[ CAS No. 356058-42-9 ] {[proInfo.proName]}

Name: 356058-42-9|2-(2-((4-Fluorobenzyl)thio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid|97%
Brand: Ambeed
SKU: A210426
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Quality Control of [ 356058-42-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 356058-42-9 ]

SDS Specification

Alternatived Products of [ 356058-42-9 ]

Product Details of [ 356058-42-9 ]

CAS No. :	356058-42-9	MDL No. :	MFCD21337366
Formula :	C₁₆H₁₅FN₂O₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DJGRXBDYBUKPOC-UHFFFAOYSA-N
M.W :	334.37	Pubchem ID :	9880779
Synonyms :

Calculated chemistry of [ 356058-42-9 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.31
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	85.13
TPSA :	97.49 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.62
Log Po/w (XLOGP3) :	2.26
Log Po/w (WLOGP) :	2.52
Log Po/w (MLOGP) :	2.5
Log Po/w (SILICOS-IT) :	3.29
Consensus Log Po/w :	2.44

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.39
Solubility :	0.135 mg/ml ; 0.000405 mol/l
Class :	Soluble
Log S (Ali) :	-3.94
Solubility :	0.0381 mg/ml ; 0.000114 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.62
Solubility :	0.00793 mg/ml ; 0.0000237 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.11

Safety of [ 356058-42-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 356058-42-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 356058-42-9 ]
Downstream synthetic route of [ 356058-42-9 ]

[ 356058-42-9 ] Synthesis Path-Upstream 1~8

1
[ 1349902-20-0 ]
[ 352-11-4 ]
[ 356058-42-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With 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;	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 (50.9percent 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, 97percentth). 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).
76%	With potassium carbonate; potassium hydroxide In water; isopropyl alcohol at 40℃; for 3 h;	Compound 1 (0.3603 g, 1.6 mmol, 1 eq) was stirred in a mixture of water (2 mL) and isopropyl alcohol (360 μL). KOH aqueous solution (50percent w/v, 500 μL, 1.9 eq) was added. K2CO3 (0.0332 g, 0.24 mmol, 0.15 eq) was added and the solution was heated to 40° C. Then 4-fluorobenzyl chloride (0.2197 g, 1.52 mmol, 0.95 eq) was added and the reaction was stirred at 40 °C for 3 hours. The reaction was cooled to room temperature and formic acid (30 μL, 0.8 mmol, 0.5 eq) was added to crystallize the product. After 30 min, more formic acid (103 μL, 2.7 mmol, 1.7 eq) was slowly added and the reaction was stirred for at least an hour until crystallization was complete. The product was isolated through filtration and washed twice with a 4:1 mixture of water and isopropyl alcohol (1 mL), then with isopropyl alcohol (1 mL). The product was stirred in ether for 2 hours to remove remaining organic impurities and filtered again. Product was dried in vacuo at 50 °C to yield 2 (0.4082g, 1.22 mmol, 76percent).
60%	With potassium carbonate; potassium hydroxide In Isopropyl acetate; water at 40℃; for 3 h;	Compound 1 (1 eq, 1.62 mmol) was stirred in a mixture of water (3 mL) and isopropyl alcohol (820 μL). KOH aqueous solution (50percent w/v, 1.9 eq, 3.08 mmol) was added followed by K₂CO₃ (0.15 eq, 0.24 mmol) and the reaction was heated to 40° C under stirring. 4-fluorobenzyl chloride (0.95 eq, 1.52 mmol) was then added and the reaction was stirred at 40° C for 3 hours. The reaction was cooled to room temperature and formic acid (0.5 eq, 0.8 mmol) was added to crystallize the product. After 1h, more formic acid (1.7 eq, 2.7 mmol) was slowly added and the reaction was stirred for an hour until crystallization was complete. The product was collected through filtration and washed twice with a 4:1 (v:v) mixture of water and isopropyl alcohol (1 mL) followed by isopropyl alcohol (1 mL). The product was stirred in ether overnight and filtered again. Product was dried at 50° C to obtain the title compound as a colourless solid (300 mg, 60percent). ¹H NMR (DMSO-d₆) δ: 12.54 (s, 1H), 7.47 (m, 2H), 7.11 (m, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 1.99 (quint, J = 7.3 Hz, 2H).

