247257-48-3

Basic information

• Product Name: 2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one
• Synonyms: 2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one;Fimasartan;Unii-p58222188p;2-(1-((2'-(2H-Tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-methyl-6-oxo-1,6-dihydropyrim;2-(2-butyl-4-Methyl-6-oxo-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)Methyl)-1,6-dihydropyriMidin-5-yl)-N,N-diMethylethanethioaMide;2-(2-butyl-4-Methyl-6-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)Methoxy)pyriMidin-5-yl)-N,N-diMethylacetaMide-yl)-N,N-diMethylacetaMide;BR-A-657;Kanarb
• CAS NO: 247257-48-3
• Molecular Formula: C27H31N7OS
• Molecular Weight: 501.65
• Product Categories: Inhibitors
• Mol File: 247257-48-3.mol

Chemical Properties

• Boiling Point: 693.0±65.0 °C(Predicted)
• Appearance: white-off powder or granule
• Density: 1.25
• Storage Temp.: 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 4.16±0.10(Predicted)
• CAS DataBase Reference: 2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one(247257-48-3)
• EPA Substance Registry System: 2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one(247257-48-3)

Safety Data

• Hazardous Substances Data: 247257-48-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one is used as a potential therapeutic agent for various medical conditions. Its unique molecular structure may allow it to interact with specific biological targets, such as receptors or enzymes, which could make it a valuable tool in the development of new drugs.
Used in Chemical Research:
2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one can also be used as a research tool in the field of chemistry, particularly in the study of reaction mechanisms, synthetic methodologies, and the development of new chemical processes. Its complex structure and various functional groups may provide insights into new reaction pathways and help researchers understand the behavior of similar compounds.
Used in Materials Science:
2-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one may have potential applications in the development of new materials, such as polymers, coatings, or advanced materials with specific properties. Its unique structure and reactivity could be harnessed to create novel materials with improved performance characteristics.

Biological Activity

Fimasartan (Kanarb) is a non-peptide angiotensin II receptor antagonist (ARB) with noncompetitive, insurmountable binding with the AT1 receptor. It is used for the treatment of hypertension and heart failure.

Mechanism of action

Angiotensin II activates AR1 leading to vasoconstriction and increased noradrenaline release which further increases vasoconstriction via action at α1-adrenergic receptors. It also stimulates secretion of aldosterone which acts to increase sodium and water reabsorption in the renal tubules. Fimasartan bind to and antagonizes AR1 preventing vasoconstriction and reducing aldosterone secretion to increase natriuresis leading to a reduction in blood volume. Together these effects produce an anti-hypertensive effect.

Synthetic route

2-n-butyl-5-(N,N-dimethylaminothioformylmethyl)-6-methyl-3-[[2'-(N-triphenylmethyl-5-tetrazolyl)biphenyl]-4-methyl]pyrimidin-4-one (1361024-52-3) → Fimasartan (247257-48-3)

Conditions	Yield
With acetic acid In tetrahydrofuran; water for 2h; Reflux;	92%
With hydrogenchloride In methanol; water for 3h; Reflux;	80%
With hydrogenchloride; water In methanol Reflux;

BR-A-557 → Fimasartan (247257-48-3)

Conditions	Yield
With Lawessons reagent In toluene for 3h; Reflux;	80%

C13H20N2O3 (503155-65-5) → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: lithium hydride / ethyl acetate; N,N-dimethyl-formamide 2: water; sodium hydroxide / methanol / 20 °C 3: 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / chloroform 4: Lawessons reagent / toluene / Reflux 5: hydrogenchloride; water / methanol / Reflux View Scheme

C46H44N6O3 (503155-66-6) → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: water; sodium hydroxide / methanol / 20 °C 2: 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / chloroform 3: Lawessons reagent / toluene / Reflux 4: hydrogenchloride; water / methanol / Reflux View Scheme

C44H40N6O3 (1361024-33-0) → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / chloroform 2: Lawessons reagent / toluene / Reflux 3: hydrogenchloride; water / methanol / Reflux View Scheme

2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one (503155-67-7) → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: Lawessons reagent / toluene / Reflux 2: hydrogenchloride; water / methanol / Reflux View Scheme
Multi-step reaction with 2 steps 1: P2S5-pyridine / toluene / 3 h / Reflux 2: hydrogenchloride / methanol; water / 3 h / Reflux View Scheme

pentanonitrile (110-59-8) → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 7 steps 1: hydrogenchloride / methanol / 0 °C 2: sodium ethanolate / ethanol 3: lithium hydride / ethyl acetate; N,N-dimethyl-formamide 4: water; sodium hydroxide / methanol / 20 °C 5: 4-methyl-morpholine; benzotriazol-1-ol; dicyclohexyl-carbodiimide / chloroform 6: Lawessons reagent / toluene / Reflux 7: hydrogenchloride; water / methanol / Reflux View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride / methanol / 9 h / 0 - 10 °C 1.2: 0 - 20 °C / pH 8.5 2.1: potassium hydroxide / methanol / 15 h / 20 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dichloromethane / 5 h / 0 - 20 °C / Inert atmosphere 4.1: Lawessons reagent / toluene / 2 h / 110 °C / Inert atmosphere 5.1: lithium hydride / N,N-dimethyl-formamide; hexane / 1 h / 0 °C / Inert atmosphere 5.2: 24 h / 70 °C / Inert atmosphere 6.1: acetic acid / tetrahydrofuran; water / 2 h / Reflux View Scheme

