830346-48-0

Basic information

• Product Name: 5-Bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione
• Synonyms: 5-Bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione;2,4(1H,3H)-Pyrimidinedione, 5-bromo-1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methyl-;5-Bromo-1-[2-Fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione;5-bromo-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
• CAS NO: 830346-48-0
• Molecular Formula: C₁₃H₉BrF₄N₂O₂
• Molecular Weight: 381.1203728
• Mol File: 830346-48-0.mol
• Article Data: 11

Chemical Properties

• Appearance: /
• Density: 1.685g/cm³
• Refractive Index: 1.548
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly, Heated), DMSO (Slightly), Methanol (Slightly)
• PKA: 7.83±0.40(Predicted)
• CAS DataBase Reference: 5-Bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 5-Bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione(830346-48-0)
• EPA Substance Registry System: 5-Bromo-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione(830346-48-0)

Safety Data

• Hazardous Substances Data: 830346-48-0(Hazardous Substances Data)

Usage

Uses

5-Bromo-1-[2-Fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione is an intermediate in the synthesis of Elagolix, a gonadotropin-releasing hormone antagonist (GnRH) used in the treatment of endometriosis.

InChI:InChI=1/C13H9BrF4N2O2/c1-6-10(14)11(21)19-12(22)20(6)5-7-8(13(16,17)18)3-2-4-9(7)15/h2-4H,5H2,1H3,(H,19,21,22)

Synthetic route

1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (830346-47-9) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0)

Conditions	Yield
With bromine In acetic acid at 20℃;	97.5%
With bromine; acetic acid for 14h;	96%
With bromine; acetic acid at 20℃; for 3h;	87%

5-bromo-6-methyluracil (15018-56-1) + 1-(bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene (239087-08-2) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 75 - 85℃;	81%

N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}urea (830346-46-8) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium iodide / acetonitrile / 20 h / 0 - 20 °C 2: bromine; acetic acid / 2 h View Scheme
Multi-step reaction with 2 steps 1: sodium iodide; chloro-trimethyl-silane / acetonitrile / 16 h / 0 - 25 °C / Inert atmosphere 2: acetic acid; bromine / 14 h View Scheme

2-fluoro-6-(trifluoromethyl)benzonitrile (133116-83-3) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: borane-THF / tetrahydrofuran / 60 °C / Heating / reflux 1.2: 20 °C 2.1: hydrogenchloride; water / 6 h / Heating / reflux 3.1: sodium iodide / acetonitrile / 20 h / 0 - 20 °C 4.1: bromine; acetic acid / 2 h View Scheme

(2-fluoro-6-(trifluoromethyl) phenyl)methanamine (239087-06-0) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; water / 6 h / Heating / reflux 2: sodium iodide / acetonitrile / 20 h / 0 - 20 °C 3: bromine; acetic acid / 2 h View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / water / 12 h / 100 °C 2: sodium iodide; chloro-trimethyl-silane / acetonitrile / 16 h / 0 - 25 °C / Inert atmosphere 3: acetic acid; bromine / 14 h View Scheme

N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}urea (830346-46-8) + ethyl 2-bromoacetoacetate (84911-18-2, 609-13-2) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0)

Conditions	Yield
With trimethylsilyl bromide In N,N-dimethyl acetamide at 0 - 80℃; for 16h; Inert atmosphere;	32.7 g

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + (R)-N-(tert-butoxycarbonyl)phenylglycinol (67341-01-9, 117049-14-6, 138457-46-2, 102089-74-7) → {(R)-2-[5-bromo-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (830346-49-1)

Conditions	Yield
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h;	100%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 14h;	99%
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In toluene at 5 - 20℃;	70%

N-(benzyloxycarbonyl)-1(R)-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (832711-65-6) + 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[N-(benzyloxycarbonyl)-1(R)-1,2,3,4-tetrahydroisoquinoline]methylpyrimidine-2,4(1H,3H)-dione (832711-58-7)

Conditions	Yield
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 16h;	100%

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + C7H6FIOZn → 5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione (1150560-59-0)

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine In dimethyl sulfoxide at 60 - 70℃; for 6h; Inert atmosphere;	83%