Reference： [1] Patent: WO2011/146494, 2011, A1, . Location in patent: Page/Page column 11
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 839 - 843
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 787 - 792

2
[ 1417526-07-8 ]
[ 356058-42-9 ]

Yield	Reaction Conditions	Operation in experiment
4.3 g	With lithium hydroxide monohydrate; water In isopropyl alcohol at 20℃; for 2 h;	General procedure: Intermediate A4- 2-(2-(4-fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-1H-cyaopenta[d]pyrimidin-1-yl)acetic acid A solution of intermediate A3 (6.9g, 1equiv), LiOH·H₂O (2.5g, 3equiv) in isopropanol/water (1:2, 60ml) was stirred at room temperature for 2h to obtain a clear solution. The solution was acidified with concd. HCl to pH<3 in an ice bath, the solid thus obtained was collected by filtration, washed with water several times and the moisture was evacuated as much as possible. The solid was transferred to a 100 mL flask and 30 ml acetone was added to obtain a mixture, which was refluxed for 0.5 h. Then the mixture was placed in refrigerator for several hours until the recrystallization was complete. The solid obtained was filtered and washed by acetone, then dried to afford the title compound as a white solid (4.3g). ¹H-NMR (d₆-DMSO, 300 MHz) δ1.96(m 2H), 2.58 (t, 2H, J=7.2), 2.82 (t, 2H, J=7.5), 4.42 (s, 2H), 4.69 (s, 2H), 7.13 (t, 2H, J=9.0), 7.47 (dd, 2H, J=8.9 ,5.6), 13.5 (vbrs, 1H); MS (ESI): 333 (M-H).
4.3 g	With lithium hydroxide monohydrate In water; isopropyl alcohol at 20℃; for 2 h;	A solution of intermediate A3 (6.9 g, 1 equiv), LiOH.H20 (2.5 g, 3 equiv) in isopropanol/water (1:2, 60 ml) was stirred at room temperature for 2 h to obtain a clear solution. The solution was acidified with concd. HC1 to pH<3 in an ice bath, the solid thus obtained was collected by filtration, washed with water several times and the moisture was evacuated as much as possible. The solid was transferred to a100 mE flask and 30 ml acetone was added to obtain a mixture, which was refluxed for 0.5 h. Then the mixture was placed in refrigerator for several hours until the recrystallization was complete. The solid obtained was filtered and washed by acetone, then dried to afford the title compound as a white solid (4.3 g). ‘H-NMR (d5-DMSO, 300 MHz) öl.96 (m, 2H), 2.58 (t, 2H, J=7.2), 2.82 (t, 2H, J=7.5), 4.42 (s, 2H), 4.69 (s, 2H), 7.13 (t, 2H, J=9.0), 7.47 (dd, 2H, J8.9, 5.6),13.5 (vbrs, 1H); MS (ESI): 333 (M—H).

Reference： [1] Patent: EP2725024, 2014, A1, . Location in patent: Paragraph 0156
[2] Patent: US2014/171431, 2014, A1, . Location in patent: Paragraph 0502

3
[ 451487-18-6 ]
[ 356058-42-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 6, p. 1067 - 1070
[2] Patent: EP2725024, 2014, A1,
[3] Patent: US2014/171431, 2014, A1,
[4] Patent: WO2015/87239, 2015, A1,

4
[ 10472-24-9 ]
[ 356058-42-9 ]

Reference： [1] Patent: WO2011/146494, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 839 - 843
[3] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 787 - 792

5
[ 35563-27-0 ]
[ 356058-42-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 6, p. 1067 - 1070

6
[ 1349902-19-7 ]
[ 356058-42-9 ]

Reference： [1] Patent: WO2011/146494, 2011, A1,
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 839 - 843

7
[ 459-46-1 ]
[ 356058-42-9 ]

