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[ CAS No. 138402-11-6 ] {[proInfo.proName]}

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Chemical Structure| 138402-11-6
Chemical Structure| 138402-11-6
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Quality Control of [ 138402-11-6 ]

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Product Details of [ 138402-11-6 ]

CAS No. :138402-11-6 MDL No. :MFCD00864464
Formula : C25H28N6O Boiling Point : -
Linear Structure Formula :- InChI Key :YOSHYTLCDANDAN-UHFFFAOYSA-N
M.W : 428.53 Pubchem ID :3749
Synonyms :
BMS-186295;SR-47436

Calculated chemistry of [ 138402-11-6 ]

Physicochemical Properties

Num. heavy atoms : 32
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.4
Num. rotatable bonds : 7
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 132.72
TPSA : 87.13 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.48
Log Po/w (XLOGP3) : 4.15
Log Po/w (WLOGP) : 3.86
Log Po/w (MLOGP) : 3.95
Log Po/w (SILICOS-IT) : 5.54
Consensus Log Po/w : 4.2

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.04
Solubility : 0.00389 mg/ml ; 0.00000907 mol/l
Class : Moderately soluble
Log S (Ali) : -5.69
Solubility : 0.00088 mg/ml ; 0.00000205 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -8.61
Solubility : 0.00000104 mg/ml ; 0.0000000024 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.3

Safety of [ 138402-11-6 ]

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 [ 138402-11-6 ]

* 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.

  • Downstream synthetic route of [ 138402-11-6 ]

