138402-10-5

Basic information

• Product Name: Trityl Irbesartan
• Synonyms: TRITYL IRBESARTAN;TRIPHENYLMETHYL IRBESARTAN;2-butyl-3-[[4-[2-(2-trityl-tetrazol-5-yl)phenyl]phenyl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one;Trityl Irbestartan;2-N-BUTYL-4-SPIROCYCLOPENTANE-1-[(2'-(TRIPHENYL-METHYLTETRAZOL-5-YL)BIPHENYL-4-Y;TRIPHENYL IRBESARTAN;N-TriphenylMethyl Irbesartan;Irbesartan N1-Trityl IMpurity
• CAS NO: 138402-10-5
• Molecular Formula: C₄₄H₄₂N₆O
• Molecular Weight: 670.84
• EINECS: 1312995-182-4
• Product Categories: Irbesartan;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 138402-10-5.mol
• Article Data: 13

Chemical Properties

• Boiling Point: 834.612 °C at 760 mmHg
• Flash Point: 458.557 °C
• Appearance: White powder
• Density: 1.201 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.662
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• PKA: 2.60±0.20(Predicted)
• CAS DataBase Reference: Trityl Irbesartan(CAS DataBase Reference)
• NIST Chemistry Reference: Trityl Irbesartan(138402-10-5)
• EPA Substance Registry System: Trityl Irbesartan(138402-10-5)

Safety Data

• Hazardous Substances Data: 138402-10-5(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 138402-10-5 differently. You can refer to the following data:
1. Irbesartan (I751000) derivative.
2. 2-Butyl-3-((2''-(2-trityl-2H-tetrazol-5-yl)-[1,1''-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one (CAS# 138402-10-5) is a useful building block, especially in the preparation of the antihypertensive drug, irbesartan.

InChI:InChI=1/C44H42N6O/c1-2-3-25-40-45-43(30-15-16-31-43)42(51)49(40)32-33-26-28-34(29-27-33)38-23-13-14-24-39(38)41-46-47-48-50(41)44(35-17-7-4-8-18-35,36-19-9-5-10-20-36)37-21-11-6-12-22-37/h4-14,17-24,26-29H,2-3,15-16,25,30-32H2,1H3

Synthetic route

3-[4-bromobenzyl]-2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (731851-41-5) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: 2-(N-triphenylmethyl-tetrazol-5-yl)-phenylboronic acid; palladium diacetate; triphenylphosphine In tetrahydrofuran; 1,2-dimethoxyethane at 20℃; for 0.666667h; Stage #2: 3-[4-bromobenzyl]-2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one With water; potassium carbonate In tetrahydrofuran; 1,2-dimethoxyethane at 20 - 80℃; for 3.5h; Heating / reflux;	90%

N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole (124750-51-2) + 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride → trityl irbesartan (138402-10-5)

Conditions	Yield
In N,N-dimethyl-formamide for 0.0194444h; microwave irradiation;	90%

2-(2-thienyl)-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (1199814-94-2) → trityl irbesartan (138402-10-5)

Conditions	Yield
With hydrogen; Raney nickel In N,N-dimethyl-formamide at 20℃;	88%

3-[4-bromobenzyl]-2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (731851-41-5) + 2-(N-triphenylmethyl-tetrazol-5-yl)-phenylboronic acid (144873-97-2) → trityl irbesartan (138402-10-5)

Conditions	Yield
With potassium carbonate; palladium diacetate; triphenylphosphine In water; toluene at 95 - 100℃; for 3 - 4h; Product distribution / selectivity;	80%
With caesium carbonate; palladium diacetate; triphenylphosphine In water; toluene at 95 - 100℃; for 3 - 4h; Product distribution / selectivity;	80%
With potassium hydroxide; palladium diacetate; triphenylphosphine In water; toluene at 95 - 100℃; for 3 - 4h; Product distribution / selectivity;	72%

N-pentanoylaminocyclopentane-1-carboxylic acid (15026-80-9) + 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine (134603-82-0) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: N-pentanoylaminocyclopentane-1-carboxylic acid; 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine With methanesulfonic acid In toluene at 20℃; for 48h; Heating / reflux; Stage #2: With sodium hydroxide In water; ethyl acetate for 0.5h;	80%
Stage #1: N-pentanoylaminocyclopentane-1-carboxylic acid; 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine With methanesulfonic acid In toluene at 20℃; for 48h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate for 0.5h;	80%

2-n-butyl-3-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)benzyl]-1,3-diazaspiro[4.4]non-1-ene-4-one (894806-38-3) + N-trityl-5-(2-bromophenyl)tetrazole (143945-72-6) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: With triphenylphosphine; palladium diacetate In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 2-n-butyl-3-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)benzyl]-1,3-diazaspiro[4.4]non-1-ene-4-one; N-trityl-5-(2-bromophenyl)tetrazole With potassium phosphate In tetrahydrofuran for 48h; Product distribution / selectivity; Heating / reflux;	54%
With potassium phosphate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In tetrahydrofuran for 48h; Product distribution / selectivity; Heating / reflux;	32%