Reference： [1] Patent: EP2725024, 2014, A1,
[2] Patent: US2014/171431, 2014, A1,

8
[ 35563-27-0 ]
[ 356058-42-9 ]

Reference： [1] Patent: EP2725024, 2014, A1,
[2] Patent: US2014/171431, 2014, A1,

[ 356058-42-9 ] Synthesis Path-Downstream 1~26

1
[ 304693-36-5 ]
[ 356058-42-9 ]
1-(N-(2-(diethylamino)ethyl)-N-(4-(4-chlorophenyl)benzyl)aminocarbonyl-methyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1067 - 1070

2
[ 304694-40-4 ]
[ 356058-42-9 ]
N-[2-(diethylamino)ethyl]-2-(2-[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.63%	With boric acid; In toluene; at 110℃; for 6h;	Example 9: Preparation of darapladib Toluene (400 mL) and NN-diethyl-N'-{ [4'-(trifluoromethyl)biphenyl-4- yl]methyl} ethane- 1,2-diamine (Formula 2; 50 g) were mixed in a round bottom flask at 25C and stirred. {2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-lH- cyclopenta[d]pyrimidin-l-yl}acetic acid (Formula 1; 50g), boric acid (4.45 g), and trifluoromethyl phenyl boronic acid (2.71 g) were added to the reaction mixture at 25C. The temperature of the reaction mixture was raised to 110C and refluxed for 6 hours. The reaction mixture was monitored by HPLC until the reaction was completed. The reaction mixture was cooled to 25C and a 5% NaOH solution (350 mL) was added, and then the mixture was stirred for 30 minutes at 25C. The reaction mixture was allowed to settle, and then the organic layer was collected. The organic layer was washed with water (200 mL), and then toluene was recovered completely under vacuum at 50C to obtain an oily residue. Methanol (350 mL) was added to the oily residue at 50C, and the mixture was stirred for 15 minutes. The reaction mixture was cooled to 25 C, then the solid was precipitated out, then water (200 mL) was added, and the mixture was stirred for 4 hours at 25 C. The solid was filtered, and then washed with a mixture of methanol (75 mL) and water (25 mL). The wet solid was unloaded, then dried under vacuum at 45 C for overnight to obtain the title compound. Yield: 78.60 (82.63%) Chemical Purity (by HPLC): 97.89%
78%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 50℃; for 3h;	Compound 2 (0.0100g, 0.03 mmol, 1 eq), compound 3 (0.0105 g, 0.03 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (HOAt) (0.0049 g, 0.036 mmol, 1.2 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (0.0070 g, 0.045 mmol, 1.5 eq) was stirred in DMF (0.1 mL) for 3 hours at 50 C. The reaction was diluted in ethyl acetate, washed with saturated aqueous NaHCO3, dried over Na2SO4 and filtered. The solvent was removed by rotary evaporation and the product was purified by preparative thin-layer chromatography (10% methanol in dichloromethane) to afford darapladib (0.0156 g, 0.023 mmol, 78%).
65%		General procedure: the appropriate amine (1 eq) and acid (1 eq) were dissolved in DMF (0.1 M) then stirred with DIPEA (2 eq) for 10 min at RT. The reaction was then cooled with an ice bath to 0C and COMU (1 eq) was added. The mixture was stirred at 0C for 1h then the bath was removed and the reaction was allowed to reach RT and continued for 5h. The compound was extracted using EtOAc three times. The combined organic layers were then washed several times with saturated NaHCO3. The resulting organic solution was dried, filtered and evaporated. The product was then purified using column chroma-tography with appropriate conditions indicated below.