[ 138402-11-6 ] Synthesis Path-Downstream   1~72

  • 1
  • [ 138401-24-8 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
95% With Caswell No. 744A; tributyltin chloride In o-dimethylbenzene Heating;
90% With Caswell No. 744A; N,N-diethylethanamine hydrochloride In toluene at 100℃; for 24h; Large scale; 1.2-1.3; 2.2-2.3; 3.2-3.3 (2) Preparation of crude irbesartan: (cyclization reaction) Biphenyl imidazoline toluene with stirring,Add 200g of triethylamine hydrochloride,95g sodium azide,Heating up,Temperature control reacts at 100 ° C,Reaction for 24h,Cool down to 30 ° C,Slowly add the prepared 10% sodium hydroxide solution,Extract layering,Toluene layer is added to drinking water 500 ml,Extract layering,The lower layer of water is transferred to the separatory funnel.Add 150 ml of toluene,Extract layering,The lower layer of water is transferred to the beaker.Add 200ml of ethanol to the beaker,98g sodium nitrite solution,Temperature control 15 ° C,Slowly add hydrochloric acid to adjust the solution pH=44.5,Add 250ml of drinking water,Continue to stir the crystals,Filter the material,Obtained irbesartan crude (wet).The irbesartan crude (wet) was dried and dried after 26 h.Cool down to room temperature,Received irbesartan crude 295.6g,Sampling and inspection, purity ≥99%,The molar yield was 93.9% (calculated as brominated biphenyl). (3) Irbesartan refinedAdd 750ml of ethanol to the beaker.Stir,Add irbesartan crude 100g,10g activated carbon,Temperature control 80 ° C,Keep warm for 30 minutes.Solution filtration,The filter cake was washed with 100 ml of ethanol.The washing solution and filtrate are cooled to 10 ± 5 ° C,Insulation crystallization for 2h,filter,Erbesartan boutique wet,Dry for 18h,Received 95.9g of irbesartan dry product, the total yield was 90.0%The purity is 99.94%.
89% With trimethylsilylazide; N,N,N-tributylbutan-1-aminium fluoride In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 120℃; for 36h;
87% Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; N,N-diethylethanamine hydrochloride In 1-methyl-pyrrolidin-2-one at 122℃; Stage #2: With sodium hydroxide In 1-methyl-pyrrolidin-2-one; lithium hydroxide monohydrate at 20 - 45℃; for 0.5h; 1; 3 A reactor was charged with Compound 11 (1 kg), triethylamine chlorhydrate (0.713 kg), sodium azide (0.337 kg) and N-methylpyrrolidinone (2.07 kg), and the reaction mixture was heated to about 122° C. under stirring. After completion of the reaction as determined by HPLC, the reaction mixture was cooled to about 45° C., and an aqueous solution of sodium hydroxide (35%, 5.99 kg) and water (3.0 kg) were added, the resulting mixture was stirred at a temperature between about 20 and about 40° C. for about 0.5 hours. The aqueous phase was discarded and the organic phase was treated with toluene (1.73 kg) and water (5.0 kg), and stirred for about 0.5 hours at about 20-about 30° C. The toluene phase was discarded and the aqueous phase was washed with ethyl acetate (1.8 kg) and treated with aqueous HCl until pH was adjusted to about 4.8-about 5.2. Precipitation occurred and the resulting suspension was stirred for about 1 hour at about 20-about 25° C. The precipitation was collected and washed with water three times (1.0 kg×3). The crude wet product was recrystallized using a mixture of iso-propanol (0.393 kg) and water (4.5 kg). HPLC retention time: 11.725 min. The yield for Compound I was about 87%.
86% Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; tributyltin chloride; tetrabutylammonium bromide In toluene for 20h; Heating / reflux; Stage #2: With glacial acetic acid In lithium hydroxide monohydrate; toluene at 20℃; for 0.25h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages; 1.B; 3.B A mixture of 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-1,3-diazaspiro-[4.4]non-l-ene-4-one of Formula II as obtained in example 1 step A) (25 g), tributyltinchloride (63.4 g), sodium azide (12.7 g) and tetrabutyl ammonium bromide (2.5 g) intoluene (75 ml) was refluxed for 20 hrs. The reaction mixture was cooled to roomtemperature and to it was added water (100 ml) and acetic acid (12.5 ml). The mixturewas stirred at room temperature for 15 min. To it was added methanol (100 ml), water(100 ml) and toluene (100 ml) and the entire mass was filtered. After washing the wetsolid with toluene and water, the solids were dissolved in a mixture of water (250 ml)and IN sodium hydroxide solution (100 ml). The aqueous phase was washed withethyl acetate (2 x 100 ml). To the resulting aqueous phase was added 6N HC1 slowly to adjust the pH of the solution to about 4.8 - 5.3. After stirring at room temperaturefor 30 min, the crystals were filtere'd, washed with water (200 ml) and dried at 50°C toyield the compound of Formula I in 99.7% purity (24 g) which was purified, althoughthis purification is optional.To this was added ethanol (96%, 250 ml) and the resulting mixture was heated to reflux until the product completely dissolved. The mixture was cooled to 15°C and stirred at 15 - 20°C for 30 min. The separated crystals were filtered and washed with 96% ethanol and dried at 50°C under reduced pressure to yield Irbesartan.Yield: 23 g (86%)HPLC Purity: 99.95%
86.5% With Caswell No. 744A; N,N-diethylethanamine hydrochloride In toluene at 100 - 110℃; 1-3; 1 Example 1 Preparation of Compound I-1 In a three-neck bottle,Adding compound II-1 to about 50g,Triethylamine hydrochloride36g,17 g of sodium azide and 100 g of toluene, stirred and heated to 100-110 ° C reaction,After the reaction is over, cool down,After washing with 10% NaOH solution,Extracted with 180g of water,Separate the water layer,72g of ethanol and 50% hydrogen peroxide were added to the water layer.Slowly add hydrochloric acid and adjust the pH to 4~4.5 (the residual ion of the ferric chloride indicator detection system,If it is insufficient, add hydrogen peroxide).Filtration, washing and drying to obtain Compound I-1, yield: 86.5%,HPCL purity 99.10%, azide: not detected, NDEA content: not detected.
85% With Caswell No. 744A; N,N-diethylethanamine hydrochloride; 1,8-diazabicyclo[5.4.0]undec-7-ene In o-dimethylbenzene at 125 - 130℃; for 20h; 1 Example- 1 a) Preparation of 2-butyl-3-[[2'-(2H-tetrazol5yl[l,l'-biphenyl]-4-yl]methyl]-l,3- diazaspiro[4.4]non-l-en-4-one (Irbesartan) In a round bottom flask, 4'-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]-[l,l'- Biphenyl]-2-carbonitrile (lOg; 0.0259 moles), sodium azide (5.9g; 0.0907 moles), triethylamine hydrochloride (12.5g; 0.0908 moles) and l,8-Diazabicyclo[5.4.0]undec-7-ene (lgm; 0.0065 moles) in o-xylene (40 ml) was charged and the reaction mixture was gradually heated to 125-130°C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water (30ml) and 30% sodium hydroxide solution (10ml) were added to the reaction mixture. The two layers formed were separated. To the aqueous layer was then added ethyl acetate (70 ml) and the pH of the reaction mixture was adjusted to 2.0-4.5 using aqueous hydrochloric acid to precipitate a solid. The precipitated solid was filtered and washed with water (40ml) and then with ethyl acetate (40 ml). The solid was dried under vacuum at a temperature of 60-65°C to yield the compound of formula I (Irbesartan). Yield 95%, HPLC purity 99%. The compound of formula I (Irbesartan) obtained was crystallized using aqueous isopropyl alcohol and dried under vacuum at 60-65 °C to yield pure white the compound of formula I (Irbesartan). Yield 85%, Purity 99.95%. 1H NMR in DMSO-D6 : 7.68 (d. 2H, Ar-H), 7.52 (d, 2 H, Ar-H), 7.08 (s, 4 H, Ar-H), 4.68(s, 2H, -CH2), 2.69(t,2H,-CH2),2.18(m,2H,-CH2),1.83(m,2H,-CH2),1.81 (t, 2H, -CH2), 1.65 (t, 2H, -CH2), 1.45 (m, 2 H, -CH2), 1.24(m , 2H, -CH2), 0.77 (t, 3H, -CH3), IR (KBR): 3061 (Aromatic C-H stretching), 2960 (Aliphatic C-H stretching), 3443 (N-H stretching), 1733 (C=0 stretching), 1617(CN stretching), 1337.99(CN stretching), 1407(N=N stretching) cm"1.
85% Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; N,N-diethylethanamine hydrochloride In o-dimethylbenzene at 125 - 130℃; for 24 - 40h; Stage #2: With hydrogenchloride; lithium hydroxide monohydrate In ethyl acetate 1; 2 Example 1 Preparation of 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-l,3-diazaspiro [4.4] non-1 -en-4-one (Irbesartan) :Triethylamine hydrochloride (12.5 g), sodium azide (3.4g), tetrabutylammonium bromide (1.Og) and 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro-[4.4]non- 1 -en-4-one (10 g) were taken in o-xylene and heated at 125 - 130°C under stirring for 24 hours. The reaction mixture was cooled at 25 - 30°C. This was followed by the addition of water (30 ml) and 30% sodium hydroxide solution (10 ml) under 30 minutes. The aqueous layer was separated from the settled reaction mixture and washed with xylene(20 ml) followed by the addition of sodium nitrite (3.0 g). Ethyl acetate (70 ml) was added to the aqueous phase and adjusted the pH to about 2.0 - 4.0 with 6N HCl. The precipitated solid was stirred for 1 hour, filtered washed with water (40 ml) and ethyl acetate (40 ml) to produce Irbesartan (Yield: 85%, HPLC Purity: 99.90%);Level of organic volatile impurities: o-xylene - 3 parts per million (ppm), toluene - 5 ppm, N,N-dimethylformamide - Not detected, ethyl acetate - Not detected, methyl tert-butyl ether - Not detected, triethylamine - Not detected, tin-Not detectedExample 2Preparation of_2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-l,3-diazaspiro [4.4]non-l-en-4-one (Irbesartan):Triethylamine hydrochloride (45 g), sodium azide (13 g), tetrabutylammonium bromide (2.5g) and 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro- [4.4]non-l -en-4-one (50g) were taken in o-xylene and heated at 125 - 130°C under stirring for 40 hours. The reaction mixture was cooled at 25 -30°C. This was followed by the addition of water (150 ml) and 30% sodium hydroxide solution (50 ml) under 30 minutes. The aqueous layer was separated from the settled reaction mixture and washed with xylene (100 ml). Ethyl acetate (350 ml) was added to aqueous phase and adjusted the pH at about 2.0 - 4.5 with 6N HCl. The precipitated solid was stirred for 1 hour and filtered washed with water (200 ml) and ethyl acetate (200 ml) to produce Irbesartan (Yield: 85%, HPLC Purity: 99.95%), Level of organic volatile impurities: o-xylene - 2 parts per million (ppm), toluene - 6 ppm, N,N-dimethylforrnamide - Not detected, ethyl acetate - Not detected, methyl tert-butyl ether - Not detected, triethylamine - Not detected and tin-Not detected.
81% With azido-tri-n-butylstannane In o-dimethylbenzene for 80h; Heating / reflux; 5; 6; 7 Preparation of Irbesartan 2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-1,3 diazaspiro [4.4] non-1-ene-4-one of formula (VII) obtained in above step is reacted with tributyl tin azide in o-xylene at reflux temperature for 80 hours to give crude Irbesartan. The mass is treated with 1N NaOH. The phases were separated and aq. phase is washed with o-xylene and isopropyl ether. Aq phase is treated with charcoal, filtered through hyflobed and then treated with 3N HCl. The product title compound is filtered, washed with water and dried under vacuum at 60° C. The product is crystallized from 95% ethanol to give Irbesartan. (Yield: 86%). 1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m, 4H) M+: 429.6; 2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-1,3 diazaspiro [4.4] non-1-ene-4-one of formula (VII) obtained in above step is reacted with tributyl tin azide in o-xylene at reflux temperature for 80 hours to give crude Irbesartan. The mass is treated with 1N NaOH. The phases were separated and aq. phase is washed with o-xylene and isopropyl ether. Aq phase is treated with charcoal, filtered through hyflobed and then treated with 3N HCl. The product title compound is filtered, washed with water and dried under vacuum at 60° C. The product is crystallized from 95% ethanol to give Irbesartan. (Yield: 81%) 1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m, 4H) M+: 429.6 ; 2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-1,3 diazaspiro [4.4] non-1-ene-4-one of formula (VII) obtained in above step is reacted with tributyl tin azide in o-xylene at reflux temperature for 80 hours to give crude Irbesartan. The mass is treated with 1N NaOH. The phases were separated and aq. phase is washed with o-xylene and isopropyl ether. Aq phase is treated with charcoal, filtered through hyflobed and then treated with 3N HCl. The product title compound is filtered, washed with water and dried under vacuum at 60° C. The product is crystallized from 95% ethanol to give Irbesartan. (Yield: 85%) 1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m, 4H) M+: 429.6
81% With azido-tri-n-butylstannane In o-dimethylbenzene for 80h; Heating / reflux; 5; 6; 7 2-(n-Butyl)-3-(2'-cyanobiphenyl-4-ylmethyl)-4-oxo-l,3 diazaspiro [4.4] non-l-ene-4-one of formula (VII) obtained in above step is reacted with tributyl tin azide in o-xylene at reflux temperature for 80 hours to give crude Irbesartan. The mass is treated with IN NaOH. The phases were separated and aq. phase is washed with o-xylene and isopropyl ether. Aq phase is treated with charcoal, filtered through hyflobed and then treated with 3N HCl. The product title compound is filtered, washed with water and dried under vacuum at 600C. The product is crystallized from 95% ethanol to give Irbesartan. (Yield: 86%).1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50- 7.68 (m, 4H) M+: 429.6; 2-(n-Butyl)-3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-l,3 diazaspiro [4.4] non-l-ene-4-one of formula (VII) obtained in above step is reacted with tributyl tin azide in o-xylene at reflux temperature for 80 hours to give crude Irbesartan. The mass is treated with IN NaOH. The phases were separated and aq. phase is washed with o-xylene and isopropyl ether. Aq phase is treated with charcoal, filtered through hyflobed and then treated with 3N HCl. The product title compound is filtered, washed with water and dried under vacuum at 60°C. The product is crystallized from 95% ethanol to give Irbesartan. (Yield: 81%)1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50- 7.68 (m, 4H) M+: 429.6; 2-(n-Butyl)τ3-[2'cyanobiphenyl-4-ylmethyl]-4-oxo-l,3 diazaspiro [4.4] non-l-ene-4-one of formula (VII) obtained in above step is reacted with tributyl tin azide in o-xylene at reflux temperature for 80 hours to give crude Irbesartan. The mass is treated with IN NaOH. The phases were separated and aq. phase is washed with o-xylene and isopropyl ether. Aq phase is treated with charcoal, filtered through hyflobed and then treated with 3N HCl. The product title compound is filtered, washed with water and dried under vacuum at 600C. The product is crystallized from 95% ethanol to give Irbesartan. (Yield: 85%)1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50- 7.68 (m, 4H) M+: 429.6
81% Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; anhydrous zinc chloride In N,N-dimethyl-formamide for 15h; Heating / reflux; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20℃; for 1h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate for 3h; 2 Example-2; Preparation of 2-n-butyl-3-[(2'-(tetrazol-5-yl) biphenyl-4-yl) methyl)-1,3-diazospiro-(4,4)-non-1-ene-4-one [Irbesartan] : To a solution of 1-(2'-cyanobiphenyl-4-yl) methyl)-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (Cyano irbesartan) (50g, 0.129mol) in DMF was added, zinc chloride (22.12 g, 0,162mol) and sodium azide (21.10g, 0.324mol). The reaction mass was refluxed for 15 hrs and the progress of the reaction was monitored by TLC. After the reaction was over, it was cooled to room temperature and basified using 10% sodium hydroxide solution to pH 11-12. The reaction mass was stirred for 1hr and filtered. The filtrate was washed with toluene (250ml). 75 ml of IPA was added to the aqueous layer and pH was adjusted to 4-5 with con. HCl. Reaction mass was stirred for 3 hours, filtered and washed with water. The product was dried at 60°C to give 45g (81%) of irbesartan.
73% With Caswell No. 744A; tributyltin chloride; tetrabutylammonium bromide In N,N-dimethyl-formamide at 220℃; for 1h; microwave irradiation;
68% With azido-tri-n-butylstannane In xylene for 88h; Heating;
66.2% Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; tributyltin chloride In o-dimethylbenzene at 25 - 146℃; for 24h; Stage #2: With hydrogenchloride In o-dimethylbenzene; lithium hydroxide monohydrate at 18 - 20℃; for 0.25h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages; II.IV Stage IV: Preparation of Irbesartan (I); 1 - [(2' -Cy anobiphenyl-4-yl)methyl] -2-n-butyl-4-spirocyclopentane-2-imidazolin-5 - one (IV) (2 g, 0.0052 mole), tributylitin chloride (2.42 g, 0.0074 mole), sodium azide (0.48 g, 0.0074 mole) were added respectively to o-xylene at 25-30°C. The mixture was heated to reflux temperature (144-146°C) for 24 h and cooled to 20°C. Water (2 ml) was added followed by hydrochloric acid (1.8 ml, 15% w/v) at 18- 200C and the slurry obtained was stirred for 15 min at 18-200C. Solid was filtered, washed with water (6 ml) followed by toluene (6 ml, 4O0C). Finally, washed with water (6 ml). The wet solid (3.6 g) was suspended in water (15 ml) at 25-3O0C and adjusted the pH to 12.0 with 5% w/v aqueous sodium hydroxide (4.7 ml) in 5 min and treated with carbon for 30 minutes and filtered. The filtrate was washed with ethyl acetate (12 ml). pH of the aqueous layer was adjusted to 4.6-4.8 with hydrochloric acid (0.5 ml, 15% w/v) at 25-300C. The slurry obtained was stirred for 30 min at 25-3O0C. Solid was filtered, washed with water (5 ml, 35-40°C) and dried to get the crude Irbesartan as an off-white powder (1.47 g, 66.2% 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 Caswell No. 744A; tributyltin chloride In toluene for 20h; Heating / reflux; Stage #2: With glacial acetic acid In lithium hydroxide monohydrate; toluene at 20℃; for 0.25h; 1 A mixture of 2-n-butyl-3- [ [2'-cyanobiphenyl-4-yl] methyl] -1, 3-diazaspiro- [4.4] non-1-ene-4-one of Formula II (A) (25 g), tributyltin chloride (63.4 g), sodium azide (12.7 g) and tetrabutyl ammonium bromide (2.5 g) in toluene (75 ml) was refluxed for 20 hrs. The reaction mixture was cooled to room temperature and to it added water (100 ml) and acetic acid (12.5 ml). The mixture was stirred at room temperature for 15 min. To it was added methanol (100 ml), water (100 ml) and toluene (100 ml) and the entire mass was filtered. After washing the wet solid with toluene and water, the solids were dissolved in a mixture of water (250 ml) and 1N sodium hydroxide solution (100 ml). The aqueous phase was washed with ethyl acetate (2 x 100 ml). To the resulting aqueous phase was added 6N HCl slowly to adjust the pH of the solution to about 4.8-5. 3. After stirring at room temperature for 30 min, the crystals were filtered, washed with water (200 ml) and dried at 50°C to afford the compound of Formula la in 99.7% purity (24 g) which was optionally purified. To this was added ethanol (96%, 250 ml) and the resulting mixture was heated to reflux until the product completely dissolved. The mixture was cooled to 15°C and stirred at 15 - 20°C for 30 min. Then the crystals were filtered and washed with 96% ethanol and dried at 50°C under reduced pressure to get irbesartan. Yield: 23 g (86%) HPLC Purity: 99.95%