(2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide) (1315478-13-7) → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium hydride / toluene; N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 1.2: 24 h / 80 - 85 °C 2.1: zinc(II) chloride; sodium azide / N,N-dimethyl-formamide / 28 h / 80 - 130 °C / Inert atmosphere 2.2: 0 - 5 °C 3.1: Lawessons reagent / toluene / 3 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: Lawessons reagent / toluene / 2 h / 110 °C / Inert atmosphere 2.1: lithium hydride / N,N-dimethyl-formamide; hexane / 1 h / 0 °C / Inert atmosphere 2.2: 24 h / 70 °C / Inert atmosphere 3.1: acetic acid / tetrahydrofuran; water / 2 h / Reflux View Scheme

methyl 2-(N,N-dimethylaminocarbonylmethyl)acetoacetate (1315478-14-8) → Fimasartan (247257-48-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium hydroxide / methanol / 0.5 h / Cooling with ice 1.2: 10 h / 30 °C / Cooling with ice 2.1: lithium hydride / toluene; N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 2.2: 24 h / 80 - 85 °C 3.1: zinc(II) chloride; sodium azide / N,N-dimethyl-formamide / 28 h / 80 - 130 °C / Inert atmosphere 3.2: 0 - 5 °C 4.1: Lawessons reagent / toluene / 3 h / Reflux View Scheme

ethyl 2-(N,N-dimethylaminocarbonylmethyl)acetoacetate (1315478-15-9) → Fimasartan (247257-48-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: sodium hydroxide / ethanol / 0.5 h / Cooling with ice 1.2: 10 h / 30 °C / Cooling with ice 2.1: lithium hydride / toluene; N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 2.2: 24 h / 80 - 85 °C 3.1: zinc(II) chloride; sodium azide / N,N-dimethyl-formamide / 28 h / 80 - 130 °C / Inert atmosphere 3.2: 0 - 5 °C 4.1: Lawessons reagent / toluene / 3 h / Reflux View Scheme

2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)acetic acid (1315478-16-0) → Fimasartan (247257-48-3)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 4-methyl-morpholine / dichloromethane / 5 h / 0 - 20 °C / Inert atmosphere 2.1: Lawessons reagent / toluene / 2 h / 110 °C / Inert atmosphere 3.1: lithium hydride / N,N-dimethyl-formamide; hexane / 1 h / 0 °C / Inert atmosphere 3.2: 24 h / 70 °C / Inert atmosphere 4.1: acetic acid / tetrahydrofuran; water / 2 h / Reflux View Scheme

2-n-butyl-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium hydroxide; water / methanol; tetrahydrofuran / 3 h / 20 °C 2: 1-hydroxy-pyrrolidine-2,5-dione; diisopropyl-carbodiimide; triethylamine / dichloromethane / 3 h / 30 - 35 °C 3: lithium hydroxide / N,N-dimethyl-formamide; toluene / 24 h / 60 - 65 °C 4: P2S5-pyridine / toluene / 3 h / Reflux 5: hydrogenchloride / methanol; water / 3 h / Reflux View Scheme

2-butyl-1,6-dihydro-4-methyl-6-oxo-5-pyrimidineacetic acid → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1-hydroxy-pyrrolidine-2,5-dione; diisopropyl-carbodiimide; triethylamine / dichloromethane / 3 h / 30 - 35 °C 2: lithium hydroxide / N,N-dimethyl-formamide; toluene / 24 h / 60 - 65 °C 3: P2S5-pyridine / toluene / 3 h / Reflux 4: hydrogenchloride / methanol; water / 3 h / Reflux View Scheme

2-(2-n-butyl-4-hydroxy-6-methylpyrimidin-5-yl) -N,N-dimethylacetamide → Fimasartan (247257-48-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium hydroxide / N,N-dimethyl-formamide; toluene / 24 h / 60 - 65 °C 2: P2S5-pyridine / toluene / 3 h / Reflux 3: hydrogenchloride / methanol; water / 3 h / Reflux View Scheme

Fimasartan (247257-48-3) → fimasartan potassium salt monohydrate

Conditions	Yield
With 2-Ethylhexanoic acid; potassium hydroxide In isopropyl alcohol for 1h; Reflux;	95.5%

Fimasartan (247257-48-3) + cholin hydroxide (123-41-1) → fimasartan cholinic salt

Conditions	Yield
In water; ethyl acetate; isopropyl alcohol at 20℃; for 24h;	93%

Fimasartan (247257-48-3) + 2-amino-2-hydroxymethyl-1,3-propanediol (77-86-1) → fimasartan tromethamine salt