1-(1'-ethoxy)pentanaminylcyclopentent carboxylate (745814-10-2) + 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine (134603-82-0) → trityl irbesartan (138402-10-5)

Conditions	Yield
acetic acid In toluene for 3h; Heating / reflux;	50%

4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]phenylboronic acid (894806-37-2) + N-trityl-5-(2-bromophenyl)tetrazole (143945-72-6) → trityl irbesartan (138402-10-5)

Conditions	Yield
With potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In water; ethyl acetate; N,N-dimethyl-formamide; toluene at 85℃; for 48h; Product distribution / selectivity;	50%
With sodium carbonate; tetrakis(triphenylphosphine) palladium(0) In ethanol; water; toluene for 5 - 6h; Suzuki Coupling; Heating / reflux;
With 1-(2,6-diisopropylphenyl)-3-(2-oxo-2-(2,4,6-tri-tert-butylphenylamino)ethyl)-1H-imidazol-3-ium bromide; palladium diacetate; potassium carbonate In water; N,N-dimethyl-formamide at 120℃; for 6h;

1-(pentanoylamino)cyclopentanecarboxamide (177219-40-8) + N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole (124750-51-2) → trityl irbesartan (138402-10-5)

Conditions	Yield
With sodium hydroxide; potassium carbonate; tetra(n-butyl)ammonium hydrogensulfate In toluene at 50 - 90℃; for 4h;	32%
With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In water; toluene at 90℃; for 1.5h;

C13H23NO3 (745814-11-3) + 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine (134603-82-0) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: C13H23NO3 With 2,6-dimethylpyridine; oxalyl dichloride In toluene at 0℃; for 1h; Stage #2: 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine In toluene at 0 - 20℃; for 1h;	30%

N-pentanoyl-N-[[2'-[N-(triphenylmethyl)tetrazol-5-yl]-1,1'-biphenyl-4-yl]methyl]amine (439904-79-7) + ethyl 1-aminocyclopentanecarboxylate (1664-35-3) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: N-pentanoyl-N-[[2'-[N-(triphenylmethyl)tetrazol-5-yl]-1,1'-biphenyl-4-yl]methyl]amine With 2,6-dimethylpyridine; oxalyl dichloride In toluene at 0℃; for 1h; Stage #2: ethyl 1-aminocyclopentanecarboxylate In toluene at 0 - 20℃; for 1h;	25%

2-(1-TRITYL-1H-TETRAZOL-5-YL)-4'-(1''-ETHOXYPENTANAMINYL)BIPHENYL (745814-08-8) + ethyl 1-aminocyclopentanecarboxylate (1664-35-3) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: 2-(1-TRITYL-1H-TETRAZOL-5-YL)-4'-(1''-ETHOXYPENTANAMINYL)BIPHENYL; ethyl 1-aminocyclopentanecarboxylate In toluene at 20℃; for 2h; Stage #2: acetic acid In toluene for 5h; Heating / reflux;	20%

5-(4-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole + 2-butyl-1,3-diaza-spiro[4.4]non-1-en-4one (138402-05-8) → trityl irbesartan (138402-10-5)

Conditions	Yield
With potassium hydroxide; tetrabutylammomium bromide In acetonitrile at 31 - 40℃; for 2.5h; Product distribution / selectivity;

trityl chloride (76-83-5) + 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile (138401-24-8) → trityl irbesartan (138402-10-5)

Conditions	Yield
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With tributyltin azide In xylene for 66h; Heating / reflux; Stage #2: trityl chloride With sodium hydroxide In tetrahydrofuran; dichloromethane; water for 26h;
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With sodium azide; tributyltin chloride; tetrabutylammomium bromide In toluene for 20h; Heating / reflux; Stage #2: With acetic acid In water; toluene at 20℃; for 0.25h; Stage #3: trityl chloride With triethylamine In dichloromethane at 25 - 30℃; for 2h;

trityl irbesartan (138402-10-5) → 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one (138402-11-6)

Conditions	Yield
Stage #1: trityl irbesartan With hydrogenchloride In water; acetone at 35 - 45℃; for 1.5 - 2h; Stage #2: In water; acetone at 15℃; pH=11 - 13; Alkaline aqueous solution;	98.75%
With sulfuric acid In water; acetone at 35 - 40℃; for 7h;	93%
With sodium hydroxide In methanol at 20℃;	87%

trityl irbesartan (138402-10-5) → 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one hydrochloride sesquihydrate

Conditions	Yield
With hydrogenchloride; water In toluene at 55℃; for 1h; Product distribution / selectivity;	95%

trityl irbesartan (138402-10-5) → methoxytriphenylmethane (596-31-6) + 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one (138402-11-6)

Conditions	Yield
Stage #1: trityl irbesartan With hydroxylamine hydrochloride In methanol; water; acetone at 20℃; for 2h; Stage #2: With sodium hydroxide In methanol; water; acetone at 20 - 25℃; pH=3.8 - 12.5;	A n/a B 91%
Stage #1: trityl irbesartan With hydroxylamine hydrochloride In methanol; water; isopropyl alcohol; acetone at 20℃; for 2h; Stage #2: With sodium hydroxide In methanol; water; acetone at 20 - 25℃; pH=12.0 - 12.5;	A n/a B 89%

methanol (67-56-1) + trityl irbesartan (138402-10-5) → methoxytriphenylmethane (596-31-6) + 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one (138402-11-6)