With Caswell No. 744A; tributyltin chloride In xylene for 24h; Heating / reflux; 1 Example-1: Preparation of Irbesartan form-A; A mixture of 100 g. of 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl) methyl] l,3-diazaspiro-p4.4]- non-l-en-4-one, 59 g of sodium azide and 240 g of tributyl tin chloride are refluxed in 800 ml of xylene for 24 hrs. After completion of the reaction, the reaction mixture is cooled to room temperature, filtered and extracted with 2 x 1.0 lit of IN sodium hydroxide solution. The combined aqueous layer containing the product is washed with toluene and the pH of the aqueous layer is adjusted to 4.0 - 6.0 with dilute hydrochloric acid. The product is filtered and dried at 50-650C till constant weight to get Irbesartan form-A.Yield= 110 g; HPLC purity = 96%.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With azido-tri-n-butylstannane In o-dimethylbenzene at 145 - 148℃; for 24 - 30h; Stage #2: With hydrogenchloride In o-dimethylbenzene; propan-2-one at 25 - 27℃; for 3 - 4h; 4.I Sodium azide (300 gm), water are added to tributyl tin chloride for 1 hour to 2 hours at 0 - 5° C. Maintained for 2 hours at 0 - 5° C. o-Xylene (2000 ml) is added under stirring and the temperature is raised to 25 - 30° C. Maintained for 30 minutes to 45 minutes at 25 - 30° C. The layers are separated and the aqueous layer is extracted with o-Xylene (2000 ml). The total organic layer is washed with 10% sodium chloride (1500 ml). The organic layer is poured into 10 Lt reaction flask and added 1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-n-butyl-4- spirocyclopentane-2-imidazolin-5-one (500 gm) under Dean and Starck apparatus set up. The contents are heated to reflux for 24 - 30 hrs at 145 - 148° C. Reaction mass is cooled to 25 - 27° C and added acetone (2500 ml). The pH is adjusted to 2 by using acetone-HCI (Assay: 4.9%, Moisture content: 3%) (Acetone-HCI 2250 ml). The contents are stirred for 3 hours to 4 hours at 25 - 27° C, filtered the compound and washed with acetone (1000 ml) to give 542 gm of irbesartan (HPLC purity: 99.70%, 1-Pentanoylamino-cyclopentane carboxylic acid-[2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]amide: 0.08%).Step-llIrbesartan (obtained in Step-I) and water (5000 ml) are stirred for 15 to 30 minutes and added toluene (1500 ml). The pH is adjusted in between 11.0 and 11.5 at 20 - 25° C by using 5% sodium hydroxide solution (1000 ml). The layers are separated and aqueous layer is washed with toluene (3000 ml). The aqueous layer is passed over hi-flow bed and washed with water (1000 ml). Initially the pH of the aqueous layer is adjusted between 3.0 to 3.5 and maintained for 15 to 20 minutes, again the pH is adjusted in between 0.5 to 1.0 using 1N sulfuric acid solution (920 ml). Stirred for 2 hours, filtered the compound and washed with water (5000 ml). Water (2500 ml) is added to the compound and the pH is re-adjusted in between 0.5 to 1.0 using 1N sulfuric acid solution (180 - 200 ml). Stirred for 2 hours at 25 - 30° C to give 493 gm of irbesartan (HPLC purity: 97.02%, Tin content: 172.8ppm, 1-Pentanoylamino- cyclopentane carboxylic acid-[2'-(1 H-tetrazole-5-yI)biphenyl-4-yl)methyl]amide: 2.32%). Step-IllMethylene dichloride (5000 ml) and methanol (500 ml) are added to Irbesartan (obtained in Step-ll), washed with water (2500 ml) and the pH is adjusted to 3 by usingl N sulfuric acid solution (10 ml). The layers are separated and washed with water (2000 ml) at the pH 3. The organic layer is washed with sodium chloride solution (2000 ml), dried, distilled off the solvent completely and then codistilled with acetone (1500 ml). Acetone (2500 ml) is added to the compound and stirred for 30 - 45 minutes at 25 - 30° C and maintained at 0 - 5° C for 1 hour to 1 hour 15 minutes. The compound is filtered and washed with acetone (250 ml). Methanol (5000 ml) is added to the compound and heated to reflux (60 - 65° C) till a clear solution is obtained. Added carbon, passed over a hi-flo bed and washed with hot methanol. Distilled off methanol and then codistilled with Acetone (1500 ml). Acetone (2500 ml) is added and stirred for 1 hour 30 minutes to 2 hours at 25 - 27° C, cooled to 0 - 5° C and again stirred for 1 hour to 1 hour 30 minutes. Filtered the compound and washed with chilled acetone (400 ml) to give 430 gm of irbesartan (HPLC purity: 99.8%, Tin content: less than 1ppm, 1-Pentanoylamino-cyclopentane carboxylic acid-[2'-(1H- tetrazole-5-yl)biphenyl-4-y.)methyl]amide: 0.04%).
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; tributyltin chloride In o-dimethylbenzene at 145 - 148℃; Stage #2: With hydrogenchloride In o-dimethylbenzene; propan-2-one at 25 - 27℃; 4.1 Example 4Step-ISodium azide (300 gm), water are added to tributyl tin chloride for 1 hour to 2 hours at 0-5° C. Maintained for 2 hours at 0-5° C. o-Xylene (2000 ml) is added under stirring and the temperature is raised to 25-30° C. Maintained for 30 minutes to 45 minutes at 25-30° C. The layers are separated and the aqueous layer is extracted with o-Xylene (2000 ml). The total organic layer is washed with 10% sodium chloride (1500 ml). The organic layer is poured into 10 Lt reaction flask and added 1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (500 gm) under Dean and Starck apparatus set up. The contents are heated to reflux for 24-30 hrs at 145-148° C. Reaction mass is cooled to 25-27° C. and added acetone (2500 ml). The pH is adjusted to 2 by using acetone-HCl (Assay: 4.9%, Moisture content: 3%) (Acetone-HCl 2250 ml). The contents are stirred for 3 hours to 4 hours at 25-27° C., filtered the compound and washed with acetone (1000 ml) to give 542 gm of irbesartan (HPLC purity: 99.70%, 1-Pentanoylamino-cyclopentane carboxylic acid-[2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyliamide: 0.08%).
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine In acetic acid butyl ester at 115 - 120℃; for 24h; Stage #2: With sodium hydroxide In acetic acid butyl ester; lithium hydroxide monohydrate for 0.166667h; Stage #3: With hydrogenchloride In acetic acid butyl ester; lithium hydroxide monohydrate for 1h; 6 Example 6. Preparation of 2-n-butyl)-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (I): A RB flask was charged with n-butyl Acetate (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (10 g) and sodium Azide (3.4 g) was added to the flask and the reaction mixture was heated at 115-12O0C for 24 hrs, followed by cooling. The reaction was then quenched by addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and then stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and then stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl Acetate (5 ml) and dried at 90-1000C.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine In butan-1-ol at 115 - 120℃; for 24h; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; butan-1-ol for 0.166667h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate; butan-1-ol for 1h; 9 Example 9. A RB flask was charged with n-butanol (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-l-en-4- one (10 g) and sodium azide (3.4 g) was added to the flask and the reaction mixture was heated at 115-1200C for 24 hrs, followed by cooling. The reaction was then quenched by the addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100°C.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine In n-heptane at 100 - 105℃; for 24h; Stage #2: With sodium hydroxide In n-heptane; lithium hydroxide monohydrate for 0.166667h; Stage #3: With hydrogenchloride In n-heptane; lithium hydroxide monohydrate for 1h; 7 Example 7. A RB flask was charged with, n-heptane (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3 -[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro [4.4]non-1-en-4-one (10 g) and sodium azide (3.4 g) was added to the flask and the reaction mixture was heated at 100-105°C for 24 hrs, followed by cooling. The reaction was then quenched by addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and then stirred for 10 min. Layers were separated and pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl acetate (5 ml) and then dried at 90- 100°C.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine In toluene at 115 - 120℃; for 24h; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; toluene for 0.166667h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate; toluene for 1h; 8 Example 8. A RB flask was charged with toluene (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4- one (10 g) and sodium azide (3.4 g) was added to the flask and the reaction mixture was heated at 115-1200C for 24 hrs, followed by cooling. The reaction was then quenched by the addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100°C
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine In methyl iso-butyl ketone at 115 - 120℃; for 24h; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; methyl iso-butyl ketone for 0.166667h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate; methyl iso-butyl ketone for 1h; 10 Example 10. A RB flask was charged with methyl isobutyl ketone (50 ml), triethyl amine (22 ml) and acetic acid (9 ml) and stirred. 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-l,3- diazaspiro[4.4]non-1-en-4-one (10 g) and sodium azide (3.4 g) was added to the flask and the reaction mixture was heated at 115-12O0C for 24 hrs, followed by cooling. The reaction was then quenched by the addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and stirred for 1 hour, filtered to obtain solid material which was washed with water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100°C.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine In xylene at 115 - 120℃; for 24h; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; xylene for 0.166667h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate; xylene for 1h; 11 Example 11. A RB flask was charged with xylene (50 ml), triethyl amine (15 ml) and acetic acid (6 ml) and stirred. 2-(n-butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4- one (10 g) and sodium azide (3.4 g) was added to the flask and the reaction mixture was heated at 120-125°C for 24 hrs, followed by cooling. The reaction was then quenched by the addition of water (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and stirred for 1 hour, filtered to obtain solid material which was then washed with water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100°C.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; glacial acetic acid; triethylamine at 90 - 100℃; for 24h; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; xylene for 0.166667h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate; xylene for 1h; 12 Example 12. A RB flask was charged with triethyl amine 22 ml and acetic acid 9 ml and stirred. 2-(n- butyl)-3-[[2'-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (10 g) and sodium azide (3.4 g) was added to the flask and the reaction mixture was heated at 90-100°C for 24 hrs, followed by cooling. The reaction was then quenched by the addition of water (30 ml) and xylene (30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxide and stirred for 10 min. Layers were separated and oily layer was treated with water and xylene. The pH of the aqueous layer was adjusted between 2 and 3 by the addition of hydrochloric acid and stirred for 1 hour, filtered to obtain solid material which was then washed with water (20 ml) and ethyl acetate (5 ml) and then dried at 90-1000C. While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; piperazine bis(hydrochloride) In N,N-dimethyl-formamide for 7h; Reflux; Stage #2: With sodium hydroxide In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20℃; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate 1 A mixture of 2-n-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (5.8 g, 98% purity by HPLC). Recrystallization of the Product using ethanol results in 5.2 g of irbesartan with 99.94% purity and content of the impurity 2-n-butyl-3-[(2'-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.07%.
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With C6H16N6O3Zn In toluene at 100 - 120℃; Stage #2: With hydrogenchloride In lithium hydroxide monohydrate; toluene 9 Example 9: Preparation of 2-butyl-1-[(2’-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]spiro[2-imidazolin-4,1’-cyclopentan]-5-one (Irbesartan) (Method 1) [125] 2-butyl-3-[2’-{cyanobiphenyl-4-yl}methyl]-1,3-diazaspiro[4,4]non-1-en-4-one (5.0g) and toluene (15mL) were added into a reactor, and with stirring the solid compound (5.1g) obtained in Example 1-1 was added thereto. The temperature inside the reactor was maintained at 100~120 and the reaction was conducted for 20 hours or more. After the reaction was completed, the internal temperature was cooled to 50~60, and 28% ammonia water (15mL) and water (15mL) were added thereto dropwise for phase separation. The obtained organic layer was washed with water (25mL), and stirred with maintaining pH 2~3 by using water (25mL) and 35% hydrochloric acid. The generated solid was filtered, washed with water (25mL) and dried under nitrogen to obtain the title compound (4.8g).[126] 1H NMR (DMSO-d6), 0.78 (t, 3H), 1.17-1.30 (m, 2H), 1.40~1.50(m, 2H), 1.80~1.82 (m, 6H), 1.55 (m, 2H), 2.22~2.29 (t. 3H), 4.67 (s, 2H), 7.07 (s, 4H), 7.50~7.68 (m, 4H)
Stage #1: 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-[1,1'-biphenyl]-2-carbonitrile With Caswell No. 744A; tributyltin chloride In o-dimethylbenzene at 25 - 137℃; for 60h; Stage #2: With sodium hydroxide In o-dimethylbenzene; lithium hydroxide monohydrate at 10 - 15℃; for 1h; Stage #3: With hydrogenchloride In lithium hydroxide monohydrate at 10 - 30℃; IV EXAMPLE IV:; Preparation of Irbesartan (I); l-[(2'-Carboxaniidobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2- imidazolin-5-one(XV) (10 g, 0.0248 mole), pyridine (5 g, 0.063 mole), p- toluenesulfonyl chloride (7.5 g, 0.039 mole) were added respectively and heated to 70-75°C. Thereafter, the reaction mixture was stirred at 70-75°C for 1 h. o-Xylene (50 ml) and water (25 ml) were added at 70-75°C and stirred for 10 min. Organic layer was separated, washed with water (25 ml) and dried over sodium sulfate. Sodium sulfate was washed with o-xylene (20 ml). Tributyltinchloride (11.70 g, 0.036 mole) and sodium azide (2.34 g, 0.036 mole) were added respectively to the xylene layer at 25-30°C. The reaction mixture was heated to reflux at 136-137°C for 60 h. Thereafter, cooled to 10-15°C and water (100 ml) was added. pH was adjusted to 11.5-12 with 10% w/w sodium hydroxide solution and stirred the reaction mass for 1 hour. Organic layer was separated and again extracted with water (100 ml). The combined aqueous layer was washed with ethyl acetate (2x25 ml) at 10-150C. The aqueous layer pH was adjusted to 4.6-4.8 with 15% w/w hydrochloric acid at 25-30°C. Precipitated solid was filtered, washed with water (100 ml) and dried to obtain Irbesartan-crude as an off-white powder (5 g, 45% yield). It was purified as per the method given in Example I.
With Caswell No. 744A; tributyltin chloride; tetrabutylammonium bromide In toluene for 20h; Reflux; 3; 4; 5 Reference Example 3: WO 2005/051929 A mixture of 2-n-butyl-3-[[2′-cyanobiphenyl-4-yl]methyl]-1,3-diazaspiro-[4.4]non-1-ene-4-one of (50 gm), tributyltin chloride (126.8 g), sodium azide (25.4 g) and tetrabutyl ammonium bromide (5 gm) in toluene (150 ml) was refluxed for 20 hrs. The reaction mixture was cooled to room temperature and to it added water (200 ml) and acetic acid (25 ml). The mixture was stirred at room temperature for 15 minutes. To it was added methanol (200 ml), water (200 ml) and toluene (200 ml), stirred and was filtered. After washing the wet solid with toluene and water, the solids were dissolved in a mixture of water (500 ml) and IN sodium hydroxide solution (200 ml). The aqueous phase was washed with ethyl acetate (2×200 ml). To the resulting aqueous phase was added 6N HCl slowly to adjust the pH of the solution to about 4.8-5.3. After stirring at room temperature for 30 min, the crystals were filtered, washed with water (500 ml) and dried at 50° C. to yield 35 gm of Irbesartan.) Charged Irbesartan (30 gm), ethanol (312 ml) and the resulting mixture was heated to reflux until the product completely dissolved. The mixture was cooled to 15° C. and stirred at 15-20° C. for 30 minutes. Then the crystals were filtered and washed with ethanol (30 ml) and dried at 50° C. under reduced pressure to get 24 gm of irbesartan. The inventors observed NDMA, NDEA, NDIPA, NEIA, NDBA, NMBA-BDL (BDL-0.03 ppm); NDBA (BDL; DL: 0.033 ppm; QL: 0.10 ppm).