65%	With 1-[(1-(cyano-?2-?ethoxy-?2-?oxoethylidenaminooxy)?dimethylamino-?morpholino)]-uronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h;Inert atmosphere;	Amine 8 (1 eq, 52 mg) and acid 12' (1 eq, 50 mg) were dissolved in DMF (1 mL) then stirred with DIPEA (2 eq, 52 mu) for 10 min at rt. The reaction was then cooled with an ice bath to 0C and COMU (1 eq, 64 mg) was added. The mixture was stirred at 0C for lh then the bath was removed and the reaction was allowed to reach rt and continued for 5h. The compound was extracted using EtOAc three times (5 mL x 3). The combined organic layers were then washed several times with saturated NaHC03 until washing solution was colourless. The resulting organic solution was dried, filtered and evaporated. The product was then purified using column chromatography on silica gel DCM/MeOH (90/10) (Rf = 0.2) as a pale yellow solid (65 mg, 65%). 1H NMR (600 MHz, CDC13) Mix of rotamers ratio (1/1) delta 7.69 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 6.7 Hz, 1H), 7.46 (m, 2H), 7.37-7.26 (m, 4H), 6.96 (t, J = 7.4 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 4.95 (s, 1H), 4.69 (m, 3H), 4.50 (s, 1H), 4.40 (s, 1H), 3.64 (m, 1H), 3.30 (m, 1H), 2.88 (m, 1H), 2.81 (t, J = 6.7 Hz, 1H), 2.76 (t, J = 6.7 Hz, 4H), 2.59 (t, J = 7.1Hz, 2H), 2.51 (q, J = 7.0 Hz, 2H), 2.11 (quint, J = 7.4 Hz, 1H), 2.05 (quint, J = 7.4 Hz, 1H), 1.10 (t, J = 7.1Hz, 3H), 0.98 (t, J = 7.1Hz, 3H). 13C-NMR (CDC13, 150 MHz) Mix of rotamers delta: 167.5, 166.5, 162.2 (d, JCF = 240 Hz), 161.4, 161.3, 156.8, 156.5, 144.1, 143.6, 139.8, 139.3, 136.8, 135.4, 131.5 (d, JCF = 3 Hz), 131.2 (d, JCF = 9 Hz), 131.1 (d, JCF = 3 Hz), 129.8 (m), 128.8, 128.0 (m), 127.7 (m), 127.4, 127.3, 127.2, 125.9 (m), 124.4 (m), 121.3, 121.2, 115.7 (d, JCF = 23 Hz), 115.6 (d, JCF = 23 Hz), 51.4, 50.4, 50.3, 50.1, 49.2, 47.8, 47.3, 46.1, 36.6, 36.5, 32.1, 32.0, 28.5, 28.4, 20.9, 20.8, 11.8;
		Example 3(a) 1-(N-(2-(Diethylamino)ethyl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5,6-trimethylenepyrimidin-4-one Intermediate B69 (87.1 g, 0.26 mol.) was suspended in dichloromethane (2.9 liter). 1-Hydroxybenzotriazole hydrate (35.2 g, 0.26 mol.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99.7 g, 0.52 mol.) were added and the suspension stirred for 45 minutes by which time complete solution had been obtained. Intermediate A30 (91.2 g, 0.26 mol.) was added as a solution in dichloromethane (100 ml) over 5 minutes and the solution stirred for 4 hours. Saturated ammonium chloride solution:water mixture (1:1, 1 liter) was added and the solution stirred for 10 minutes. The organic phase was separated and extracted with saturated ammonium chloride:water mixture (1:1, 1 liter), extracts were pH 6. The organic phase was separated and extracted with water (1 liter) containing acetic acid (10 ml), extract pH 5. The dichloromethane layer was separated and extracted with saturated sodium carbonate solution:water:saturated brine mixture (1:3:0.2, 1 liter), pH 10.5, then with saturated brine:water mixture (1:1, 1 liter). The brown solution was dried over anhydrous sodium sulfate in the presence of decolourising charcoal (35 g), filtered and the solvent removed in vacuo to give a dark brown foam. The foam was dissolved in iso-propyl acetate (100 ml) and the solvent removed in vacuo. The dark brown gummy residue was dissolved in boiling iso-propyl acetate (500 ml), cooled to room temperature, seeded and stirred overnight. The pale cream solid produced was filtered off and washed with iso-propyl acetate (100 ml). The solid was sucked dry in the sinter for 1 hour then recrystallized from iso-propyl acetate (400 ml). After stirring overnight the solid fowled was filtered off, washed with iso-propyl acetate (80 ml) and dried in vacuo to give the title compound, 110 g, 63.5% yield. 1H NMR (CDCl3, ca 1.9:1 rotamer mixture) delta 0.99 (6H, t), 2.10 (2H, m), 2.50 (4H, q), 2.58/2.62 (2H, 2t), 2.70/2.82 (2H, 2t), 2.86 (2H, t), 3.28/3.58 (2H, 2t), 4.45/4.52 (2H, 2s), 4.68/4.70 (2H, 2s), 4.93 (2H, s), 6.95 (2H, m), 7.31 (2H, d), 7.31/7.37 (2H, 2m), 7.48/7.52 (2H, d), 7.65 (2H, m), 7.72 (2H, m); MS (APCI) (M+H)+ 667; mp 125 C. (by DSC-assymetric endotherm).