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + (2-fluoro-3-methoxyphenyl)boronic acid (352303-67-4) → 5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione (1150560-59-0)

Conditions	Yield
Stage #1: (2-fluoro-3-methoxyphenyl)boronic acid With potassium iodide; potassium hydroxide In water; acetone at 25 - 30℃; for 0.166667h; Inert atmosphere; Stage #2: 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione With tri tert-butylphosphoniumtetrafluoroborate In water; acetone at 25 - 45℃; for 0.583333h; Inert atmosphere; Further stages;	79.2%
Stage #1: 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione; (2-fluoro-3-methoxyphenyl)boronic acid With potassium hydroxide In water; acetone for 0.5h; Stage #2: With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In water; acetone at 70℃; for 10h;	76%
Stage #1: 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione; (2-fluoro-3-methoxyphenyl)boronic acid With potassium hydroxide In water; acetone at 30℃; for 0.166667h; Stage #2: With palladium diacetate; ruphos In water; acetone at 30 - 52℃; for 6h;

1-phenylmethylpiperazine (2759-28-6) + 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 5-(4-benzyl-piperazin-1-yl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (1308380-31-5)

Conditions	Yield
In acetonitrile at 120℃; for 1.5h; microwave irradiation;	79%
In acetonitrile at 120℃; for 1.5h; Microwave irradiation;	79%
In acetonitrile at 120℃; for 1.5h; Microwave irradiation;	79%
In acetonitrile at 120℃; Microwave irradiation;	79%

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + C7H6BrFMgO → 5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione (1150560-59-0)

Conditions	Yield
With iron(III)-acetylacetonate; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 0 - 45℃;	77%

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + (R)-tert-butyl N-(2-hydroxy-1-phenylethyl)-N-methylcarbamate (152547-72-3) → 3-[2(R)-{N-tert-butoxycarbonyl-N-methylamino}-2-phenylethyl]-5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione (832711-54-3)

Conditions	Yield
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + tert-butyl N-[2-hydroxy-1-(2-methoxyphenyl)ethyl]carbamate (869984-24-7) → C27H28BrF4N3O5 (869984-25-8)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + C15H23NO4 (869984-29-2) → C28H30BrF4N3O5 (869984-30-5)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 3h;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + N-(tert-butyloxycarbonyl)-O-benzyl-L-serinol (79069-15-1) → C28H30BrF4N3O5 (1044526-13-7)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Mitsunobu reaction;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + (R)-2-tertbutoxycarbonylamino-1-propanol (79069-13-9, 127516-56-7, 147252-84-4, 106391-86-0) → C21H24BrF4N3O4 (1044526-16-0)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Mitsunobu reaction;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + (S)-2-t-butoxycarbonylaminopropan-1-ol (79069-13-9) → C21H24BrF4N3O4 (1044526-09-1)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Mitsunobu reaction;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + (S)-tert-butyl 1-hydroxybutan-2-ylcarbamate (150736-72-4) → C22H26BrF4N3O4 (1044526-11-5)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Mitsunobu reaction;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) + tert-butyl (R)-(1-hydroxybutan-2-yl)carbamate (150736-71-3) → C22H26BrF4N3O4 (1044526-18-2)

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Mitsunobu reaction;