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[28]Current Patent Assignee: AUROBINDO PHARMA LIMITED - WO2007/122508, 2007, A2 Location in patent: Page/Page column 3-4; 20
[29]Current Patent Assignee: HETERO DRUGS LIMITED - US2022/127238, 2022, A1 Location in patent: Paragraph 0081-0084; 0086-0090; 0091-0095
  • 2
  • [ 138402-11-6 ]
  • [ 74-88-4 ]
  • 2-n-butyl-3-<<2'-(2-methyltetrazol-5-yl)biphenyl-4-yl>methyl>-1,3-diazaspiro<4.4>non-1-en-4-one [ No CAS ]
  • 2-n-butyl-3-<<2'-(1-methyltetrazol-5-yl)biphenyl-4-yl>methyl>-1,3-diazaspiro<4.4>non-1-en-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydride 1.) DMF, RT, 0.5 h, 2.) DMF, RT, 4 h; Yield given. Multistep reaction. Yields of byproduct given;
  • 3
  • [ 57820-69-6 ]
  • [ 138402-11-6 ]
  • (2S,3S,4S,5R,6R)-3,4,5-Triacetoxy-6-{5-[4'-(2-butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-ylmethyl)-biphenyl-2-yl]-tetrazol-1-yl}-tetrahydro-pyran-2-carboxylic acid methyl ester [ No CAS ]
  • (2S,3S,4S,5R,6R)-3,4,5-Triacetoxy-6-{5-[4'-(2-butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-ylmethyl)-biphenyl-2-yl]-tetrazol-2-yl}-tetrahydro-pyran-2-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 30% 2: 59% With silver carbonate In toluene at 100℃; for 18h; protection from light;
  • 4
  • [ 138402-11-6 ]
  • [ 120568-11-8 ]
YieldReaction ConditionsOperation in experiment
In phosphate buffer at 37℃;
  • 5
  • [ 731851-41-5 ]
  • [ 144873-97-2 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
84% With potassium hydroxide; tetrakis(triphenylphosphine) palladium(0) In methanol for 10h; Heating;
22% Stage #1: 3-[4-bromobenzyl]-2-n-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 2-(N-triphenylmethyl-tetrazol-5-yl)-phenylboronic acid With potassium carbonate In water; toluene at 25 - 85℃; for 0.5h; Stage #2: With hydrogenchloride In water; 4-methyl-2-pentanone 8 EXAMPLE 8; The preparation of Irbesartan is accomplished by adding a mixture of 3-[4- Bromo benzyl]-2-butyl-1,3-diazaspiro [4.4]non-1-en-4-one (5.0 grams, prepared according to preceding Example 7), 2-(2'-Triphenylmethyl-2'H-tetrazol-5'-yl)- phenylboronic acid (6.1 grams, prepared according to Example 1 of U. S. Patent No. 5,310,928), and potassium carbonate (4.7 grams) to toluene (60 ml) followed by water addition (0.7 ml) under a nitrogen atmosphere. Tetrakis(triphenyl phosphine) palladium (0.4 grams) was added to the above reaction mixture at a temperature of 25-35°C, and the reaction mixture was heated to a temperature of 80-85°C and stirred until completion of the reaction as shown by TLC analysis. The reaction mixture was cooled to a temperature of 25-35°C and water (50 ml) was added and stirred for 30 minutes at a temperature of 25-35°C. The resultant reaction mixture was filtered and washed with toluene (20 ml), then the organic layer was separated and washed with water (20 ml). Solvent was distilled from the organic layer under reduced pressure. The resulting residue was dissolved in dichloromethane (50 ml) and washed with saturated sodium chloride solution (2 X 20 ml). Solvent was distilled from the organic layer. Methyl isobutyl ketone (50 ml) was added to the resulting residue followed by addition of 30% aqueous hydrochloric acid (10 ml) and stirring until the reaction was complete, as shown by TLC analysis. Solvent was distilled from the reaction mixture under a reduced pressure. Sodium hydroxide (3 grams) in water (30 ml) was added followed by water (100 ml) and the mixture was stirred for 30 minutes. The aqueous layer was washed with toluene (3 X 15 ml) at a temperature of 10-15°C, then the aqueous layer was separated and its pH was adjusted to 5 using dilute acetic acid. Upon stirring for 1-2 hours at a temperature of 25-35°C the produced solid mass was filtered and washed with water (25 ml) to afford the desired compound. (Yield: 1.3 grams, 22%).
  • 6
  • [ 138402-11-6 ]
  • 4-{4-oxo-3-[2'-(1<i>H</i>-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-spiro[4.4]non-1-en-2-yl}-butyric acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium iodate; potassium iodide In water; dimethyl sulfoxide at 30℃;
  • 7
  • [ 329055-24-5 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
In ethanol; dichloromethane; water Heating / reflux; 2 Example 2.To a solution of compound 1 (13.93 g) in the 240 ml mixture of ethanol/water (2:1 ), 7.0 ml of cone. (45%) HBr was added and stirred at r.t. for 3 hours. Suspension was filtered and filtrate concentrated in vacuo to remove ethanol. Concentrate was stirred at r.t. for 2h, to form white precipitate which was collected by filtration and recrystallized from acetone. Crystalline product was dissolved in 120 ml mixture of hot ethanol/water (2:1 ) and 150 ml of CH2CI2. Diphase system was stirred vigorously while heating to reflux temperature, then solution of 1 .46g NaHCO3 in 70 ml water was added. Phases were separated, water solution was extracted with hot CH2CI2 (2x150 ml), organic phases were collected and concentrated. Oily residue was dissolved in 60 ml of boiling ethanol, and then left to crystallize. Crystalline product was then filtered and dried to give 5.42g of irbesartan (99.83 area%; assay: 99.7%).
  • 8
  • [ 852357-70-1 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-butyl-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl}-1,3-diaza-spiro[4.4]non-1-en-4-one With hydrogenchloride; water In toluene at 15 - 20℃; for 4h; Stage #2: With sodium acetate In water 5 Removal of the Protecting Group from a Compound (VI) EXAMPLE 5 Removal of the Protecting Group from a Compound (VI) 124 g (0.228 moles) of 2-butyl-3-{2'-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-biphenyl-4-ylmethyl }-1,3-diaza-spiro[4.4]non-1-en-4-one are dissolved in 500 ml of toluene and 900 ml of 37% aqueous hydrochloric acid are added thereto under stirring at a temperature of 15-20° C. The mixture is stirred for a further 4h, then the aqueous phase is separated and washed twice with 250 ml of toluene. The aqueous phase is poured into a solution of 125 g of sodium acetate in water, the formed precipitate is filtered, thoroughly washed with water and dried under vacuum at 70° C., thereby obtaining 77 g of irbesartan. NMR: 1H (DMSO, 300 mHz): δ0.80 (3H, t,); 1.26-(2H, m), 1.46 (2H, m); 1.65-1.84 (8H, m); 2.29 (2H, t); 4.67 (2H, s); 7.08 (4H,s); 7.60 (4H, m).
  • 9
  • [ 1310-73-2 ]
  • [ 138402-11-6 ]
  • irbesartan sodium [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% In ipa at 60℃; for 2.5h; Heating / reflux; 2 EXAMPLE 2; Preparation of Amorphous Irbesartan Na from Irbesartan by using SodiumHydroxide; A 100 mL flask was charged with 5.0 g Irbesartan and 20 niL IPA. In another flask 0.47g (leq) NaOH was dissolved in 30 mL IPA at 60 0C. This solution was added to the Irbesartan solution dropwise. The reaction mixture was refluxed for 1.5 h. The mixture was concentrated to 30 mL under reduced pressure. The reaction mixture was refluxed again for 1 h and let to cool to room temperature. 100 mL of tert- butylmethyleter was added to the mixture and it was concentrated to 20 mL. 100 mL of heptane was added and the reaction mixture was heated to 55-60 0C. To precipitate Irbesartan Na the mixture was concentrated under reduced pressure. The mixture was stirred for 1 hour, filtered and washed with heptane. After drying amorphous Irbesartan Na (3.5g) was obtained as a white solid (66 % yield).
In water 1; 2 42.8 g of irbesartan are dissolved in a solution prepared from 4 g of sodium hydroxide in 430 ml of water. This solution is poured into a solution prepared from 11.1 g of calcium chloride in 500 ml of water. The reaction medium thus obtained is heated at 50° C. for 4 hours and is then allowed to return to ambient temperature. The salt obtained is filtered off, rinsed 3 times with 100 ml of water and then dried under vacuum at 50° C. to constant weight. 47.1 g of the expected salt are obtained. The purity of the product is determined by HPLC to be 99.6%. The analysis of the NMR (nuclear magnetic resonance) spectrum shows the absence of the peak corresponding to the proton of the tetrazole, the said peak being present in the NMR spectrum of the non-salified irbesartan. The percentage analysis gives the following result: C25H27N6O.0.5Ca.4H2O The irbesartan content of the irbesartan salt, determined by HPLC, is 81.34% (theoretical: 82.26%). The calcium content, determined by ionic HPLC, is 3.86% (theoretical: 3.90%). Potentiometry shows 2 jumps equivalent to 40.83% and 39.04%; these jumps correspond to the theoretical expected value (82.26% in total). Potentiometry makes it possible to quantify, by titrating the 2 basic functional groups of the said salt with perchloric acid, the amount of irbesartan present in the irbesartan salt. The water content of the salt obtained is measured by the Karl-Fischer method (15.4%, i.e. 4H2O) and by thermogravimetric analysis: thermogravimetric analysis makes it possible to measure the loss in weight at 100° C., that is to say the loss of water by weight: 12.96% i.e. 4 mol of water per mole of product.; 42.8 g of irbesartan are dissolved in a solution prepared from 4 g of sodium hydroxide in 430 ml of water. This solution is poured into a solution prepared from 9.52 g of magnesium chloride in 500 g of water. The reaction medium thus obtained is heated at 50° C. for 4 hours and is then allowed to return to ambient temperature. The salt obtained is filtered off, rinsed 3 times with 100 ml of water and then dried under vacuum at 50° C. to constant weight. 47.5 g of the expected salt are obtained. The purity of the product is determined by HPLC to be 99.6%. The analysis of the NMR (nuclear magnetic resonance) spectrum shows the absence of the peak corresponding to the proton of the tetrazole; The percentage analysis gives the following result: C25H27N6O.0.5Mg.4H2O; The irbesartan content of the salt, determined by HPLC, is 82.39% (theoretical: 83.50%). The magnesium content, determined by ionic HPLC, is 2.35% (theoretical: 2.87%). Potentiometry shows 2 jumps equivalent to 41.29% and 88.12%. The water content of the salt obtained is measured by Karl-Fischer (15.86%, i.e. 4H2O) and thermogravimetric analysis: 12.26%, i.e. 4 mol of water per mole of product. The powder X-ray diffractogram recorded for the salt obtained is given in FIG. 2.
  • 10
  • [ 1310-58-3 ]
  • [ 138402-11-6 ]
  • irbesartan potassium [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In ipa at 50℃; for 1.58333h; Heating / reflux; 3 EXAMPLE 3; Preparation of Amorphous Irbesartan K from Irbesartan by using PotassiumHydroxide; A 100 mL flask was charged with 5.0 g Irbesartan and 30 mL IPA. In another flask0.65 g (leq) KOH was dissolved in 20 mL IPA at 50 0C. This solution was added to the Irbesartan solution dropwise in 5 min. The mixture was refluxed for 1.5 h. The mixture was concentrated under reduced pressure. 100 mL of tert-butylmethyleter was added and the solution was again concentrated under reduced pressure. 100 mL of n-heptane was then added to the solution. To precipitate Irbesartan K the mixture was concentrated under reduced pressure. The mixture was stirred for 1 hour, filtered and washed with heptane. After drying amorphous Irbesartan K was obtained (4.7g) as a white solid (86 % yield).
51.4% In ipa at 50℃; for 1.5h; Heating / reflux; 4 EXAMPLE 4; Preparation of Crystalline Irbesartan K from Irbesartan by using PotassiumHydroxide; A 100 mL flask was charged with 30.0 g Irbesartan and 100 mL IPA. In another flask 3.92 g (leq) KOH was dissolved in 200 mL IPA at 50 0C. This solution was added slowly to the Irbesartan solution. The mixture was refluxed for 1.5 h. The mixture was concentrated under reduced pressure. 200 mL of tert-butyl methyl ether was added and the solution was concentrated under reduced pressure. The mixture was stirred for 4 hours and then filtered. After drying crystalline Irbesartan K (Form Ul) was obtained (16.4 g) as a white solid (51.4 % yield).
  • 11
  • [ 144625-34-3 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
80% With sodium azide; tributyltin chloride; N,N-dimethyl-formamide In o-xylene at 150 - 155℃; for 40h;
77% Stage #1: 1-[(2'-carboxamidobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one With sodium azide; tributyltin chloride In o-xylene at 25℃; Heating / reflux; Stage #2: With hydrogenchloride In dichloromethane; o-xylene; water at 20 - 25℃; for 2.25h; Stage #3: With ammonia In dichloromethane; o-xylene; water at 20 - 25℃; for 2h; V EXAMPLE V:; Preparation of Irbesartan (I); l-[2'-Carboxamidobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2- imidazolin-5-one (XV) (5 g, 0.0124 mole) was added to a mixture of tributyl tin chloride (8.48 g, 0.026 mole) and o-xylene (5 ml) at 25-300C. Sodium azide (1.69 g, 0.026 mole) was added to the above suspension and heated to reflux. Thereafter, reflux was continued till completion of the reaction. The reaction mass was cooled to 20-250C and o-xylene (10 ml), water (60 ml) were added followed by the addition of methylene chloride (60 ml) at 20-25°C. Hydrochloric acid (3 ml, 35% w/w) was added in 15 min at 20-25°C and continued the stirring for 2 h at the same temperature. Thereafter, pH was adjusted to 4.5-4.8 with aqueous ammonia solution at 20-250C and continued the stirring for 2 h. Product was filtered, washed with a 1:3 v/v mixture of o-xylene and methylene chloride (10 ml). Product was dried at 70-75°C under reduced pressure (10 mm Hg). The dried product was suspended in water (50 ml), heated to 5O0C and stirred for 30 min at 45-50°C. Product was filtered, washed with water (50 ml) and dried to afford Irbesartan as a white solid. (4.1 g, 77% yield).
  • 12
  • [ 945540-18-1 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
88.5% Stage #1: 4-[(α-N-pentanoylamino)cyclopentamidomethyl]-2'-carboxamidobiphenyl With sodium azide; tributyltin chloride; N,N-dimethyl-formamide In o-xylene at 15 - 155℃; for 1h; Stage #2: With hydrogenchloride In dichloromethane; o-xylene; water at 20 - 25℃; for 1.5h; I.IV Stage IV: Preparation of 2-buty-3-[p-(o-lH-tetrazol-5-ylphenyI)benzyl]-l,3- diazaspiro [4.4] non-l-en-4-one (Irbesartan); Tributyltin chloride (47.80 g, 0.147 mole) and sodium azide (9.57 g, 0.147 mole) were stirred for 30 min at 15-30°C. N,N-Dimethylformamide (6.90 g, 0.095 mole) was added and stirred for 30 min. Thereafter, 4-[(α-N- pentanoylaminocyclopentamidomethyl]-2'-carboxamidobiphenyl (XFV) (20 g, 0.0475 mole) was added followed by o-xylene (20 ml). The reaction mass was heated to 150-155°C and stirred for completion of the reaction. The reaction mixture was cooled to 20°C, o-xylene (40 ml), methylene chloride (40 ml) were added followed by water (40 ml). Hydrochloric acid (4.95 g, 35 % w/w) was added at 20- 250C slowly in 30 min and the slurry obtained was stirred for 60 min. The solid was filtered, washed with 1 : 1 v/v mixture of o-xylene and methylene chloride (40 ml) and dried to get the crude Irbesartan as a pale yellow powder (18 g, 88.5 % yield).
65% With sodium azide; tributyltin chloride; N,N-dimethyl-formamide for 50h;
Multi-step reaction with 2 steps 1: 65 percent / trifluoroacetic acid / o-xylene / 17 h / Heating 2: 80 percent / sodium azide; tributyltin chloride; DMF / o-xylene / 40 h / 150 - 155 °C
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 1.2: 0.17 h / 25 - 30 °C / pH 9 2.1: sodium azide; tributyltin chloride / o-xylene / 25 °C / Heating / reflux 2.2: 2.25 h / 20 - 25 °C 2.3: 2 h / 20 - 25 °C / pH 4.5 - 4.8
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 1.2: 0.17 h / 25 - 30 °C / pH 9 2.1: pyridine; p-toluenesulfonyl chloride / 1 h / 70 - 75 °C 3.1: sodium azide; tributyltin chloride / o-xylene / 60 h / 25 - 137 °C 3.2: 1 h / 10 - 15 °C / pH 11.5 - 12 3.3: 10 - 30 °C / pH 4.6 - 4.8