Reference： [1]Patent: WO2015/87239,2015,A1 .Location in patent: Page/Page column 19; 20
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 839 - 843
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 787 - 792
[4]Patent: WO2019/63634,2019,A1 .Location in patent: Page/Page column 35
[5]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1067 - 1070
[6]Patent: US9266841,2016,B2 .Location in patent: Page/Page column 41; 42

3
tert-butyl-2-(2-((4-fluorobenzyl)thio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate [ No CAS ]
[ 356058-42-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1067 - 1070

4
[ 611-10-9 ]
4-oxo-1-methyl-tetrahydro-2<i>H</i>-thiopyrylium iodide [ No CAS ]
[ 356058-42-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1067 - 1070

5
[ 35563-27-0 ]
[ 356058-42-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1067 - 1070

6
[ 451487-18-6 ]
[ 356058-42-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1067 - 1070
[2]Patent: EP2725024,2014,A1
[3]Patent: US2014/171431,2014,A1
[4]Patent: WO2015/87239,2015,A1

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 20℃;Inert atmosphere;	General procedure: 1-(Carboxymethyl)-2-(4-fluorobenzylthio)-5-methylpyrimidin-4-one Intermediate B40 (3.88 g) was added to solution of trifluoroacetic acid (10 ml) in dichloromethane (20 ml) under argon, and stirred overnight at room temperature. Evaporation of the solvent and trituration with ether gave the title compound as a white solid (3.04 g). 1H-NMR (d6-DMSO) delta 1.81 (3H,d), 4.42 (2H,s), 4.66 (2H,s), 7.14 (2H,m), 7.47 (2H,m), 7.63 (1H,m); MS (APCI+) found (M+1)=309; C14H13FN2O3S requires 308.

8
[ 1349902-20-0 ]
[ 352-11-4 ]
[ 356058-42-9 ]