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-5-(piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione (1308380-33-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetonitrile / 1.5 h / 120 °C / microwave irradiation 2: hydrogen / palladium 10% on activated carbon / dichloromethane; methanol / 5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 2 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → (R)-3-(2-amino-2-(2-methoxyphenyl)ethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-5-(4-(3-nitrobenzyl)piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione (1308378-40-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: acetonitrile / 1.5 h / 120 °C / microwave irradiation 2: hydrogen / palladium 10% on activated carbon / dichloromethane; methanol / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5: trifluoroacetic acid / dichloromethane / 3 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5: trifluoroacetic acid / dichloromethane / 3 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C 5: trifluoroacetic acid / dichloromethane / 3 h / 20 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → [(R)-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-1-(2-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (1308380-37-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetonitrile / 1.5 h / 120 °C / microwave irradiation 2: hydrogen / palladium 10% on activated carbon / dichloromethane; methanol / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-5-(4-(3-nitrobenzyl)piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione (1308378-32-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetonitrile / 1.5 h / 120 °C / microwave irradiation 2: hydrogen / palladium 10% on activated carbon / dichloromethane; methanol / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → (R)-3-(2-amino-2-(2-hydroxyphenyl)ethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-5-(4-(3-nitrobenzyl)piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione (1308379-59-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3.1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5.1: boron trihalide / dichloromethane; 1,2-dichloro-ethane / 48 h / -78 - 40 °C / Inert atmosphere 5.2: 0.33 h / 20 °C / Inert atmosphere View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → (R)-tert-butyl (2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-5-(4-(3-nitrobenzyl)piperazin-1-yl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-(2-hydroxyphenyl)ethyl)carbamate

Conditions

Yield

Multi-step reaction with 6 steps 1.1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3.1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5.1: boron trihalide / dichloromethane; 1,2-dichloro-ethane / 48 h / -78 - 40 °C / Inert atmosphere 5.2: 0.33 h / 20 °C / Inert atmosphere 6.1: triethylamine / 1,2-dichloro-ethane / 3 h / 40 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → (R)-2-(2-(1-amino-2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-5-(4-(3-nitrobenzyl)piperazin-1-yl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)ethyl)phenoxy)acetic acid (1308379-69-2)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3.1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5.1: boron trihalide / dichloromethane; 1,2-dichloro-ethane / 48 h / -78 - 40 °C / Inert atmosphere 5.2: 0.33 h / 20 °C / Inert atmosphere 6.1: triethylamine / 1,2-dichloro-ethane / 3 h / 40 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 70 °C 8.1: trifluoroacetic acid / dichloromethane / 5 h / 20 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 4-[2-((R)-1-amino-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-ethyl)-phenoxy]-butyric acid (1308379-70-5)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3.1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5.1: boron trihalide / dichloromethane; 1,2-dichloro-ethane / 48 h / -78 - 40 °C / Inert atmosphere 5.2: 0.33 h / 20 °C / Inert atmosphere 6.1: triethylamine / 1,2-dichloro-ethane / 3 h / 40 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 70 °C 8.1: trifluoroacetic acid / dichloromethane / 5 h / 20 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → C43H50F4N6O9

Conditions

Yield

Multi-step reaction with 7 steps 1.1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3.1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5.1: boron trihalide / dichloromethane; 1,2-dichloro-ethane / 48 h / -78 - 40 °C / Inert atmosphere 5.2: 0.33 h / 20 °C / Inert atmosphere 6.1: triethylamine / 1,2-dichloro-ethane / 3 h / 40 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 70 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → C45H54F4N6O9

Conditions

Yield

Multi-step reaction with 7 steps 1.1: acetonitrile / 1.5 h / 120 °C / Microwave irradiation 2.1: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 5 h / 20 °C / 760.05 Torr 3.1: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C / Inert atmosphere 4.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 5.1: boron trihalide / dichloromethane; 1,2-dichloro-ethane / 48 h / -78 - 40 °C / Inert atmosphere 5.2: 0.33 h / 20 °C / Inert atmosphere 6.1: triethylamine / 1,2-dichloro-ethane / 3 h / 40 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 70 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-5-(4-((5-(trifluoromethyl)furan-2-yl)methyl)piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione (1308378-34-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → C37H40F4N6O6

Conditions	Yield
Multi-step reaction with 4 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → C38H42F4N6O6

Conditions	Yield
Multi-step reaction with 4 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C View Scheme

5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione (830346-48-0) → C37H39F5N6O6

Conditions	Yield
Multi-step reaction with 4 steps 1: acetonitrile / 120 °C / Microwave irradiation 2: palladium 10% on activated carbon; hydrogen / dichloromethane; methanol / 20 °C 3: N-ethyl-N,N-diisopropylamine / 1,2-dichloro-ethane / 2 h / 50 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C View Scheme