Conditions	Yield
for 10h; Heating / reflux;	A 73% B 71%

trityl irbesartan (138402-10-5) → 2-n-butyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one hydrobromide (329055-24-5)

Conditions	Yield
With hydrogen bromide In ethanol; water at 20℃; for 3h;

trityl irbesartan (138402-10-5) → triphenylmethyl alcohol (76-84-6) + 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one (138402-11-6)

Conditions	Yield
With hydrogenchloride; water In acetone

trityl irbesartan (138402-10-5) → 2-n-butyl-4-spirocyclopentane-1-[((2'-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one hydrochloride (329055-23-4)

Conditions	Yield
Stage #1: trityl irbesartan With methanol; potassium hydroxide for 2.5h; Heating / reflux; Stage #2: With hydrogenchloride In water at 20℃; for 4h; pH=0.99; Product distribution / selectivity;
Stage #1: trityl irbesartan With methanol; toluene-4-sulfonic acid In thioguanin for 24h; Heating / reflux; Stage #2: With sodium hydroxide In water pH=12.7; Stage #3: With hydrogenchloride; sodium hydroxide Product distribution / selectivity; more than 3 stages;
With hydrogenchloride In ethanol; water at 20℃; for 3h; Product distribution / selectivity;

Upstream product

• 731851-41-5 3-[4-bromobenzyl]-2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one 
• 144873-97-2 2-(N-triphenylmethyl-tetrazol-5-yl)-phenylboronic acid 
• 745814-08-8 2-(1-TRITYL-1H-TETRAZOL-5-YL)-4'-(1''-ETHOXYPENTANAMINYL)BIPHENYL 
• 1664-35-3 ethyl 1-aminocyclopentanecarboxylate 
• 138402-05-8 2-butyl-1,3-diaza-spiro[4.4]non-1-en-4one 
• 15026-80-9 N-pentanoylaminocyclopentane-1-carboxylic acid 
• 134603-82-0 1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanamine 
• 124750-51-2 N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole 
• 894806-38-3 2-n-butyl-3-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)benzyl]-1,3-diazaspiro[4.4]non-1-ene-4-one 
• 143945-72-6 N-trityl-5-(2-bromophenyl)tetrazole 
• 894806-37-2 4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]phenylboronic acid 
• 745814-11-3 C₁₃H₂₃NO₃ 
• 439904-79-7 N-pentanoyl-N-[[2'-[N-(triphenylmethyl)tetrazol-5-yl]-1,1'-biphenyl-4-yl]methyl]amine 
• 76-83-5 trityl chloride 

Downstream Products

• 329055-24-5 2-n-butyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one hydrobromide 
• 138402-11-6 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one 
• 596-31-6 methoxytriphenylmethane 
• 329055-23-4 2-n-butyl-4-spirocyclopentane-1-[((2'-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one hydrochloride 
• 76-84-6 triphenylmethyl alcohol 

Relevant articles and documents

Synthesis of amido-N-imidazolium salts and their applications as ligands in suzuki-miyaura reactions: Coupling of hetero- aromatic halides and the synthesis of milrinone and irbesartan

A new catalytic system based on palladium-amido-N-heterocyclic carbenes for Suzuki-Miyaura coupling reactions of heteroaryl bromides is described. A variety of sterically bulky, amido-N-imidazolium salts were synthesized in high yields from the corresponding anilines. This catalytic system effectively promoted Suzuki-Miyaura couplings of heteroaryl bromides and chlorides with a range of boronic acids to give the corresponding aryl compounds in high yield. The yield was increased with increasing steric bulkiness of the substituted group. Especially, 1-(2,6-diisopropylphenyl)-3-N-(2,4,6-tri-tert- butylphenylacetamido)imidazolium bromide (4bc) exhibited 850,000 TON in the coupling reaction of 2-bromopyridine and phenylboronic acid. In addition, pharmaceutical compounds such as milrinone and irbesartan were synthesized via Suzuki-Miyaura coupling using sterically bulky, amido-N-imidazolium salt (4bc) as a ligand. Copyright

Process for the preparation of 2-alkyl-1-((2'-substituted-biphenyl-4-yl) Methyl)-imidazole, dihydroimidazole or benzimidazloe derivatives

The invention relates to a new process for the preparation of sartans 2-butyl-3-[[2′-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one is disclosed, which proceeds via novel intermediate, 4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]phenylboronic acid (Formula (II)) or its analogs. Compound (II) reacts with 5-(2-bromophenyl)-1-(triphenylmethyl)-1H-tetrazole (III) in the presence of catalyst, using conditions of Suzuki reaction, to give trityl irbesartan (I), whereas analogs to compound (II) may give candesartan, valsartan, telmisartan, losartan and olmesartan.

INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF ANGIOTENSIN II RECEPTOR ANTAGONISTS

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