Yield	Reaction Conditions	Operation in experiment
97%		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) delta 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).
76%	With potassium carbonate; potassium hydroxide; In water; isopropyl alcohol; at 40℃; for 3h;	Compound 1 (0.3603 g, 1.6 mmol, 1 eq) was stirred in a mixture of water (2 mL) and isopropyl alcohol (360 muL). KOH aqueous solution (50% w/v, 500 muL, 1.9 eq) was added. K2CO3 (0.0332 g, 0.24 mmol, 0.15 eq) was added and the solution was heated to 40 C. Then 4-fluorobenzyl chloride (0.2197 g, 1.52 mmol, 0.95 eq) was added and the reaction was stirred at 40 C for 3 hours. The reaction was cooled to room temperature and formic acid (30 muL, 0.8 mmol, 0.5 eq) was added to crystallize the product. After 30 min, more formic acid (103 muL, 2.7 mmol, 1.7 eq) was slowly added and the reaction was stirred for at least an hour until crystallization was complete. The product was isolated through filtration and washed twice with a 4:1 mixture of water and isopropyl alcohol (1 mL), then with isopropyl alcohol (1 mL). The product was stirred in ether for 2 hours to remove remaining organic impurities and filtered again. Product was dried in vacuo at 50 C to yield 2 (0.4082g, 1.22 mmol, 76%).
60%	With potassium carbonate; potassium hydroxide; In Isopropyl acetate; water; at 40℃; for 3h;	Compound 1 (1 eq, 1.62 mmol) was stirred in a mixture of water (3 mL) and isopropyl alcohol (820 muL). KOH aqueous solution (50% w/v, 1.9 eq, 3.08 mmol) was added followed by K2CO3 (0.15 eq, 0.24 mmol) and the reaction was heated to 40 C under stirring. 4-fluorobenzyl chloride (0.95 eq, 1.52 mmol) was then added and the reaction was stirred at 40 C for 3 hours. The reaction was cooled to room temperature and formic acid (0.5 eq, 0.8 mmol) was added to crystallize the product. After 1h, more formic acid (1.7 eq, 2.7 mmol) was slowly added and the reaction was stirred for an hour until crystallization was complete. The product was collected through filtration and washed twice with a 4:1 (v:v) mixture of water and isopropyl alcohol (1 mL) followed by isopropyl alcohol (1 mL). The product was stirred in ether overnight and filtered again. Product was dried at 50 C to obtain the title compound as a colourless solid (300 mg, 60%). 1H NMR (DMSO-d6) delta: 12.54 (s, 1H), 7.47 (m, 2H), 7.11 (m, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.60 (t, J = 7.3 Hz, 2H), 1.99 (quint, J = 7.3 Hz, 2H).

60%

With potassium carbonate; potassium hydroxide; In water; isopropyl alcohol; at 40℃; for 3h;

Compound 11' (1 eq, 1.62 mmol) was stirred in a mixture of water (3 mL) and isopropyl alcohol (820 mu). KOH aqueous solution (50% w/v, 1.9 eq, 3.08 mmol) was added followed by K2CO3 (0.15 eq, 0.24 mmol) and the reaction was heated to 40C under constant stirring. 4-fluorobenzyl chloride (0.95 eq, 1.52 mmol) was then added and the reaction was stirred at 40C for 3 hours. The reaction was cooled to room temperature and formic acid (0.5 eq, 0.8 mmol) was added to crystallize the product. After lh, more formic acid (1.7 eq, 2.7 mmol) was slowly added and the reaction was stirred for at least an hour until crystallization was complete. The product was collected through filtration and washed twice with a 4: 1 (v:v) mixture of water and isopropyl alcohol (1 mL) followed by isopropyl alcohol (1 mL). The product was stirred in ether overnight to remove remaining organic impurities and filtered again. Product was dried at 50C to afford the title compound as a colourless solid (300 mg, 60%). M.p. 183-185C 1H-NMR (CDCI3, 600 MHz) delta 12.54 (s, 1H), 7.45 (dd, J = 8.6, 5.6, 2H), 7.11 (t, J = 8.6, 2H), 4.63 (s, 2H), 4.43 (s, 2H), 2.82 (t, J = 7.3, 2H), 2.59 (t, J = 7.3, 2H), 1.97 (q, J = 1.3, 2H); 13C-NMR (CDCI3, 150 MHz) delta: 168.3, 165.7, 161.6 (d, JCF = 240 Hz), 156.7, 133.2 (d, JCF = 3 Hz), 131.3 (d, JCF = 7.5 Hz), 119.8, 115.3 (d, JCf = 21Hz), 50.1, 34.6, 31.4, 28.0, 20.2 ;

Reference： [1]Patent: WO2011/146494,2011,A1 .Location in patent: Page/Page column 11
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 839 - 843
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 787 - 792
[4]Patent: WO2019/63634,2019,A1 .Location in patent: Page/Page column 41

9
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Reference： [1]Patent: WO2011/146494,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 839 - 843
[3]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 787 - 792
[4]Patent: WO2019/63634,2019,A1

10
[ 356058-42-9 ]
N-[2-(diethylamino)ethyl]-2-(2-[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide [ No CAS ]