  • 13
  • [ 141745-71-3 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
90% Stage #1: 1-pentanoylamino-cyclopentanecarboxylic acid (2'-cyano-biphenyl-4-ylmethyl)-amide With sodium azide; tributyltin chloride; N,N-dimethyl-formamide In o-xylene at 15 - 155℃; for 1h; Stage #2: With hydrogenchloride In dichloromethane; o-xylene; water at 20℃; for 1h; VI EXAMPLE VI:; Preparation of 2-butyl-3-[p-(o-lH-tetrazol-5-yIphenyl)benzyl]-l,3- diazaspiro[4.4]non-l-en-4-one (Irbesartan); Tributyltin chloride (12.11 g, 0.037 mole) and sodium azide (2.42 g, 0.037 mole) were stirred for 30 min at 15-3O0C. N,N-Dimethylformamide (2.00 g, 0.027 mole) was added and stirred for 30 min. Thereafter, 4-[α-N- pentanoylamino)cyclopentamidomethyl]-2'-cyanobiphenyl (XII) (10 g, 0.0248 mole) was added followed by o-xylene (10 ml). The reaction mass was heated to 150-1550C and stirred for completion of the reaction. The reaction mixture was cooled to 200C, and a mixture of o-xylene (20 ml), methylene chloride (60 ml) and water (40 ml) were added. Thereafter hydrochloric acid was added to precipitate the solid and stirred for 1 hr. The solid obtained was filtered, washed with 1:1 v/v mixture of o-xylene and methylene chloride (20 ml) and dried to get the crude Irbesartan as pale yellow powder (9.55 g, 90 % yield).
71% With sodium azide; tributyltin chloride; N,N-dimethyl-formamide In o-xylene at 150 - 155℃; for 20h;
Multi-step reaction with 2 steps 1: 81 percent / trifluoro acetic acid / toluene / Heating 2: 95 percent / tributyl tin chloride; sodium azide / o-xylene / Heating
  • 14
  • [ 194984-24-2 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 654 g / aq. hydrochloric acid / 2 h / 55 - 60 °C 2: 93 percent / dicyclohexylcarbodiimide; 1-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 7 h / 38 - 41 °C 3: 71 percent / sodium azide; tributyltin chloride; N,N-dimethylformamide / o-xylene / 20 h / 150 - 155 °C
  • 15
  • [ 15026-80-9 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 93 percent / dicyclohexylcarbodiimide; 1-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 7 h / 38 - 41 °C 2: 71 percent / sodium azide; tributyltin chloride; N,N-dimethylformamide / o-xylene / 20 h / 150 - 155 °C
Multi-step reaction with 3 steps 1: 90 percent / dicyclohexylcarbodiimide; N-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 4.5 h / Heating 2: 65 percent / trifluoroacetic acid / o-xylene / 17 h / Heating 3: 80 percent / sodium azide; tributyltin chloride; DMF / o-xylene / 40 h / 150 - 155 °C
Multi-step reaction with 2 steps 1: 90 percent / dicyclohexylcarbodiimide; N-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 4.5 h / Heating 2: 65 percent / sodium azide; tributyltin chloride; DMF / 50 h
Multi-step reaction with 3 steps 1: 96 percent / 1-hydroxybenzotriazole; dicyclohexyl carbodiimide / CH2Cl2 / 25 - 35 °C 2: 81 percent / trifluoro acetic acid / toluene / Heating 3: 95 percent / tributyl tin chloride; sodium azide / o-xylene / Heating
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / acetone / 24 h / 25 - 32 °C 2.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 2.2: 1.5 h / 20 - 25 °C
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / acetone / 24 h / 25 - 32 °C 2.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 2.2: 0.17 h / 25 - 30 °C / pH 9 3.1: sodium azide; tributyltin chloride / o-xylene / 25 °C / Heating / reflux 3.2: 2.25 h / 20 - 25 °C 3.3: 2 h / 20 - 25 °C / pH 4.5 - 4.8
Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / acetone / 24 h / 25 - 32 °C 2.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 2.2: 0.17 h / 25 - 30 °C / pH 9 3.1: pyridine; p-toluenesulfonyl chloride / 1 h / 70 - 75 °C 4.1: sodium azide; tributyltin chloride / o-xylene / 60 h / 25 - 137 °C 4.2: 1 h / 10 - 15 °C / pH 11.5 - 12 4.3: 10 - 30 °C / pH 4.6 - 4.8

  • 16
  • [ 638-29-9 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / CH2Cl2 / 2.67 h / 0 - 5 °C 2: 654 g / aq. hydrochloric acid / 2 h / 55 - 60 °C 3: 93 percent / dicyclohexylcarbodiimide; 1-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 7 h / 38 - 41 °C 4: 71 percent / sodium azide; tributyltin chloride; N,N-dimethylformamide / o-xylene / 20 h / 150 - 155 °C
Multi-step reaction with 4 steps 1: 82 percent / sodium hydroxide / H2O; toluene / 2 h / 0 - 10 °C 2: 96 percent / 1-hydroxybenzotriazole; dicyclohexyl carbodiimide / CH2Cl2 / 25 - 35 °C 3: 81 percent / trifluoro acetic acid / toluene / Heating 4: 95 percent / tributyl tin chloride; sodium azide / o-xylene / Heating
  • 17
  • 1-aminocyclopentanecarbonitrile hydrochloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / CH2Cl2 / 2.67 h / 0 - 5 °C 2: 654 g / aq. hydrochloric acid / 2 h / 55 - 60 °C 3: 93 percent / dicyclohexylcarbodiimide; 1-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 7 h / 38 - 41 °C 4: 71 percent / sodium azide; tributyltin chloride; N,N-dimethylformamide / o-xylene / 20 h / 150 - 155 °C
  • 18
  • 2-(4-aminomethylphenyl)benzamide hydrochloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 90 percent / dicyclohexylcarbodiimide; N-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 4.5 h / Heating 2: 65 percent / trifluoroacetic acid / o-xylene / 17 h / Heating 3: 80 percent / sodium azide; tributyltin chloride; DMF / o-xylene / 40 h / 150 - 155 °C
Multi-step reaction with 2 steps 1: 90 percent / dicyclohexylcarbodiimide; N-hydroxybenzotriazole; diisopropylethylamine / CH2Cl2 / 4.5 h / Heating 2: 65 percent / sodium azide; tributyltin chloride; DMF / 50 h
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 2.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 2.2: 1.5 h / 20 - 25 °C
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 2.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 2.2: 0.17 h / 25 - 30 °C / pH 9 3.1: sodium azide; tributyltin chloride / o-xylene / 25 °C / Heating / reflux 3.2: 2.25 h / 20 - 25 °C 3.3: 2 h / 20 - 25 °C / pH 4.5 - 4.8
Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 2.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 2.2: 0.17 h / 25 - 30 °C / pH 9 3.1: pyridine; p-toluenesulfonyl chloride / 1 h / 70 - 75 °C 4.1: sodium azide; tributyltin chloride / o-xylene / 60 h / 25 - 137 °C 4.2: 1 h / 10 - 15 °C / pH 11.5 - 12 4.3: 10 - 30 °C / pH 4.6 - 4.8

  • 19
  • [ 133690-92-3 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 96 percent / 1-hydroxybenzotriazole; dicyclohexyl carbodiimide / CH2Cl2 / 25 - 35 °C 2: 81 percent / trifluoro acetic acid / toluene / Heating 3: 95 percent / tributyl tin chloride; sodium azide / o-xylene / Heating
Multi-step reaction with 2 steps 1.1: triphenyl phosphate / pyridine / 0.17 h / 150 °C / microwave irradiation 1.2: 75 percent / pyridine / 0.17 h / 250 °C / 7500.6 Torr / microwave irradiation 2.1: 73 percent / tri-n-butyltin chloride; sodium azide; tetrabutylammonium bromide / dimethylformamide / 1 h / 220 °C / 6000.48 Torr / microwave irradiation
Multi-step reaction with 3 steps 1.1: potassium hydroxide; <i>tert</i>-butyl alcohol / 70 - 75 °C 1.2: 1 h / 2 - 5 °C / pH 1.2 - 1.4 2.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 3.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 3.2: 1.5 h / 20 - 25 °C
Multi-step reaction with 4 steps 1.1: potassium hydroxide; <i>tert</i>-butyl alcohol / 70 - 75 °C 1.2: 1 h / 2 - 5 °C / pH 1.2 - 1.4 2.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 3.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 3.2: 0.17 h / 25 - 30 °C / pH 9 4.1: sodium azide; tributyltin chloride / o-xylene / 25 °C / Heating / reflux 4.2: 2.25 h / 20 - 25 °C 4.3: 2 h / 20 - 25 °C / pH 4.5 - 4.8
Multi-step reaction with 5 steps 1.1: potassium hydroxide; <i>tert</i>-butyl alcohol / 70 - 75 °C 1.2: 1 h / 2 - 5 °C / pH 1.2 - 1.4 2.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 3.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 3.2: 0.17 h / 25 - 30 °C / pH 9 4.1: pyridine; p-toluenesulfonyl chloride / 1 h / 70 - 75 °C 5.1: sodium azide; tributyltin chloride / o-xylene / 60 h / 25 - 137 °C 5.2: 1 h / 10 - 15 °C / pH 11.5 - 12 5.3: 10 - 30 °C / pH 4.6 - 4.8