Conditions	Yield
With water In isopropyl alcohol at 0℃; for 2h; Solvent; Reflux;	91%
In isopropyl alcohol Reflux;	90%

Fimasartan (247257-48-3) → potassium 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4-(3H)-one

Conditions	Yield
With 2-Ethylhexanoic acid; potassium hydroxide In isopropyl alcohol for 4h; Reflux;

Fimasartan (247257-48-3) + α-ethyl (αR,γS)-γ-<(3-carboxy-1-oxopropyl)amino>-α-methyl<1,1'-biphenyl>-4-pentanoate (149709-62-6) → C24H28NO5(1-)*C27H30N7OS(1-)*2K(1+)

Conditions	Yield
With potassium hydroxide In Isopropyl acetate; water; acetone at -5 - 20℃; Autoclave;	50 g

Upstream product

• 1315478-16-0 2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)acetic acid 
• 1315478-15-9 ethyl 2-(N,N-dimethylaminocarbonylmethyl)acetoacetate 
• 1315478-14-8 methyl 2-(N,N-dimethylaminocarbonylmethyl)acetoacetate 
• 1315478-13-7 (2-(2-n-butyl-4-hydroxy-6-methyl-pyrimidin-5-yl)-N,N-dimethylacetamide) 
• 110-59-8 pentanonitrile 
• 1361024-52-3 2-n-butyl-5-(N,N-dimethylaminothioformylmethyl)-6-methyl-3-[[2'-(N-triphenylmethyl-5-tetrazolyl)biphenyl]-4-methyl]pyrimidin-4-one 
• 503155-67-7 2-n-butyl-5-dimethylaminocarbonylmethyl-6-methyl-3-[[2'-(N-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one 
• 1361024-33-0 C₄₄H₄₀N₆O₃ 
• 503155-66-6 C₄₆H₄₄N₆O₃ 
• 503155-65-5 C₁₃H₂₀N₂O₃ 

Relevant articles and documents

Process for Preparation of Fimasartan and Intermediate for Preparing the Same

The present invention relates to a simple and economically process for preparing fimasartan and its preparation intermediates. (by machine translation)

Method for preparing Fimasartan

The invention discloses a method for preparing Fimasartan. The method comprises the steps that valeronitrile is used as a raw material to prepare pentanimidamide hydrochloride, then pentanimidamide hydrochloride and acetylsuccinic acid diethyl ester conduct a cyclization reaction and an amidation reaction to prepare 2-(2-normal-butyl-4-hydroxyl-6-methylpyrimidine-5-radical)-N,N-dimethylacetamide (intermediate II), the intermediate II is subjected to sulfo-carbonylation through a Lawesson's reagent to obtain 2-(2-normal-butyl-4-hydroxyl-6-methylpyrimidine-5-radical)-N,N-dimethylacetamide (intermediate III), the intermediate III is subjected to an N-alkylation reaction, radicals are protected through detritylation, and Fimasartan is prepared. The preparation method has the advantages of highreaction selectivity, high synthesis yield, high reaction efficiency and the like.

Method for synthesizing Fimasartan

The invention discloses a method for synthesizing Fimasartan. The method comprises the steps: subjecting a compound VI and a compound VII to a reaction in toluene, so as to obtain a compound V; subjecting the compound V and pentamidine hydrochloride to a reaction in the presence of alkali metal hydroxide, so as to obtain a compound IV; subjecting the compound IV to hydrogen drawing with lithium hydride in a mixed solvent prepared from toluene and DMF, and then, carrying out an N-alkylation reaction with 2-cyano-4'-bromo-methyl biphenyl, so as to obtain a compound III; subjecting the compound III and sodium azide to a reaction in DMF in the presence of zinc chloride, so as to obtain a compound II; and subjecting the compound II to a thio amidation reaction with a Lawesson's reagent, therebyobtaining the target product I. According to the method, the process is simple, the operation is simple and convenient, the raw materials are readily available, and the method is economical and efficient, so that the production cost of the Fimasartan is greatly reduced, and the industrial production is easy to achieve.

Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists

The discovery, in vitro and in vivo studies of the highly potent AT1 antagonist 12a (BR-A-657, Fimasartan) are presented. A series of pyrimidin-4(3H)-one derivatives as losartan analogue were synthesized and evaluated for a novel class of AT1 receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity [IC50 = 0.42 and 0.13 nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED50 of 0.018 mg/kg. Moreover, in vivo evaluation in furosemide-treated rat and conscious renal hypertensive rat models and the pharmacokinetic study showed that 12a is a highly potent and orally active AT1 selective antagonist having stronger in vivo potency than losartan.

Pyrimidinone compounds, pharmaceutical compositions containing the compounds and the process for preparing the same

The present invention relates to a novel pyrimidinone compounds and the pharmaceutical acceptable salts thereof having remarkable antagonistic action against angiotensin II receptor, thereby, being useful in treating cardiovascular disease caused by binding angiotensin II to its receptor.