Reference： [1]Patent: WO2011/146494,2011,A1

11
[ 356058-42-9 ]
[ 1349902-21-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-carbonyldiimidazole; In isobutyl methyl ether; at 70℃;Industry scale; Inert atmosphere;	Example 6 - Preparation of A -[2-(diethylamino)ethyl]-2-(2-[(4-fluorophenyl)methyl]thio}-4-oxo- 4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidin-l-yl)-A -[4'-(trifluoromethyl)-4-biphenylyl]methyl}acetamide 6a. A stirred slurry of carbonyldiimidazole (30.9 kg, 1.2 equiv.) in methylisobutylketone (255 kg) under nitrogen was heated to 70 +/- 3C. (2-[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro- lH-cyclopenta [ /] pyrimidin-l-yl)acetic acid (53.0 kg) was added in a portionwise manner and the mixture stirred at 70 +/- 3 C until no starting material remained.

Reference： [1]Patent: WO2011/146494,2011,A1 .Location in patent: Page/Page column 10

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[ 356058-42-9 ]

Reference： [1]Patent: WO2011/146494,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 839 - 843

13
[ 70-11-1 ]
[ 356058-42-9 ]
[ 1417526-26-1 ]

Yield	Reaction Conditions	Operation in experiment
1.14 g	With potassium carbonate; In acetone; at 20℃; for 6h;	Intermediate C1-2-oxo-2-phenylethyl 2-(2-(4-fluorobenzylthio)-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate A mixture of intermediate A4 (1.67g, 1equiv), 2-bromo-1-phenylethanone (1g, 1equiv), anhydrous K2CO3 (1.38g, 2equiv) in acetone (20ml) was stirred at room temperature for 6h. TLC detection showed that the reaction was complete. Solvent was evaporated under recuded pressure and the residue was diluted with water and EA. The mixture was stirred for 10min and the solid so obtained was collected by filtration, washed with water and EA, and then dried to give the title compound as a white solid (1.14g). Then organic layer of the filtrate was separated and evaporated to remove most of the solvent to give a further batch of the title compound (0.75g). 1H-NMR (d6-DMSO, 300 MHz) delta1.99 (m, 2H), 2.60 (t, 2H, J=7.3), 2.95 (t, 2H, J=7.5), 4.45 (s, 2H), 5.02 (s, 2H), 5.66 (s, 2H), 7.15 (t, 2H, J=8.8), 7.49 (dd, 2H, J=8.8 ,5.6), 7.56 (t, 2H, J=7.3), 7.69 (t, 1H, J=7.2), 7.95 (d, 1H, J=6.6); MS (ESI): 453(M+H).
0.75 g	With potassium carbonate; In acetone; at 20℃; for 6h;	A mixture of intermediate A4 (1.67 g, 1 equiv), 2-bromo-1 -phenylethanone (1 g, 1 equiv), anhydrous K2C03 (1.38 g, 2 equiv) in acetone (20 ml) was stirred at room temperature for 6 h. TLC detection showed that the reaction was complete. Solvent was evaporated under reduced pressure and the residue was diluted with water and EA. The mixture was stirred for 10 mm and the solid so obtained was collected by filtration, washed with water and EA, and then dried to give the title compound as a white solid (1.14 g). Then organic layer of the filtrate was separated and evaporated to remove most of the solvent to give a further batch of the title compound (0.75 g). ?H-NMR (d5-DMSO, 300 MHz) oe1.99 (m, 2H), 2.60 (t, 2H, J=7.3), 2.95 (t, 2H, J=7.5), 4.45 (s, 2H), 5.02 (s, 2H), 5.66 (s, 2H), 7.15 (t, 2H, J=8.8), 7.49 (dd, 2H, J=8.8, 5.6), 7.56 (t, 2H, J=7.3), 7.69 (t, 1H, J=7.2), 7.95 (d, 1H, J=6.6); MS (ESI): 453 (M+H).

Reference： [1]Patent: EP2725024,2014,A1 .Location in patent: Paragraph 0201
[2]Patent: US2014/171431,2014,A1 .Location in patent: Paragraph 0548; 0549

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[ 459-46-1 ]
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