  • 20
  • [ 52-52-8 ]
  • [ 138402-11-6 ]
  • 21
  • (2'-cyano-biphenyl-4-ylmethyl)-carbamic acid tert-butyl ester [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 71 percent / triphenyl phosphate / pyridine / 0.17 h / 250 °C / 11250.9 Torr 2: 73 percent / tri-n-butyltin chloride; sodium azide; tetrabutylammonium bromide / dimethylformamide / 1 h / 220 °C / 6000.48 Torr / microwave irradiation
  • 23
  • [ 109-52-4 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: triphenyl phosphate / pyridine / 0.17 h / 150 °C / microwave irradiation 1.2: 75 percent / pyridine / 0.17 h / 250 °C / 7500.6 Torr / microwave irradiation 2.1: 73 percent / tri-n-butyltin chloride; sodium azide; tetrabutylammonium bromide / dimethylformamide / 1 h / 220 °C / 6000.48 Torr / microwave irradiation
  • 24
  • [ 589-15-1 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 94.6 percent / K2CO3 / dimethylformamide / 8 h / 25 - 35 °C 2: 84 percent / potassium hydroxide; Pd(PPh3)4 / methanol / 10 h / Heating
  • 25
  • 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 94.6 percent / K2CO3 / dimethylformamide / 8 h / 25 - 35 °C 2: 84 percent / potassium hydroxide; Pd(PPh3)4 / methanol / 10 h / Heating
  • 26
  • [ 138402-11-6 ]
  • (2S,3S,4S,5R,6R)-6-{5-[4'-(2-Butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-ylmethyl)-biphenyl-2-yl]-tetrazol-1-yl}-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 30 percent / Ag2CO3 / toluene / 18 h / 100 °C / protection from light 2: 100 percent / aq. H2O2, LiOH / tetrahydrofuran
  • 27
  • [ 138402-11-6 ]
  • (2S,3S,4S,5R,6R)-6-{5-[4'-(2-Butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-ylmethyl)-biphenyl-2-yl]-tetrazol-2-yl}-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 59 percent / Ag2CO3 / toluene / 18 h / 100 °C / protection from light 2: 100 percent / aq. H2O2, LiOH / tetrahydrofuran
  • 28
  • [ 1664-35-3 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 96 percent / AcOH / xylene / 6.5 h / Heating 2: 1.) NaH / 1.) DMF, RT, 0.5 h, 2.) DMF, RT, 1 h 3: 68 percent / Bu3SnN3 / xylene / 88 h / Heating
  • 29
  • [ 114772-54-2 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1.) NaH / 1.) DMF, RT, 0.5 h, 2.) DMF, RT, 1 h 2: 68 percent / Bu3SnN3 / xylene / 88 h / Heating
  • 30
  • [ 138402-05-8 ]
  • [ 138402-11-6 ]
  • 31
  • [ 999-09-7 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 96 percent / AcOH / xylene / 6.5 h / Heating 2: 1.) NaH / 1.) DMF, RT, 0.5 h, 2.) DMF, RT, 1 h 3: 68 percent / Bu3SnN3 / xylene / 88 h / Heating
  • 32
  • [ 138402-10-5 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
98.75% Stage #1: trityl irbesartan With hydrogenchloride In water; acetone at 35 - 45℃; for 1.5 - 2h; Stage #2: In water; acetone at 15℃; Alkaline aqueous solution; 17 Example 17: Preparation of 2-butyl-3r2'-(lH-tetrazol-5-ylVbiphenyl-4-yl methyll-1.3- diazaspiro [4, 4]non-l-ene-4-one (irbesartan); [0066] A mixture of Trityl Irbesartan (60.0 g) in acetone (360.0 ml) and concentrated hydrochloric acid (30.8 g) was stirred in D.M. water (96.0 ml) for 1.5 to 2 hrs at 35-45°C. The progress of the reaction was monitored by TLC.[0067] The reaction mixture was cooled to 20- 25°C by adding D.M. water (120.0 ml). The acetone was completely distilled off under vacuum and again D.M. water was added (240.0 ml). The cooled reaction mixture was basified with drop wise addition of alkali (30.0 g) solution by maintaining pH 11-13 at a temperature below 15°C. The reaction mixture was extracted with ethyl acetate (390.0 ml) at less than 15°C. The layer was adjusted to pH 3-4 at below 5°C. The isolated compound was filtered and washed with D.M. water (120.0x2 ml) and ethanol (60.0 ml). The material was unloaded and purified in ethanol. The product was dried under reduced pressure of about 500-760 mm Hg at 70-800C. [Yield: 33.0 g; Purity: 98.75 % area by HPLC]
93% With sulfuric acid In water; acetone at 35 - 40℃; for 7h; 2 Example 2: A solution [OF H2SO4] (98 %, 22.6 g, 12.3 mL, 0.225 mol, 1.5 [EQ)] in water (160 mL) was added to a suspension of IRB-03 (100.6 g, 0.150 mol) in acetone (600 mL) at 35-40 [°C] and stirred for 7 h (suspension disappeared; TLC monitoring-Hexane/EtOAc = 1 : 1). Acetone was evaporated from the reaction mixture under reduced pressure at [30-40 °C.] Water (500 mL) was added to the resulting suspension. The resulting mixture was vigorously stirred and cooled to [0-5 °C.] A solution of KOH (85 %, 39.6 g, 0.600 mol, 4 eq) in water (100 mL) was slowly added keeping the reaction temperature below [15 °C] and the mixture was stirred for 30 min until a stable pH (9-10) was obtained. Then, a second portion of KOH (3.0 g, 50 mmol, 0.3 eq) in water (10 mL) was added and the reaction was stirred for additional 30 min at [5-10 °C] (pH 10.5-11. 5). The precipitate (triphenyl methanol) was filtered, washed with water (2 x 100 mL) and dried under reduced pressure (10 [MMHG)] at 50 °C to give 36.5 g (about 95 % yield) of triphenyl methanol. The aqueous filtrate was extracted with ethyl acetate (300 mL), cooled to [10 °C] and acidified to pH 2.0-3. 5 with slow addition of 20 % aqueous [H2S04.] The resulting suspension was stirred at [0-4 °C] for an additional 30 min and filtered. The filter cake was washed twice with water (2 x 100 mL), then with EtOAc (100 mL) and dried under reduced pressure for 3 h at [50 °C] afforded 60.0 g (93 % yield) of crude Irbesartan. The crude product (60.0 g) was refluxed in 95 % aqueous ethanol (600 mL) for 1 h (clear solution was formed) and allowed to cool to room temperature with vigorous stirring. The mixture was stirred for an additional 2 h at [0-5 °C,] filtered, and washed with cold 95 % aqueous ethanol (100 mL). The collected solid was dried under reduced pressure (3 h, 50 [°C,] 10 mmHg) afforded [56.] 0 g (93 % yield), of a white powder.
87% With sodium hydroxide In methanol at 20℃;
86% With formic acid In methanol at 25 - 30℃; for 4h; 1 To 2-n-butyl-3- [ [2'- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl]methyl]-1, 3-diazaspiro- [4. 4]non-1-ene-4-one (25 gm) of Formula II (A) was added methanol (65 ml) and formic acid (16 gm). The resultant solution was stirred at25-30 C for 4 hours. After completion of the reaction, ethyl acetate (100 ml) and water (100 ml) were added and stirred for 30 minutes. The Layers were separated and the ethyl acetate layer was washed twice with sodium carbonate solution (10%, 50 ml). The ethyl acetate was concentrated under vacuum to get a residue, which was then dissolved in a mixture of water (250 ml) and 1N sodium hydroxide solution (100 ml). The aqueous phase was washed with ethyl acetate (2 x 100 ml). To the resulting aqueous phase was added 6NHC1 slowly to adjust the pH of the solution to about 4.8-5. 3. After stirring at room temperature for 30 min, the crystals were filtered, washed with water (200 ml) and dried at50 C to afford the compound of Formula Ia in 99.7% purity (24 g), which was optionally purified. To this was added ethanol (96%, 250 ml) and the resulting mixture was heated to reflux until the product completely dissolved. The mixture was cooled to15 C and stirred at15-20 C for 30 min. The separated crystals were filtered and washed with 96% ethanol and dried at50 C under reduced pressure to get Irbesartan of Formula I (A). Yield: 23 g(86%), HPLC Purity: 99.95%.
86% Stage #1: trityl irbesartan With formic acid In methanol at 25 - 30℃; for 4h; Stage #2: With sodium carbonate In water; ethyl acetate 2.B Methanol (65 ml) and formic acid (16 gm) was added to the crude residueiobtained in Example 2 step A). The resultant solution was stirred at 25-30°C for 4hours. After completion of the reaction, ethyl acetate (100 ml) and water (100 ml)were added and stirred for 30 minutes. The resulting layers were separated and theethyl acetate layer was washed with sodium carbonate solution twice (10%, 50 ml).The ethyl acetate was concentrated under vacuum to get the residue, which was thendissolved in a mixture of water (250 ml) and IN sodium hydroxide solution (100 ml).iThe aqueous phase was washed with ethyl acetate (2 x 100 ml). To the resultingaqueous phase was added 6N HC1 slowly to adjust the pH of the solution to about 4.8- 5.3. After stirring at room temperature for 30 min, the crystals were filtered, washedwith water (200 ml) and dried at 50°C to yield the compound of Formula I in 99.7%purity (24 g) which was purified, although the purification is optional.To this purified compound ethanol (96%, 250 ml) was added and the resultingmixture was heated to reflux until the product completely dissolves. The mixture wascooled to 15°C and stirred at 15 - 20°C for 30 min. The separated crystals werefiltered and washed with 96% ethanol and dried at 50°C under reduced pressure toyield Irbesartan.Yield: 23 g (86%)HPLC Purity: 99.95%.
81% Stage #1: trityl irbesartan With hydrogenchloride In water; acetone at 20℃; Stage #2: With sodium hydroxide In water A A 2 M HCI solution (4 ml) was added to a solution of 2-butyl-3-[2'-(1 -trityl-1 /-/-tetrazol-5-yl)- biphenyl-4-ylrnethyl]-1 ,3-diazaspiro[4.4]non-1-en-4-one (0.50 g, 0.75 mmol) in acetone (20 ml) at room temperature. The mixture was stirred for 4 hours at the same temperature. The volume of the solvent was then reduced to 20 % and a 1 M HCI solution (20 ml) was added dropwise over 1 hour. The precipitated solid was filtered off and the pH of filtrate was adjusted to 2.5 - 3.0 with a 1 M NaOH solution. The mixture was extracted with ethyl acetate (3 - 20 ml). The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure to yield 0.26 g (81 %) of 2-butyl-3-[[2'-1 H-tetrazol- δ-ylti .i '-biphenyl^-yllmethylJ-I .S-diazaspiro^^lnon-i-en^-one (lrbesartan) as a white solid.M.p.: 181 - 184 0C. 1H NMR (CDCI3): δ = 0.83 (t, 3H, CH3, J = 7.3 Hz)1 1.2-1.3 (m, 2H1 CH2), 1.5-1.6 (m, 2H, CH2), 1.7-1.8 (m, 8H, CH2), 2.2-2.3 (m, 2H, CH2), 4.66 (s, 2H, CH2), 7.07 (d, 2H, CH, J = 8.3 Hz), 7.17 (d, 2H, CH1 J = 8.3 Hz), 7.5-7.6 (m, 3H, CH)1 7.8-7.9 (m, 1H, CH) ppm. 13C NMR (CDCI3): δ = 13.8, 22.5, 26.2, 28.0, 28.7, 37.6, 43.5, 82.2, 123.6, 127.0, 128.5, 130.0, 130.9, 131.1 , 131.4, 136.2, 139.5, 140.9, 155.9, 162.9, 186.6 ppm. HR-MS: 429.2404 (MH+, calc. for C25H29N6O+ : 429.2403).
75% Stage #1: trityl irbesartan With hydrogenchloride; methanol In tetrahydrofuran at 0 - 20℃; Stage #2: With sodium hydroxide In water; toluene Stage #3: With hydrogenchloride In water 8 2-(n-Butyl)-3-[2'(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-4-oxo-1,3 diazaspiro [4.4] non-1-ene-4-one of formula (VIb, where A is triphenylmethyl protected tetrazolyl group) obtained in above step was treated with 5 N HCl in methanol and tetrahydrofuran at 0-5° C. and then stirred at ambient temperature for overnight. After completion of reaction tetrahydrofuran and methanol was distilled out under vacuum. The residue was partitioned between toluene and IN sodium hydroxide. Two phases were separated and aqueous phase was washed with isopropyl ether. The aqueous phase was adjusted to pH 4.6 by 3N hydrochloric acid. The product was filtered and washed with water and dried in air to get Irbesartan. (Yield: 75%) 1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50-7.68 (m, 4H) M+: 429.6
75% Stage #1: trityl irbesartan With hydrogenchloride; methanol In tetrahydrofuran at 0 - 20℃; Stage #2: With sodium hydroxide In water; toluene Stage #3: With hydrogenchloride; water 8 2-(n-Butyl)-3-[2'(l-triphenylmethyl-lH-tetrazol-5-yl)biρhenyl-4-ylmethyl]-4-oxo-l,3 diazaspiro [4.4] non-l-ene-4-one of formula (VIIb, where A is triphenylmethyl protected tetrazolyl group) obtained in above step was treated with 5 N HCl in methanol and tetrahydrofuran at 0-50C and then stirred at ambient temperature for overnight. After completion of reaction tetrahydrofuran and methanol was distilled out under vacuum. The residue was partitioned between toluene and IN sodium hydroxide. Two phases were separated and aqueous phase was washed with isopropyl ether. The aqueous phase was adjusted to pH 4.6 by 3N hydrochloric acid. The product was filtered and washed with water and dried in air to get Irbesartan. (Yield: 75%)1H-NMR (DMSO d6): δppm 0.78 (t, 3H); 1.17-1.30 (sex, 2H); 1.40-1.50 (quent, 2H); 1.64-1.66 (m, 2H); 1.80-1.82 (m, 6H); 2.22-2.29 (t, 2H); 4.67 (s, 2H); 7.07 (s, 4H); 7.50- 7.68 (m, 4H) M+: 429.6
67.8% Stage #1: trityl irbesartan In methanol at 60 - 65℃; for 2h; Stage #2: With triethylamine In methanol at 0℃; for 1h; 3 A reaction vessel equipped with a reflux condenser was charged with 3 1 methanol and 138 g hydroxylammonium chloride. The mixture was stirred at room temperature for half an hour and then heated at 40 C for a further half hour. To this solution, 600 g trityl-protected Irbesartan were added in portions. After all trityl-protected Irbesartan had been added, the reaction mixture was heated to 60 to 65 C and stirred for 2 hours at this temperature. The obtained slightly yellow solution was analyzed by HPLC and it was found that 99.4 % of the trityl- protected Irbesartan had been consumed. The mixture was cooled to 40 C. The pH of the solution was measured as 3.1 and 42 ml of triethylamine were added to bring the pH to 4.55. The reaction mixture was cooled to 0 0C and stirred for 1 hour to precipitate the formed trityl methanol resulting in a slurry. The slurry was filtered and the obtained filter cake was sucked to dryness and washed with 100 ml cold methanol.The methanol was removed from the filtrate under reduced pressure. 1.2 l ethyl acetate were added to the obtained residue and the resulting slurry was aged under agitation for 3 hours at room temperature followed by a filtration. 590 g wet Irbesartan were recovered and dried at 60 C to constant weight to yield 260 g dry Irbesartan (67.8 % yield).
62% With hydrogenchloride In 1,4-dioxane; water at 20℃; 23 Example 23 A mixture of 2-n-Butyl-3-[{2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1,1'-biphenyl-4-yl}methyl]-1,3-diazaspiro[4.4]non-1-ene-4-one (139 mg) and 1,4-dioxane (1.7 mL), water (0.3 mL) and 4 N HCl (0.21 mL) was stirred at room temperature overnight. Water (72 mL) was added and the product was extracted with ethyl acetate (72 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was treated with diethyl ether and filtered. The solid was washed with cold diethyl ether and dried to obtain 2-n-butyl-3-[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl]methyl}-1,3-diazaspiro[4.4]non-1-ene-4-one (56 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.4 Hz, 3 H, CH3), 1.34 (qn, J = 7.6 Hz, 2 H, CH3-CH2-CH2-), 1.57 (t, J = 7.6 Hz, 2 H, CH2-CH2-CH2-), 1.83 (m, 2 H, CH2), 1.97 (m, 6 H, CH2), 2.91 (bs, 2 H, CH2-CH2-C-), 4.69 (s, 2 H, Ph-CH2-N-), 7.08 (d, J = 8 Hz, 2 H, H-Ar), 7.15 (d, J = 8.4 Hz, 2 H, H-Ar), 7.47 (d, J = 7.6 Hz, 1 H, H-Ar), 7.52 (td, J = 8.8 and 1.2Hz, 1 H, H-Ar), 7.61 (td, J = 7.6 and 1.2Hz, 1 H, H-Ar), 7.82 (dd, J = 7.6 and 0.8 Hz, 1 H, H-Ar) ppm. 13C NMR (100 MHz, CDCl3) 13.3 (CH3), 21.9 (CH2), 25.8 (CH2), 27.3 (CH2), 37.2 (CH2), 43.2 (CH2), 76.1 (C), 126.5, 129.5, 127.6, 127.8, 127.9, 130.5, 130.6, 131, 135.4, 138.9, 140.9, 155.4 and 162.9 (CH-Ar and C-ipso-Ar), 186.5 (CO).IR (υ): 3450 (NH), 1733 (C=O) cm-1. MS-ES (+): 671 (M++1).
Stage #1: trityl irbesartan With hydrogenchloride In water; acetone at 20℃; for 2h; Stage #2: With potassium hydroxide In water; acetone 1.E Example 1 E. Preparation of Irbesartan (IRB-00) C-N--N N .-N N w / C-NIRB-03 IRB-00 Mw Weight, mmol Eg. volume IRB-03 670. 84 1. 0 q 1. 49 1 HCI, 3N 1. 5 mL 4. 5 3 Acetone 3 mL KOH, 85 % 56.11 0.42 g 5 IRB-03 (as produced in Example 1 D) was dissolved in acetone and 3N HCI, and stirred for 2 hours at room temperature (TLC or HPLC monitoring). A solution of KOH in 3 mL of water was slowly added, and acetone was evaporated under reduced pressure. The precipitate (Trityl alcohol) was filtered and washed with water (2 x 5 mL). The combined aqueous filtrate washed with 5 mL of ethyl acetate, and slowly acidified to pH 4 with 3N aqueous HCI. The resulting suspension was cooled down to 0-4 C, stirred for additional 30 min and filtered. The cake was washed several times with water and dried under reduced pressure at 50-60 C. The yield was 0.58 g of IRB-00..
Stage #1: trityl irbesartan With methanol; potassium hydroxide for 2.5h; Heating / reflux; Stage #2: With hydrogenchloride In water 1; 2 Example 1; Into a flask there were weighed 2-n-butyl-4-cyclopentane-2-imidazolin-5-one hydrochloride (0.83 g, 3.6 mmole), acetonitrile (15 ml), 5-(4-(bromomethyl)biρhenyl- 2-yl)-l-(tiphenylmethyl)tetrazole (1.84 g, 2.94 mmole), IM tetrabutylammonium bromide (in acetonitrile) (1.3 ml) and crushed KOH (1.1 g, 20 mmole). The mixture was stirred at 400C in an inert atmosphere for 2.5 hours. The conversion of the starting compound 5-(4-(bromomethyl)biρhenyl-2-yl)-l-(triphenylmethyl)tetrazole to trityl irbesartan was 96 %. The mixture was cooled, evaporated and methanol (17 ml) and crushed KOH (0.33 g, 5.9 mmole) were added. The reaction mixture was refluxed for 2.5 hours and then again evaporated. The conversion to irbesartan was practically 100 %. Water (17 ml) and tert-butyl methyl ether (50 ml) were added, it was stirred and the phases were separated. The aqueous phase was again extracted with 50 ml of tert-butyl methyl ether and then the aqueous phase was acidified with 2 M HCl to pH = 4.5. The suspension was cooled to 50C and the precipitate was filtered off. 1.34 g (96 %) of crude irbesartan were obtained.; Example 2; Into a flask there were added 2-n-butyl-4-cyclopentane-2-imidazolin-5-one hydrochloride (0.79 g, 3.4 mmole), acetonitrile (15 ml), 5-(4-(bromomethyl)biphenyl- 2-yl)-l-(triphenylmethyl)tetrazole (1.84 g, 2.94 mmole), tetrabutylammonium bromide (0.31 g) and crushed KOH (1.32 g, 23.5 mmole). The mixture was stirred at 310C in an inert atmosphere for 2.5 hours. The conversion of the starting compound 5-(4-(bromomethyl)biphenyl-2-yl)-l-(triphenylmethyl)tetrazole to trityl irbesartan was 95 %. The mixture was cooled, evaporated and methanol (17 ml) and crashed KOH (0.33 g, 5.9 mmole) were added. The reaction mixture was refluxed for 2.5 hours and then again evaporated. The conversion to irbesartan was practically 100 %. EPO Water (17 ml) and tert-butyl methyl ether (50 ml) were added, it was stirred and the phases were separated. The aqueous phase was again extracted with 50 ml of tert- butyl methyl ether and then the aqueous phase was acidified with 2 M HCl to pH = 2. Methylene chloride (40 ml) was added, the mixture was stirred and separated. The aqueous phase was again extracted with 10 ml of methylene chloride. The combined organic phases were washed twice with water (20 ml), dried with Na2SO4 and evaporated to dryness. 1.4 g (96 %) of crude irbesartan were obtained.
Stage #1: trityl irbesartan With hydrogenchloride In tetrahydrofuran; methanol; water at 20 - 30℃; for 4h; Stage #2: With sodium hydroxide In water 1.4 4) 2-n-Butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. 1.96 g of the product prepared in the above step are dissolved in 10 ml of methanol and 10 ml of THF. After cooling of the reaction medium to 5° C., 1.5 ml of 4N hydrochloric acid are added and the mixture is stirred for 3 hours at room temperature and for 1 hour at 30° C. After evaporation of the solvents, the residue is taken up in water and brought to pH 12 by addition of 10N sodium hydroxide. The aqueous phase is extracted with ether, with toluene and again with ether. The aqueous phase is acidified to pH 2 by addition of 1N hydrochloric acid and is then extracted with ethyl acetate, dried over Na2SO4 and evaporated. The white solid obtained is dried at 50° C. under 0.05 mm of mercury. 840 mg of the expected product are obtained. m.p.=180-181° C. [00099] NMR spectrum: 0.75 ppm: t: 3H: CH3 (nBu); 1.10 ppm: sext: 2H: CH3-CH2-; 1.20 ppm: quint: 2H: CH3-CH2-CH2-; 1.5-2 ppm: m: 8H: -C5H8; 2.2 ppm: t: 2H: CH3-CH2-CH2; 4.6 ppm: s: 2H: CH2-C6H4-; 7 ppm: s: 4H: CH2-C6H4-; 7.35-7.7 ppm: m: 4H: H3',4',5',6' aromatic.
Stage #1: trityl irbesartan With hydrogenchloride In ethanol; water at 20℃; for 5h; Stage #2: With sodium hydrogencarbonate In ethanol; water 3; 4 Example 3To a solution of compound 1 (13.93 g) in the 240 ml mixture of ethanol/water (2:1 ), 4.6 ml of cone. (36%) HCI was added and stirred at r.t. for 3 hours. Suspension was filtered; filtrate was neutralized with NaHCO3 until pH of suspension is 7-7.5. White precipitate was collected by filtration to give 1.35g of irbesartan of bad quality (34 area%).Example 4To a solution of compound 1 (13.93 g) in the 240 ml mixture of ethanol/water (2:1 ), 2.2 ml of cone. (36%) HCI was added and stirred at r.t. for 5 hours. Suspension was filtered; filtrate was neutralized with NaHCO3 until pH of suspension is 7-7.5. Suspension was extracted twice with 150 ml CH2CI2, organic phases were concentrated and crystallization was induced by addition of ethanol to give 2.83g of irbesartan (93.3 area%).
Multi-step reaction with 2 steps 1: hydrogen bromide / ethanol; water / 3 h / 20 °C 2: ethanol; dichloromethane; water / Heating / reflux