Upstream product

• 830346-46-8 N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}urea 
• 84911-18-2 ethyl 2-bromoacetoacetate 
• 15018-56-1 5-bromo-6-methyluracil 
• 239087-08-2 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene 
• 239087-06-0 (2-fluoro-6-(trifluoromethyl) phenyl)methanamine 
• 133116-83-3 2-fluoro-6-(trifluoromethyl)benzonitrile 
• 830346-47-9 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-2,4(1H,3H)-pyrimidinedione 

Downstream Products

• 832711-54-3 3-[2(R)-{N-tert-butoxycarbonyl-N-methylamino}-2-phenylethyl]-5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione 
• 832711-58-7 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[N-(benzyloxycarbonyl)-1(R)-1,2,3,4-tetrahydroisoquinoline]methylpyrimidine-2,4(1H,3H)-dione 
• 834153-87-6 4-((R)-2-[5-(2- fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl ]-1- phenylethylamino)-butyric acid 
• 1150560-59-0 5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione 
• 830346-49-1 {(R)-2-[5-bromo-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester 
• 1308380-31-5 5-(4-benzyl-piperazin-1-yl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 
• 1308380-33-7 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-5-(piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione 
• 869984-30-5 C₂₈H₃₀BrF₄N₃O₅ 
• 869984-25-8 C₂₇H₂₈BrF₄N₃O₅ 
• 1308379-70-5 4-[2-((R)-1-amino-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-ethyl)-phenoxy]-butyric acid 
• 1308379-69-2 (R)-2-(2-(1-amino-2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-5-(4-(3-nitrobenzyl)piperazin-1-yl)-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)ethyl)phenoxy)acetic acid 
• 1308379-59-0 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(3-nitro-benzyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione 
• 832720-85-1 3-[2(R)-{3-cyanopropylamino}-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-(1H,3H)-dione 
• 830346-51-5 (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamic acid tert-butyl ester 

Relevant articles and documents

AN IMPROVED PROCESS FOR THE PREPARATION OF 4-({(1 R)-2-[5-(2-FLUORO-3METHOXYPHENYL)-3-{[2-FLUORO-6-(TRIFLUORO METHYL) PHENYL]METHYL}-4-METHYL-2,6-DIOXO-3,6DIHYDROPYRIMIDIN-1(2 H)-YL]-1-PHENYLETHYL}AMINO)BUTANOIC ACID OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS

The present invention relates to an improved process for the preparation of 4- ({(1R) -2- [5- (2-fluoro- 3- methoxy phenyl) – 3 - {[ 2-fluoro- 6-(trifluoro methyl) phenyl] methyl} -4-methyl- 2,6-dioxo- 3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino) butanoic acid of formula (I) or its pharmaceutically acceptable salts. The compound of formula (I) is represented by the following structural formula.

Preparation method of oxlagrel intermediate

The invention relates to a preparation method of an oxlagrel intermediate. The preparation method comprises the following steps: dissolving a 2-fluoro-6-(trifluoromethyl)benzyl bromide compound 7 in an aprotic polar solvent, then adding alkali carbonate and urea, carrying out a heating reaction under stirring, and after the reaction is finished, carrying out post-treatment and recrystallization toobtain a compound 4, the yield being 89-95 wt%; and dissolving the compound 4 prepared in the step (1) into the aprotic polar solvent; then, adding a 2-bromoacetoacetic acid ethyl ester compound 9, and cooling to 3 DEG C or below, adding bromo-organosilane while stirring, then continuing to stir and react at 80 DEG C or below, and after the reaction is finished, carrying out aftertreatment and recrystallization to obtain the target product 5-bromo-1-(2-fluoro-6-trifluoromethylbenzyl)-6-methylpyrimidine (1H, 3H)-2,4-diketone compound 1, the yield being 75-88 wt%. The method is simple in synthetic route and simple and convenient in post-treatment mode.

PROCESS FOR THE PREPARATION OF ELAGOLIX AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to a process for the preparation of Elagolix of formula (I) and its pharmaceutically acceptable salts. The present invention also relates to an intermediate of formula (VIII) and its use in preparation of Elagolix and its pharmaceutically acceptable salts.