-fluorophenyl)Methyl]thio]-4,5,6,7-tetrahydro-4-oxo- synthesis

8synthesis methods

Product Name:1H-CyclopentapyriMidine-1-acetic acid, 2-[[(4-fluorophenyl)Methyl]thio]-4,5,6,7-tetrahydro-4-oxo-
CAS Number:356058-42-9
Molecular formula:C16H15FN2O3S
Molecular Weight:334.37

2,3,4,5,6,7-hexahydro-4-oxo-2-thioxo-1H-CyclopentapyriMidine-1-acetic acid

1349902-20-0

352-11-4

1H-CyclopentapyriMidine-1-acetic acid, 2-[[(4-fluorophenyl)Methyl]thio]-4,5,6,7-tetrahydro-4-oxo-

356058-42-9

Preparation of 2-(2-((4-fluorobenzyl)thio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid from 2,3,4,5,6,7-hexahydro-4-oxo-2-thioxo-1H-cyclopenta[d]pyrimidin-1-yl) as raw material and 4-fluorobenzylchloride (13.4 g, 1.05 eq) The general procedure was as follows: 2,3,4,5,6,7-hexahydro-4-oxo-2-thio-1H-cyclopentadienopyrimidin-1-yl-acetic acid was slurried in a mixture of water (112 mL) and isopropanol (20 mL). A 50.9% aqueous NaOH solution (13.82 g, 1.99 eq.) was added, followed by washing with water (10 mL) to obtain a solution. Next, Na2CO3 (1.50 g, 0.16 eq.) was added and the solution was heated to 40 ± 3°C. 4-fluorobenzyl chloride was then added and subsequently washed with isopropanol (12 mL). The reaction mixture was stirred at 40 ± 3°C until the reaction was complete (about 2.5 h). After cooling to 20 ± 3°C, formic acid (2.4 g, 0.6 eq.) was added and the product was crystallized within 30 min. a second batch of formic acid (6.9 g, 1.7 eq.) was added within 1 h. The slurry was stirred at 20 ± 3°C for at least 1 h. The reaction mixture was then stirred for at least 1 h. The product was then filtered to separate the product. The slurry was filtered to separate the product, washed twice successively with a mixture of water (32 mL) and isopropanol (8 mL), then with isopropanol (40 mL), and finally dried in vacuo at 50°C to give the title compound as an off-white solid (28.6 g, 97% yield).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).

1349902-20-0 Synthesis

1349902-20-0
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352-11-4 Synthesis

352-11-4
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356058-42-9
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$27.00/100mg

Yield:356058-42-9 97%

Reaction Conditions:

Stage #1: 2-(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta-[d]-pyrimidin-1-yl) acetic acid;1-chloromethyl-4-fluorobenzenewith sodium carbonate;sodium hydroxide in water;isopropyl alcohol at 40; for 2.5 h;
Stage #2: with formic acid in water;isopropyl alcohol at 20; for 2.5 h;Product distribution / selectivity;

Steps:

7

Example 7 - Alternative method for making (2-{[(4-Fluorophenyl)methyl]thio}-4-oxo-4,5,6,7- tetrahydro-lHcyclopenta[d]pyrimidin-l-yl)acetic acid) (4-Oxo-2-thioxo-2,3,4,5,6,7-hexahydro-lH- cyclopenta [ /]pyrimidin-l-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 Na₂C0₃ (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 NM R (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).

References:

WO2011/146494,2011,A1 Location in patent:Page/Page column 11