Reference: [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/27385, 2008, A2 Location in patent: Page/Page column 21
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2004/7482, 2004, A2 Location in patent: Page 7-8
[3]Srimurugan, Sankareswaran; Suresh, Paulsamy; Babu, Balaji; Hiriyanna, Salmara Ganeshbhat; Pati, Hari Narayan [Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 3, p. 383 - 384]
[4]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2005/51928, 2005, A1 Location in patent: Page/Page column 13
[5]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2005/51943, 2005, A1 Location in patent: Page/Page column 10
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/149734, 2009, A1 Location in patent: Page/Page column 14
[7]Current Patent Assignee: ALEMBIC LTD - US2007/99973, 2007, A1 Location in patent: Page/Page column 14
[8]Current Patent Assignee: ALEMBIC LTD - WO2007/49293, 2007, A1 Location in patent: Page/Page column 24
[9]Current Patent Assignee: ULKAR KIMYA SANAYII VE TICARET - WO2006/97121, 2006, A1 Location in patent: Page/Page column 14-15
[10]Current Patent Assignee: ALGRY QUIMICA S L - EP1833801, 2008, B1 Location in patent: Page/Page column 16
[11]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2004/65383, 2004, A2 Location in patent: Page 15
[12]Current Patent Assignee: KRKA DD NOVO MESTO - WO2006/73376, 2006, A2 Location in patent: Page/Page column 10-11
[13]Current Patent Assignee: SANOFI - US6800761, 2004, B1 Location in patent: Page column 8
[14]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2007/115990, 2007, A1 Location in patent: Page/Page column 11
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2007/115990, 2007, A1
  • 33
  • [ 124750-51-2 ]
  • 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
92.0% Example 5A; Example 5 was repeated but with an added isolation step before the detritylation, so as to illustrate the difference between a one-pot process of the present invention (Example 5), and a non-one-pot process of the prior art (this Example).16.4g of sodium hydroxide dissolved in 240ml of purified water was added to the mixture of 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-lH-tetrazole (59.5g) and 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4-one HCl (25g) and terra butyl ammonium bromide (2.15g) in toluene (250ml). The mixture was heated to about 850C for about 2 hours. After reaction completion, the reaction mass was cooled to about 250C and the toluene layer separated. The aqueous phase was extracted with toluene (105ml). The combined organic layer was evaporated. The residue was dissolved in acetone (208ml) and 3N HCl was added (600ml). The contents were stirred at room temperature until reaction completion (as monitored by TLC). After reaction completion, a solution of KOH (30.4 g) in water (208 ml) was slowly added and acetone was evaporated under reduced pressure. The precipitated trityl alcohol was filtered and washed with water (2 x 105 ml). The filtrate was washed with toluene and slowly acidified to pH 4 with 3 N HCl. The suspension was cooled to 0 - 4 C3 stirred for an additional 30 minutes and filtered. The cake was washed with cold isopropanol (2 x 50 ml) and dried under reduced pressure at 50 - 60 C to yield irbesartan free base (92.0%).
84.3% With potassium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In water; toluene; at 90℃; for 1.5h;Heating / reflux; A solution of KOH (10.4 g, 157.0 mmol), [IRB-01] (12.0 g, 52.0 mmol) and [BU4NHS04] [(1.] 8g, 5.3 mmol) in water (40 mL) was added to a solution of IRB-02 (24.6 g, 44.1 mmol) in toluene (240 mL), and the resulting two-phase mixture was heated at [90C] with vigorous stirring for 1.5 hours. The mixture was cooled to room temperature, the phases were separated, and the aqueous phase was extracted with toluene [(50ML).] The combined organics were evaporated; the residue was dissolved in acetone (100 mL) and 3N HC 1 (52 mL, 156 mmol, 3 eq) and stirred at room temperature (TLC monitoring). A solution of KOH (14.6 g, 260 mmol, [5] eq) in water (100 mL) was slowly added, and acetone was evaporated under reduced pressure. The precipitate formed (trityl alcohol) was filtered and washed with water (2 x 50 mL); the filtrate was washed with toluene and slowly acidified to pH 4 with 3N [HCI.] The resulting suspension was cooled to [0-4C,] stirred for additional 30 min and filtered. The cake was washed with cold iso-propanol (2 x 25 mL) and dried under reduced pressure at [50-60C] ; affording crude [IRB-00] [(14.] [5G,] 33.8 mmol). Yield 84.3%, purity 94% (by HPLC).
84% Example 26 - Example 1 of WO2004/007482; 5-(4'-bromomethyl-biphenyl-2-yl)-l-trityl-lH-tetrazole (24.6 g) was charged to toluene (240 ml). To this, a solution of KOH (10.4 g), 2n-butyl-l,3-diazaspiro (4,4) non-l-en-4 one HCl (12.0 g) and Bu4NHSO4 (1.8 g) in water (40 ml) was added. The two-phase mixture was then heated to 90 C for 90 minutes under vigorous stirring. The reaction mixture was cooled to room temperature. The toluene layer was separated and the aqueous phase was extracted with toluene (50 ml). The combined organic layer was evaporated. The residue was dissolved in acetone (100 ml) and 3N HCl (52 ml) and stirred at room temperature (TLC monitoring). A solution of KOH (14.6 g) in water (100 ml) was slowly added and acetone was evaporated under reduced pressure. The precipitated trityl alcohol was filtered and washed with water (2 x 50 ml). The filtrate was washed with toluene and slowly acidified to pH 4.0 with 3 N HCl. The suspension was cooled to 0 - 4 C, stirred for an additional 30 minutes and filtered. The cake was washed with cold isopropanol (2 x 25 ml) and dried under reduced pressure at 50 - 60 C to yield irbesartan free base (84%).
ExamplesPreparation of irbesartan (Reference example) 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride (100 gm), ethyl acetate (1000 ml) and potassium carbonate (200 gm) are added at 25 to 30C, and stirred to obtain a solution. To the solution was added potassium carbonate (200 gm), 5-[4'-(bromomethyl)biphenyl-2-yl]-l-trityl-lH-tetrazole (260 gm) and tetra butyl ammonium bromide (5 gm) at 25 to 30C. The temperature of the reaction mass was raised to 80C and maintained for 10 hours at 80C. The reaction mass was filtered and washed with ethyl acetate. The filtrate was distilled off completely under vacuum at below 40C and co-distilled with methanol to obtain residue. To the residue was added methanol (1000 ml) at 25 to 30C and the reaction mass was cooled to 0C. To the reaction mass was added slowly methanol hydrochloride (7%, 350 ml) and temperature of the reaction mass was raised to 25 to 30C. The reaction mass was maintained for 3 hours at 25 to 30C and the reaction mass was further cooled to 0C, stirred for 30 minutes at 0C. The separated solid was filtered and washed with chilled methanol. The filtrate was distilled off completely under vacuum at below 40C and co-distilled with toluene to obtain residue. To the residue was added toluene (500 ml) and water (300 ml) at 25 to 30C. The reaction mass was cooled to 0C and pH of the reaction mass was adjusted to above 12.0 with sodium hydroxide solution (20%, 600 ml) at below 5C. The temperature of the reaction mass was raised to 25 to 30C and stirred for 30 minutes at same temperature, layers were separated. The aqueous layer was washed with toluene and added methylene chloride (1300 ml) at 0C. The pH of the reaction mass was adjusted to 2.5 to 3.0 with sulphuric acid solution (30%, 250 ml) at below 10C. The reaction mass was stirred for 15 minutes at 10C, layers were separated and the total aqueous layer was extracted with methylene chloride. Combined the organic layers was added methanol (100 ml) and give the carbon treatment. Distilled off the solvent completely under vacuum at below 40C and co-distilled with isopropyl alcohol to obtain residue. To the residue was added isopropyl alcohol (1000 ml) at 40C and the temperature of the reaction mass was raised to 80C and then maintained for 30 minutes at 80C. The reaction mass was cooled to 0C and maintained for 1 hour at 0C, filtered. The solid obtained was washed with isopropyl alcohol and dried at 50C for 6 hours to obtain 135 gm of irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 - en-4-one and 3-((2'-(2-((2*-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5- yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity. Irbesartan: 99.2%;The combined contents of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one and 3- ((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one impurity (dimmer impurity): 0.7%.

  • 34
  • [ 138402-10-5 ]
  • [ 76-84-6 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; water In acetone 4 Example 4: Example 4: Mw grams, mmol Eq. volume IRB-23 212. 1 3. 3 g 15. 6 1. 5 IRB-02 557. 5 5. 8 g 10. 4 1. 0 Potassium hydroxide, 85% 56. 11 1. 85 g 28. 0 2. 7 Water 15 mL Bu4NHS04 339. 54 0. 53 g 1. 56 0. 15 Toluene 60 mL 7. 0 g/4. 7 g A solution of IRB-02 in toluene was added to a stirred suspension of IRB-23 in a solution of KOH and BU4NHS04 in water at room temperature. After 20 min of stirring at room temperature no reaction was detected by TLC. The reaction was heated to 90 °C and stirred for 1.5 h until disappearance of IRB-02 (TLC monitoring; hexane/EtOAc 6: 1). The mixture was cooled to room temperature, water (70 mL) was added and the phases were separated. The aqueous (second solvent) layer was extracted with toluene (30 mL) and the combined organics were washed with water (30 mL) and brine, dried over NA2S04, filtered, and evaporated under reduced pressure to give 7.4 g of a semisolid residue (about 87 % purity by HPLC). A portion of the residue (3.7 g) was crystallized from IPA to give 3.0 g (86 % yield) OF IRB-03 as a white powder (about 98 % purity by HPLC). Another portion (3.7 g) of the residue was dissolved in acetone (30 mL) and 7.5 ML OF AQUEOUS 3N HC1 (ABOUT 3 EQ. ) WAS ADDED. AFTER COMPLETION OF DEPROTECTION (removal OF TRITYLY group, monitored by TLC) a solution of KOH (1.3 g) in 10 mL of water was slowly added and acetone was evaporated under reduced pressure. The precipitate (trityl alcohol) was filtered and washed with water (2 x 10 mL); the combined aqueous filtrate washed with 15 mL of EtOAc and slowly acidified to pH 4 with 3N aqueous HC1. The resulting suspension was cooled down to 0-4 C, stirred for additional 30 min and filtered. The filtercake was washed several times with water and dried under reduced pressure at 50-60 C, affording 2.0 g (about 85 % yield from IRB-02) of IRB-00 (96 % purity by HPLC).
  • 35
  • [ 67-56-1 ]
  • [ 138402-10-5 ]
  • [ 596-31-6 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
1: 71% 2: 73% for 10h; Heating / reflux; 9 Example 9 2-BUTYL-3-[[2 -(LH-TETRAZOL-5-YL) [1, 1 -BIPHENYL]-4-YL] METHYL-1, 3-DIAZASPIRO [4.4] NON-1-ENE (irbesartan, VI) A suspension OF 1 g (0.0015 mol) OF 2-BUTYL-3-[2 -(1-TRITYL-LH-TETRAZOL-5-YL)-1, 1 -BIPHENYL-4- YLMETHYL]-1, 3-diaza-spiro [4.4] NON-1-EN-4-ONE (trityl irbesartan, VII) in 10 ml of anhydrous methanol was refluxed for 10 hr. The solution was then cooled to-10 °C and stirred at this temperature overnight; the precipitated crystals were sucked off and washed with a small amount of ice-cold methanol. 0.30 g (73 %) of methyltriphenylmethyl ether (XIII) were obtained. The combined mother liquors were evaporated. The resulting raw irbesartan (VI) was crystallized from isopropanol and washed with hexane. 0.45 g (71 %) of irbesartan (VI) were obtained. Mp = 180 °C-181 °C.
  • 36
  • [ 329055-20-1 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride With ammonia In water; toluene at 30 - 35℃; for 0.583333 - 0.75h; Stage #2: With sodium azide; tributyltin chloride In xylene Heating / reflux; Stage #3: With acetic acid In cyclohexane; water; acetone; xylene at 25 - 35℃; for 2h; 4 EXAMPLE 4; In a process for the preparation of 2-Butyl-3-[[2'-(1 H-tetrazol-5-yl) [1,1'- biphenyl] -4-yl]methyl]- 1,3-diazaspiro [4.4]non-1-en-4-one (I), a solution of 1-[(2'- cyanobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentane-2- imidazolin-5-one hydrochloride (50 grams, 0.1186 moles) and toluene (250 ml) was charged into a mixture of 17% liquid ammonia (29.6 ml, 0.296 moles) and water (500 ml). The reaction mass was stirred at 30-35°C for 35-45 minutes, then filtered and the solid washed with toluene (150 ml). The aqueous layer was separated and extracted with toluene (150 ml). The organic layers were combined and concentrated under reduced pressure. Xylene (50 ml) was added to the residue followed by tributyltin chloride (77.1 grams, 0.237 moles) and sodium azide (15.4 grams, 0.2369 moles), and the reaction mass heated to reflux until the reaction completed. The reaction mass was cooled to 25-35°C and water (500 ml) and acetone (400 ml) were added. Reaction mass pH was adjusted to 4.0 to 4.5 with a 1:3 solution of acetic acid and water (140 ml), then cyclohexane (500 ml) was added and the mixture stirred for 2 hours. A solid was isolated by filtering the reaction mass and was washed with cyclohexane (250 ml). After drying the solid at 70-80°C the desired compound was obtained (48 grams).
  • 37
  • [ 138402-11-6 ]
  • [ 329055-23-4 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In methanol; water at 0 - 20℃; for 1.66667h; Heating / reflux; 3 Example 3; Irbesartan (2 g) was suspended at room temperature in water (20 ml) and methanol (2 ml) was added. Then the suspension was acidified with 2M HCl to pH 1.03. The mixture was heated under reflux for 10 minutes, stirred at room temperature for one hour and on ice for 30 minutes. The precipitate was filtered off and the product was dried in a vacuum dryer at 5O0C for one hour. 2.25 g of sesquihydrate hydrochloride salt of irbesartan were isolated.
Stage #1: 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one With sodium hydroxide In water at 20℃; Stage #2: With hydrogenchloride In water at 20℃; Stage #3: With sodium hydroxide In water 13 EXAMPLE 13; 3 g of irbesartan was suspended in 36 mL of water, pH was adjusted to ph 12.69 with cca 1 mL of 40% NaOH at room trmperature. Clear solution was obtained. To this solution 25 mL of 1 M HCI was added in one portion at room temperature with stirring. Mixture was stirred at room temperature until white suspension was obtained. pH of suspension was adjusted to ph 2,00 with 30% NaOH and filtered. Product was washed with 10 mL of water and vacuum EPO dried at 500C. Yield 3,13 g of a substance in new crystalline form with melting point (Kofler microstage)110°C-123°C.
With hydrogenchloride In methanol; water Heating / reflux; Preparation of irbesartan-HCl*1.5 H2O 160 g of crude irbesartan was suspended in mixture of 1600 ml of water and 160 ml of methanol at room temperature. 400 ml of 3M HCl were added (pH under 1) and the mixture was heated to reflux temperature. The formed solution was filtered and cooled to the room temperature. The pH was adjusted to a value of under pH = 1, if necessary, by addition of 3M HCl. The mixture was then cooled to 0°C and stirred at this temperature for 1 h. The product was filtered, washed with water and dried under reduced pressure at 35°C for 3h to obtain 160 g of crude irbesartan-HCl*1.5 H2O.
  • 38
  • [ 138402-10-5 ]
  • [ 596-31-6 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
91% 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℃; 5; 7 Preparation of Irbesartan from Trityl-Proteeted Irbesartan by usingHydroxylammonium ChlorideA 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 12O g of trityl-irbesartan, 95 g of acetone, 12 g of water, and 25.0 g of hydroxylammonium chloride at room temperature. The mixture was stirred for 2 hours at this temperature. The mixture was analyzed by HPLC. The analysis showed that 99.4 of trityl protected irbesartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g methanol and sucked to dryness. Wet methoxytriphenylmethane (70 g) were obtained. The pH of the mixture was adjusted to 12.0-12.5 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C and then concentrated under reduced pressure.To remove the salt and precipitate irbesartan, 80 g of water was added and the mixture was stirred for 1 hour at room temperature. Crude irbesartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying irbesartan ( 72 g ) EPO was obtained as a white powder (95% yield).1H-NMR (DMSO) δ 7.65 (m, 2H), 7.55 (m, 2H), 7.05 (s, 4H), 4.64 (s, IH), 2.25 (m, 2H), 1.80 (s, 4H), 1.62 (m, 4H), 1.42 (m, 2H), 1.23 (m, 2H)5 0.76 (m, 3H). 13C-NMR (DMSO) δ 186.32, 161.92, 155.67, 141.67, 139.06, 136.92, 131.28, 129.93 (2C), 129.10 (2C), 128.51, 126.92 (2C), 124.14, 76.47, 42.87, 37.46, 28.13, 27.21, 26.11 (3C), 22.18, 14.30.; A 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 380 g of methanol, 120 g of trityl- irbesartan, 95 g of acetone, 12 g of water, and 28.8 g of hydroxylarnmonium chloride at room temperature. The mixture was stirred for 2 hours at this temperature. The mixture was analyzed by HPLC. The analysis showed that 99.5 of trityl protected irbesartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g methanol and sucked to dryness. Wet methoxytriphenylmethane (70 g) were obtained. The pH of the mixture was adjusted to 3.8-4.2 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C and then concentrated under reduced pressure.To remove the trace of impurity and precipitate irbesartan, 80 g of water and 80 g of eter was added and the mixture was stirred for 1 hour at room temperature. The phases were separated and the pH of the aqueous phase is adjusted to 3.8-4.2 by adding sulfuric acid. The mixture was stirred for 1 hour at room temperature and crude irbesartan was isolated by filtration. Crude irbesartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying irbesartan (68.5 g) was obtained as a white powder (91% yield).
89% 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℃; 6 Preparation of Irbesartan from Trityl-Protected Irbesartan by using Hydrochloric AcidA 2 1 3 -necked flask equipped with a reflux condenser and thermometer was charged with 300 g of methanol, 80 g of isoprapanol, 12O g of trityl- irbesartan, 95 g of acetone, 12 g of water, and 28.8 g of hydroxylammonium chloride at room temperature. The mixture was stirred for 2 hours at this temperature. The mixture was analyzed by HPLC. The analysis showed that 99.5 of trityl protected irbesartan had been consumed. The resulting slurry was filtered and the filter cake containing precipitated methoxytriphenylmethane was washed with 20 g methanol and sucked to dryness. Wet methoxytriphenylmethane (70 g) were obtained. The pH of the mixture was adjusted to 12.0-12.5 by adding 50% NaOH solution with external cooling to keep the temperature between 20-250C and then concentrated under reduced pressure.To remove the trace of impurity and precipitate irbesartan, 80 g of water and 80 g of toluene was added and the mixture was stirred for 1 hour at room temperature. The phases were separated and the pH of the aqueous phase is adjusted to 3.8-4.2 by adding HCl. The mixture was stirred for 1 hour at room temperature and crude irbesartan was isolated by filtration. Crude irbesartan was suspended into 290 g of ethyl acetate and the mixture was stirred for 1 hour at 25 to 30 0C. A homogeneous precipitate was obtained, filtered and washed with 20 g ethyl acetate. After drying irbesartan (67 g) was obtained as a white powder (89% yield).
YieldReaction ConditionsOperation in experiment
88% 2 EXAMPLE 2 EXAMPLE 2 In another preparation, by operating under the conditions described in Example 1, steps (a) and (b), 970 g of partially amorphous crude 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one which are pure at 98% were obtained (yield: 88%).
1.a EXAMPLE 1 (a) A mixture of 1 kg of 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl]methyl-1,3-diazaspiro[4.4]non-1-en-4-one, 713 g of triethylamine hydrochloride, 337 g of sodium azide in 2 I of 1-methylpyrrolidin-2-one is heated 12 hours under stirring at a temperature of 121°-123° C., then it is left to cool at a temperature of 40°-50° C. A 35% aqueous solution of sodium hydroxide and water are added under stirring thereto and stirring is continued for 30 minutes at a temperature of 20°-40° C. Stirring is stopped, the medium is allowed to settle, the aqueous phase is eliminated and the organic phase is treated with a mixture of water/toluene 5/2. The medium is stirred for 30 minutes at 20°-30° C., then stirring is stopped, the medium is left to settle, the organic phase is eliminated and the aqueous phase is washed by adding ethyl acetate thereto under stirring and the aqueous phase containing the sodium salt of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one is recovered.
1.b EXAMPLE 1 (b) To the resulting aqueous solution of pH 9-11, 36% of hydrochloric acid are slowly added until the pH is 4.7-5.3. At the end of the hydrochloric acid addition, the precipitation of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one is complete.
1.b EXAMPLE 1 The resulting suspension is stirred for one hour at 20°-25° C., the product is recovered, wrung at 20°-25° C. and washed with water. A mixture of 500 ml of isopropanol and 4.5 I of water is added to the product thus obtained, the medium is heated one hour at 50°-55° C., then cooled to 20°-25° C. After one hour at this temperature the product is well wrung, the crystals are washed with water and dried at 60° C. In a preparation, 949 g of partially amorphous crude 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4one which are pure at 98%, were obtained (yield: 86%).
15.a EXAMPLE 15 (a) A solution of hydrochloric acid is added to a solution of 3 g of potassium salt of 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one in 30 ml of water until the pH is 4.7. The mixture is stirred, then the thus precipitated crude 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one is recovered and dried at 55° C. under reduced pressure.
Alpha-Blockers-Examples of alpha-blockers, include, but are not limited to:Cardura (doxazosin)...Lotensin (benazepril)Monopril (fosinopril)Prinivil and Zestril (lisinopril)Atacand (candesartan)Avapro (irbesartan)Benicar (olmesartan)Cozaar (losartan)Diovan (valsartan)...
In ethanol at 10 - 82℃; for 3h; II.IV Purification of Irbesartan crude:; Irbesartan-crude, as obtained above (1.3 g), was suspended in ethanol (absolute alcohol, 15 ml) and heated to reflux temperature (82°C) to get a clear solution. Carbon (90 mg) was added and stirred at 82°C for 30 min. Carbon was filtered, washed with hot ethanol (5 ml, 60°C). The filtrate was cooled to 25-3O0C and stirred for 1 h. Thereafter, cooled the slurry to 10-120C and stirred for 90 min at 10- 12°C. Solid was filtered, washed with precooled ethanol (5 ml, 5°C) and dried to obtain Irbesartan as a white crystalline powder (1.05 g).
With sodium hydroxide; Caswell No. 744A; N,N-diethylethanamine hydrochloride R.4 Reference Example 4: A mixture of 2-n.butyl-3-[(2'-cyanobiphenyl-4-yl]methyl-1,3-diazaspiro[4.4]non-1-en-4-one (50 gm), triethylamine hydrochloride (35.65 gm), sodium azide(16.85 gm) in 1-methylpyrrolidin-2-one (100 ml) was heated for 12 hours under stirring at a temperature of 121°-123° C., then it was left to cool at a temperature of 40°-50° C. A 35% aqueous solution of sodium hydroxide and water were added under stirring thereto and stirring continued for 30 minutes at a temperature of 20°-40° C. Stirring was stopped, the medium allowed to settle, the aqueous phase was eliminated and the organic phase was treated with a mixture of water and toluene. The medium was stirred for 30 minutes at 20°-30° C., then stirring was stopped, the medium left to settle, the organic phase was eliminated and the aqueous phase was washed with ethyl acetate thereto under stirring and the aqueous phase containing the sodium salt of the 2-n.butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one was recovered.

  • 40
  • [ 329055-23-4 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
With ammonia In water; toluene at 25 - 30℃; for 0.5h; 22; 23; 24 Example 22; lOOg of irbesartan hydrochloride sesquihydrate was taken in a mixture of 250ml toluene and 250ml water. The pH of the reaction mass was adjusted to 6.5 to 7.0 with aqueous ammonia at 25-30°C and stirred for about 30 minutes and filtered. The product was dried at 60°C under vacuum to yield Form A of irbesartan free base.; Example 23; lOOg of irbesartan hydrochloride hemihydrate was taken in a mixture of 250ml toluene and250ml water. The pH of the reaction mass was adjusted to 6.5 to 7.0 with aqueous ammonia EPO at 25-300C and stirred for about 30 minutes and filtered. The product was dried at 600C under vacuum to yield Form A of irbesartan free base.; Example 24; lOOg of anhydrous irbesartan hydrochloride was taken in a mixture of 250ml toluene and 250ml water. The pH of the reaction mass was adjusted to 6.5 to 7.0 with aqueous ammonia at 25-300C and stirred for about 30 minutes and filtered. The product was dried at 600C under vacuum to yield Form A of irbesartan free base.
In ethanol; water at 20℃; for 1h; 1 Example 1 .To a solution of compound 1 (13.93 g) in the 240 ml mixture of ethanol/water (2:1 ), 4.6 ml of cone. (36%) HCI was added and stirred at r.t. for 3 hours. Suspension was filtered and filtrate concentrated in vacuo to remove ethanol. Concentrate was stirred at r.t. for 2h, to form white precipitate which was collected by filtration and recrystallized from acetone. Crystalline product was dissolved in 120 ml mixture of ethanol/water (2:1 ), to which solution of 1.46g NaHCO3 in 70 ml water was added and stirred at r.t. for 60 min. Suspension was extracted with CH2CI2 (3x150 ml), organic phases were collected and concentrated. Oily residue was dissolved in 60 ml of boiling ethanol, and then left to crystallize. Crystalline product was then filtered and dried to give 5.48g of irbesartan (99.96 area%; assay: 99.8%).
  • 41
  • [ 886999-35-5 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: trityl irbesartan With methanol; water for 4h; Heating / reflux; Stage #2: With sodium hydroxide In methanol; water 2 EXPERIMENT 2 (IRBESARTAN)23,25 g of trityl irbesartan was dissolved in 180 ml of methanol, 1 ml of water and 0,6g of p-toluensulphonic acidwas added. Reaction mixture was stirred at the temperature of reflux for 4 hours and evaporated to dryness. Water was added, and ph was adjusted to pH 12 with NaOH 30%. Reaction mixture was extracted with 150 ml of diethylether, 150 ml of toluene and 150 ml of diethyl ether successively. Layers were separated. pH of water layer was adjusted to pH 2 with 1 N HCI. Suspension was stirred at room temperature and filtered. Product was washed with 30 ml of ethyl acetate and vacuum dried at 5O0C. Yield: 14 g
Stage #1: trityl irbesartan With methanol; water In dichloromethane at 20℃; for 96h; Stage #2: With sodium hydroxide In methanol; dichloromethane; water 5 EXPERIMENT 5 (IRBESARTAN)23,25 g of trityl irbesartan was dissolved in 90 ml of dichloromethane. To a clear solution 90 ml of methanol, 1 ml of water and 0,15 ml of MSK was added. Reaction mixture was stirred at room temperature for 4 days, then 63 ml of dichloromethane and 121 ,2 ml of water was added. pH of reaction mixture was adjusted to ph 12 with NaOH 30%, layers were separated and water layer was washed with 63 ml of dichloromethane. pH of water layer was adjusted to ph 2 with 1 N HCI, suspension was filtered and washed with 50 ml of water and 30 ml of ethyl acetate and vacuum dried at 5O0C. Yield: 11 ,37 g
Acidic conditions; 2-n-Butyl-3-spirocyclopentane-l-[(2'-(triphenylmethyl-tetrazole-5yl)-biphenyl)-4-yl) methyl]-2-imidazolin-5-one which is a precursor of Irbesartan was obtained by the coupling reaction of N-(Triphenylmethyl)-5-(4'-bromomethylbiphenyl)-2-yl- )tetrazole and 2-n-Butyl-l,3-diazaspiro(4,4')non-l-en-4-one hydrochloride in the presence of a base selected from the group of KOH, K2CO3, NaOH5 Na2Cθ3 or their mixtures in a polar solvent like DMF or Isopropyl alcohol. Following deprotection of the trityl group under acidic conditions yields crude Irbesartan with a purity of about 98% (based on relative percent area).
  • 42
  • [ 138402-11-6 ]
  • 2-n-butyl-4-spirocyclopentane-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one hydrochloride sesquihydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In water; toluene at 100℃; for 2h; 25 Example 25; lOOg of irbesartan free base (Form A) was taken in a mixture of 500ml toluene and 500ml 4N hydrochloric acid and heated to about 1000C for about 2 hours, cooled to 25-300C and filtered. The product was dried at 600C under vacuum to yield irbesartan hydrochloride sesquihydrate.
  • 43
  • N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amine hydrochloride [ No CAS ]
  • [ 15026-81-0 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
70.5% With methanesulfonic acid In 1-methyl-pyrrolidin-2-one at 160℃; for 2.5h; 5 EXAMPLE 5; 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-1,3-diazaspiro[4.4]non-1-en-4-one; A solution of 0.44 g (2.25 mmol) of 2-n-butyl-3-oxa-1-azaspiro-[4.4]-non-1-en-4-one in 0.4 mL of N-methylpirrolidone was added over 10 min to a mixture of 0.4 g (1.39 mmol) of (2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methanamine hydrochloride and 0.08 g (0.83 mmol) of methanesulfonic acid in 1.6 mL of N-methylpirrolidone heated at 160 °C. The reaction was left for 2.5 h at 160 °C and 200 mbar and after removing the N-methylpirrolidone by distillation under reduced pressure and cooling to room temperature 4 mL of 10 % aqueous sodium hydroxide solution was added. Then, 6 mL of ethyl acetate were added and the mixture was acidified with concentrated hydrochloric acid until pH 4-5. After a while, the mixture started to precipitate and after leaving for 1 h at 20-25 °C the solid was filtered, washed with water and ethyl acetate and, finally, the solid was dried under reduced pressure at 60 °C affording 0.42 g (70,5 %) of 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-1,3-diazaspiro[4.4]non-1-in-4-one.
60.4% In 1-methyl-pyrrolidin-2-one at 140℃; for 5h; 4 EXAMPLE 4; 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-1,3-diazaspiro[4.4]non-1-en-4-one; Under nitrogen atmosphere, a solution of 1.03 g (5.27 mmol) of 2-n-butyl-3-oxa-1-azaspiro-[4.4]-non-1-en-4-one in 1 mL of N-methylpirrolidone was added over 30 min to a mixture of 1.0 g (3.47 mmol) of (2 '-(1H-tetrazol-5-yl) biphenyl-4-yl) methanamine hydrochloride in 3 mL of N-methylpirrolidone heated at 140 °C. The reaction was left for 5 h at 140 °C and 200 mbar and after cooling to room temperature 15 mL of 10 % aqueous sodium hydroxide solution was added. Then, 15 mL of ethyl acetate were added and the mixture was acidified with concentrated hydrochloric acid until pH 4-5. After a while, the mixture started to precipitate and after leaving for 1 h at 20-25 °C the solid was filtered, washed with water and ethyl acetate and, finally, the solid was dried under reduced pressure at 65 °C affording 0.90 g (60.4 %) of 2-n-butyl-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-1,3-diazaspiro [4.4] non-1-in-4-one. RMN 1H (CDCl3), δ(ppm): 0.82 (t, 3H, -CH2-CH2-CH2-CH3); 1.18-1.33 (m, 2H, -CH2-CH2-CH2-CH3); 1.40-1.52 (m, 2H, -CH2-CH2-CH2-CH3); 1.62-1.86 (m, 8H, cyclopentane); 2.17 (t, 2 H, -CH2-CH2-CH2-CH3); 4.65 (s, 2H, Ar-CH2-); 7.04 (d, 2H, ArH); 7.15 (d, 2H, ArH); 7.44 (dd, 1H, ArH); 7.49-7.65 (m, 2H, ArH); 7.87 (dd, 1H, ArH). M.P. = 182°C
  • 44
  • 2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
In ethanol; water at 25 - 65℃; for 21.33h; 3 Example 3 Irbesartan hydrate (100 gm) is stirred with water (500 ml) and ethanol (2000 ml) for 10 to 15 minutes at 25°C to 30°C, heated to 50°C to 55°C to form a clear solution and then stirred for 5 minutes at 50°C to 55°C. The reaction mass is slowly cooled to 25°C to 30°C and the solid separation is observed after 4 hours. The reaction mass is maintained for 12 hours more. The separated solid is filtered, washed with water (300 ml) and dried for 5 hours under vacuum at 60°C to 65°C to give 75 gm of irbesartan form-A (HPLC purity: 99.89%)
In ethanol at 10 - 55℃; for 5h; 6 Example 6The mixture of amorphous irbesartan hydrate (10 gm, Moisture content:3.5%) and ethanol (50 ml) is heated to 45°C - 50°C and stirred for 1 hour at 45°C- 50°C. Then, the contents are cooled to 10°C - 15°C, filtered and dried at 50°C -55°C for 4 hours to give 9.2 gm amorphous irbesartan
  • 45
  • [ 138402-11-6 ]
  • 2-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; sodium hydroxide In dichloromethane; water at 5 - 55℃; for 7.33h; 2 Example 2Irbesartan form-A (50 gm) and water (500 ml) are stirred for 15 minutes, cooled to 5°C and pH is adjusted to 10.5 to 11 with 10% sodium hydroxide solution for 45 minutes at 5°C to 10°C. The contents are stirred for 3 hours at5°C to 10°C and the resulting solution is washed with methylene chloride (350 ml). The aqueous solution is cooled to 5°C and the pH is adjusted to 5.0 with 10% HCI solution for 20 minutes at 5°C to 10°C. Then the separated solid is filtered, washed with chilled water (800 ml) and dried at 50°C to 55°C for 3 hours to give 38 gm of amorphous irbesartan hydrate (Moisture content: 3.5%, HPLC purity: 99.3%).
  • 46
  • [ 138402-11-6 ]
  • irbesartan hydrochloride sesquihydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In methanol; water at 20℃; for 2h; 1 Irbesartan (1.5 g) was suspended in water (15 mL) at room temperature and methanol (1.5 mL) was added thereto. Subsequently, the suspension was acidified with 1 M HC1 to the pH 0.8, wherefor 6.8 mL of this solution were used. The suspension was stirred for 2 hours at room temperature, whereafter the precipitate was filtered off. The product was dried in a vacuum dryer at 50 °C for 1 hour and sesquihydrate hydrochloride salt of irbesartan (1.58 g) was isolated.IR (characteristic peaks): 1760, 1639, 1513, 1323, 943, 741 cm'1.NMR: corresponds to irbesartanWater (KF) 6.25 %Elemental analysis for sesquihydrate hydrochloride salt of irbesartan:Calculated for irbesartan*HCl* 1.5 H2O:61.03 % C, 6.56 % H, 17.08 % NFound:60.79 % C, 6.70 % H, 17.02 % N
  • 47
  • [ 104-15-4 ]
  • [ 138402-11-6 ]
  • irbesartan tosylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; isopropyl alcohol at 5 - 10℃; for 120h; Heating / reflux; 1; 2 Crystalline unsalted irbesartan (0.5 g) and crystalline p-toluenesulfonic acid hydrate (0.8 g) were slurried in water (20 ml) and heated to reflux temperature. At about 50°C the solid material converted to a gum which did not dissolve at reflux. Propan-2-ol (10 ml) and a further quantity of water (10 ml) were added and a clear solution was obtained at reflux. When the solution was cooled crystals precipitated from solution. After standing for 5 days at about 5-10°C the crystals were isolated by filtration and dried under vacuum. Yield 0.60 g of large, well-formed, colourless crystals.The infra-red spectrum showed prominent absorption maxima at about 1770, 1627, 1509,1225, 1173, 1149, 1011, and 682 wavenumbers; Crystalline unsalted irbesartan (0.2 g) was slurried in water (20 ml) and heated to reflux temperature. Crystalline p-toluenesulfonic acid hydrate (0.4 g) was added, but a solution was not obtained. Propan-2-ol (4 ml) was added and a clear solution was obtained at reflux. The solution was cooled, and as soon as the temperature fell significantly below reflux, the solution became cloudy. During further cooling there was rapid crystallisation. After standing overnight at about 5-10°C the crystals were isolated by filtration and dried under vacuum. Yield 0.25 g of large, well-formed, colourless crystals.
  • 48
  • [ 1199814-92-0 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
84% With hydrogen In methanol at 20℃; B A solution of 3-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-2-(2-thienyl)-1 ,3- diazaspiro[4.4]non-1 -en-one (0.20 g, 0.44 mmol) in methanol (10 ml) was added to stirred suspension of Raney nickel in methanol (10 ml) under atmosphere of hydrogen. The mixture was stirred at room temperature until conversion reached more than 98 % (monitored by HPLC). After completion the Raney nickel residue was filtered off washed with methanol (2 x 5 ml) and water (100 ml) was added to combined filtrates. The mixture was extracted with ethyl acetate (3 x 20 ml). The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure to yield 0.16 g (84 %) of 2-butyl-3-[[2'-1/-/-tetrazol-5-yl)[1 ,1 '-biphenyl]-4-yl]methyl]-1 ,3-diazaspiro[4.4]non-1-en-4- one (Irbesartan) as a white solid. M.p.: 181 - 184 0C. 1H NMR (CDCI3): δ = 0.83 (t, 3H, CH3, J = 7.3 Hz) 1.2-1.3 (m, 2H, CH2), 1.5-1.6 (m, 2H, CH2), 1.7-1.8 (m, 8H, CH2), 2.2-2.3 (m, 2H, CH2), 4.66 (s, 2H, CH2), 7.07 (d, 2H, CH, J = 8.3 Hz), 7.17 (d, 2H, CH, J = 8.3 Hz), 7.5-7.6 (m, 3H, CH), 7.8-7.9 (m, 1 H, CH) ppm. 13C NMR (CDCI3): δ = 13.8, 22.5, 26.2, 28.0, 28.7, 37.6, 43.5, 82.2, 123.6, 127.0, 128.5, 130.0, 130.9, 131.1 , 131.4, 136.2, 139.5, 140.9, 155.9, 162.9, 186.6 ppm. HR-MS: 429.2404 (MH+, calc. for C25H29N6O+ : 429.2403).
  • 49
  • [ 67-56-1 ]
  • [ 7732-18-5 ]
  • silver nitrate [ No CAS ]
  • [ 138402-11-6 ]
  • [Ag2(2-butyl-3-[p-(o-(1H-tetrazol-5-yl)phenyl)benzyl]-1,3-diazospiro[4.4]non-1-en-4-one(-H))2]*methanol*0.17water [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% In methanol; water; acetonitrile mixing CH3CN soln. of silver compd., water and methanolic soln. of tetrazole deriv., keeping at room temp. in dark with slow evapn.; isolation of crystals, elem. anal.;
YieldReaction ConditionsOperation in experiment
Stage #1: 2-butyl-3-{4-[2-(1H-tetrazol-5-yl)phenyl]benzyl}-1,3-diazaspiro[4.4]non-1-en-4-one In water for 0.25 - 0.5h; Stage #2: With sodium hydroxide In water; toluene at 20 - 25℃; Stage #3: With sulfuric acid In water 4.2 Step-IIIrbesartan (obtained in Step-I) and water (5000 ml) are stirred for 15 to 30 minutes and added toluene (1500 ml). The pH is adjusted in between 11.0 and 11.5 at 20-25° C. by using 5% sodium hydroxide solution (1000 ml). The layers are separated and aqueous layer is washed with toluene (3000 ml). The aqueous layer is passed over hi-flow bed and washed with water (1000 ml). Initially the pH of the aqueous layer is adjusted between 3.0 to 3.5 and maintained for 15 to 20 minutes, again the pH is adjusted in between 0.5 to 1.0 using 1N sulfuric acid solution (920 ml). Stirred for 2 hours, filtered the compound and washed with water (5000 ml). Water (2500 ml) is added to the compound and the pH is re-adjusted in between 0.5 to 1.0 using 1N sulfuric acid solution (180-200 ml). Stirred for 2 hours at 25-30° C. to give 493 gm of irbesartan (HPLC purity: 97.02%, Tin content: 172.8ppm, 1-Pentanoylamino-cyclopentane carboxylic acid-[2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]amide: 2.32%).
In methanol; water Reflux; 2 Purification of Formula I lOOg Crude Irbesartan was taken in 700ml (95:5 % v/v) methanol/water and heated to reflux to get clear solution treated with charcoal. The solution was filter through calcite .the clears filtrate was then charged back into RB flask and again heated to reflux .the clear solution was then cooled gradually to 25-30°C , further cooled to 0-5°C for 1 hr and filtered .The wet product was then washed with chilled methanol and dried. Yield: 88-90% Purity: 99.91 %, Impurity A: 0.02%, other total unspecified impurities 0.07%
In methanol; acetone at 0℃; Reflux; 2 Example 2:Process for the purification of irbesartanIrbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl- 4-yl)methyl)-2 -butyl- l ,3-diazaspiro[4.4]non-l-en-4-one impurity (10 gm) was dissolved in methanol (100 ml) and acetone (100 ml) at room temperature. The contents were heated to reflux to obtain clear solution and the solution was cooled to room temperature, stirred for 1 hour at room temperature. The solution was further cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The solid obtained was washed with in a mixture of chilled methanol and chilled acetone and then dried at 50 to 55°C for 4 hours to obtain 7.5 gm of irbesartan substantially free of 3-((2'-(l-((2'- (lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2- butyl- l,3-diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3- diazaspiro[4.4]non-l-en-4-one impurity.Irbesartan: 99.94%;The combined contents of dimmer impurity: Not detected.
  • 51
  • [ 114772-54-2 ]
  • 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride With potassium carbonate In lithium hydroxide monohydrate at 25 - 60℃; Stage #2: 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile In lithium hydroxide monohydrate at 55 - 60℃; Stage #3: With Caswell No. 744A; N,N-diethylethanamine hydrochloride In toluene at 25 - 105℃; 2 Example 2: Preparation of Formula I (crude) with PTC2-n-butyl-l,3-diazaspiro[4,4] -non-l-ene-4-one hydrochloride ( 93.24 g), water (560ml) were taken into RB flask, followed by addition of 225 g potassium carbonate 23.2 gTBAB at 25-30°C. The reaction mixture was stirred for 2 hrs at 55-6O0C. 4-(Bromomethyl)-2'-cyanobiphenyl (10Og) was than charged and then resulting mass was stirred at 55-600C for 12-14 hrs .Reaction content was cooled to 25-300C and diluted with toluene( 300ml) ,layers were separated. Aqueous layer extracted with toluene. The combine toluene layer washed with water.To toluene layer containing product 2-n-buyl-3[( 2'-cyanobiphenyl)-4-yl}methyl-l,3- diazaspiro[4,4]-non-l-ene was than added Sodium azide ( 53 g ) followed by triethyl amine hydrochloride ( 92.4 g) at 25-300C .the reaction mass was stirred at 95-1050C for about 35 hrs. The reaction mass was cooled and adjusted pH to 10-11 by adding 30 % sodium hydroxide solution at 25-300C, layers were separated. The aqueous layer is then extracted with toluene .To aqueous layer added 65 ml Methanol and 52g sodium nitrite and then adjusted pH to 4-4.5 with dilute hydrochloric acid maintaining 10-15°C, the precipitated product was filtered and washed with water. The wet product was taken back into RB flask and stirred with Ethyl acetate (520ml) at reflux temperature. The suspended mass is filtered and washed with ethyl acetate. Yield: 120 g, 79 %.HPLC purity: 99.28 %. Impurity A: 0.37 %, Total unspecified impurities: 0.35 %
165 g Stage #1: 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile; 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride With tetra-(n-butyl)-phosphonium bromide In toluene at 40 - 45℃; Stage #2: With Caswell No. 744A; anhydrous zinc chloride In diethylene glycol dimethyl ether at 85 - 130℃; 3 Preparation of Irbesartan Charged Toluene, 2-N-Butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride (100 gm), 4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (118 gm), tetrabutylphosphonium bromide (3 gm) and added CS lye slowly and raised the mass temperature to 40-45° C. Stirred for 12 hours to 14 hours at 40-45° C., added water and separated the organic layer. Distilled off the solvent under vacuum completely and added diglyme (255 ml). Added zinc chloride (75 gm), sodium Azide (70 gm) and raised the temperature to 85-90° C. and stirred forl hour. Further, stirred for 48 hours to 54 hours at 120-130° C. Added water and cooled the mass temperature to below 25° C. Added CS lye and separated the bottom aqueous layer at below 25° C. Added water to the product layer, stirred for 10 minutes to 15 minutes. Added toluene and stirred for 20 minutes to 30 minutes and separated the layers at below 35° C. Added methanol (Lot-I), acetone (Lot-I), water (Lot-V) and the pH was adjusted with HCl to 3.5-4.5 at below 35° C. Heated to 55-65° C. and stirred for 1 hour to 1 hour 30 minutes. Filtered the material and washed with water, acetone and dried the material under vacuum at 50-60° C. for 18 hours to 20 hours. Added acetone, water and the pH was adjusted to 3.5-4.5. Heated to reflux and stirred for 2 hours to 3 hours. Cooled to 0-10° C., stirred for 2 hours, filtered and washed with acetone. Dried the material under vacuum at 50-60° C. for 10 hours to 12 hours to yield 120 gm of Irbesartan. Added Methanol and raised the temperature to 60-65° C. and stirred for 30 minutes to 45 minutes. Given carbon treatment and filtered the mass through hyflo bed and washed with methanol. Distilled off the solvent completely under vacuum below 50° C. and codistilled with acetone. Added acetone, heated to reflux and stirred for 2 hours to 3 hours. Cooled, stirred, filtered, washed with acetone and dried under vacuum at 65-75° C. for 12 hours to 14 hours to yield 105 gm of Irbesartan. NDMA-ND, NDEA: ND, NDIPA-ND, NEIA-ND, NDBA-ND, NMBA-ND
Multi-step reaction with 2 steps 1: tetrabutylammonium bromide / toluene / 0.17 h / 25 - 35 °C 2: Caswell No. 744A; tributyltin chloride; tetrabutylammonium bromide / toluene / 20 h / Reflux
  • 54
  • 3-[2'-(1-benzyl-1H-tetrazol-5-yl)biphenyl-4-yl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
With ammonium formate In water; isopropyl alcohol at 55 - 80℃; for 7h; 24.2 Step 2 A mixture of crude 3-[2'-(1-benzyl-1H-tetrazol-5-yl)biphenyl-4-yl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (crude product of compound 17a, 153 mg, 0.295 mmol), isopropyl alcohol/purified water (3:2, 2.0 mL), 5% palladium carbon (134 mg, 2.9 mg, 0.028 mmol (Pd conversion)) and ammonium formate (119 mg, 1.88 mmol) was heated with stirring at 55-60° C. for 3 hr. To the reaction mixture was added 5% palladium carbon (136% mg, 3.0 mg (Pd conversion), 0.028 mmol), and the mixture was heated at 80° C. for 4 hr. The reaction was monitored by HPLC and TLC (eluent: chloroform/methanol (20:1)). The reaction mixture was allowed to cool to room temperature, and filtered using isopropyl alcohol (about 20 mL). The filtrate was concentrated to 0.15 g, and 0.5 mol/L aqueous sodium hydroxide solution (1.5 mL), water (1.6 mL), tert-butyl methyl ether (3.0 ml) and 1 mol/L aqueous sodium hydroxide solution (0.2 mL) were added thereto. The organic layer was separated. The aqueous layer was washed with tert-butyl methyl ether (3.0 mL), and 4 mol/L hydrochloric acid (0.17 mL), 0.2 mol/L hydrochloric acid (0.15 mL) and 1 mol/L hydrochloric acid (0.11 mL) were added dropwise thereto to adjust the pH of the mixture to 6.0. The precipitated solid was collected by filtration, washed with water (5.0 mL), and dried under reduced pressure at 40-60° C. to give a crude product of irbesartan (compound 18) (63.9 mg, 50.5% of the theoretical yield). 1H-NMR (DMSO-d6): δ=7.68 (t, J=7.8 Hz, 1H, biphenyl), 7.64 (d, J=7.8 Hz, 1H, biphenyl), 7.57 (t, J=7.8 Hz, 1H, biphenyl), 7.04 (d, J=7.8 Hz, 1H, biphenyl), 7.08 (s, 4H, biphenyl), 4.68 (s, 2H, CH2N), 2.29 (t, J=7.5 Hz, 2H, 1-CH2 of Bu), 1.86-1.60 (m, 8H, cyclopentanediyl), 1.47 (quint, J=7.5 Hz, 2H, 2-CH2 of Bu), 1.26 (sext, J=7.5 Hz, 2H, CH2Me), 0.80 (t, J=7.5 Hz, 2H, CH2). IR(KBr): 1725(C=O), 1630(C=N) cm-1 MS: m/z=429 (MH+)
  • 55
  • 1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
  • 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 h / 25 - 85 °C / Inert atmosphere 2: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 3.5 h / 25 - 55 °C
  • 56
  • 3-[2′-(1-benzyl-1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
100% With 5% palladium on barium sulphate; ammonium formate In water; isopropyl alcohol at 25 - 55℃; for 3.5h; Into a 5-mL one-neck flask were sequentially added 1e (0.1 g, 0.19mmol), ammonium formate (0.059 g, 0.94 mmol), 5% Pd/BaSO4(0.021 g, 5 mol%), i-PrOH (1.0 mL) and H2O (0.6 mL) at 25 °C.The reaction mixture was heated at 55 °C until completion (3.5 h).The mixture was cooled to 25 °C then filtered through Celite andthe Celite was washed with i-PrOH (2 × 5 mL). The filtrate wasconcentrated under reduced pressure to give 2e; yield: 0.081 g(quant.)
96% In water; isopropyl alcohol at 55℃; for 6h;
0.091 g With 5% palladium on barium sulphate; ammonium formate In water; isopropyl alcohol at 55℃; for 3.5h; 4.2.a Example 4-2(a) Deprotection Example 4-2(a) Deprotection (0369) (0370) A mixture of BIR (0.1 g, 0.19 mmol), ammonium formate (0.059 g, 0.94 mmol), 5% Pd-BaSO4 (0.021 g, 5.0 mol %), isopropyl alcohol (1.0 mL, 10 vol) and water (0.6 mL, 6 vol) was stirred at 55° C. for 3.5 hr. The conversion yield of this reaction was 87.42%. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography to give irbesartan (IR) (0.091 g). (0371) IR (KBr): νmax=1725, 1630 cm-1; (0372) 1H NMR (DMSO-d6): δ=7.68 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.08 (s, 4H), 4.68 (s, 2H), 2.29 (t, J=7.5 Hz, 2H), 1.86-1.60 (m, 8H), 1.47 (quint, J=7.5 Hz, 2H), 1.26 (sext, J=7.5 Hz, 2H), 0.80 (t, J=7.5 Hz, 2H); (0373) Mass: 429 [M+H]+.
  • 57
  • [ 106-38-7 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 12 h / 138 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 3: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 4: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
  • 58
  • [ 38612-13-4 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 138 - 140 °C / Inert atmosphere 2: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 3: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 4: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
  • 59
  • {2'-(1-benzyl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl}methyl benzoate [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 2: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 3: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
  • 60
  • [ 168265-56-3 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 2: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 3: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
  • 61
  • 1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 2: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
  • 62
  • [ 28386-90-5 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 138 - 140 °C / Inert atmosphere 2: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 3: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 4: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
Multi-step reaction with 4 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 12 h / 138 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 3: potassium carbonate / acetonitrile / 20 h / 80 - 85 °C 4: 5% palladium on barium sulphate; ammonium formate / water; isopropyl alcohol / 3.5 h / 55 °C
  • 63
  • copper(II) choride dihydrate [ No CAS ]
  • [ 138402-11-6 ]
  • [Cu(irbesartan)2(H2O)] [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With sodium hydroxide In ethanol synthesis of CuIrb A solution of CuCl2·2H2O in ethanol (0.25 mmol, 3 mL) was added under continuous stirring to an ethanol solution of irbesartan (0.5 mmol,10 mL). The obtained suspension was allowed to stir and was dissolved by the addition of an aqueous solution of 1 M NaOH. The final pH value was 6. A light green precipitate was observed and filtered off, washed several times with ethanol, and then dried in oven at 60 °C. Yield:0.210 g, 85 %. Anal. Calc. %: C, 64.1; H, 5.9; N, 17.9.Exp. %: C, 64.0; H, 5.8; N, 17.8. Thermogravimetricanalysis (TGA) confirmed the presence of one labile water molecule per copper atom (Exp. loss: 1.8 %. Calc. loss:1.9 %; broad endothermic peak, 100 °C, DTA) (Figure S1).The water molecule is removed in the range 50-150 °C with a mass loss which corresponds to the calculated value.This temperature agrees with a probable labile Cu-Ow bond due to the steric hindrance generated by the ligands.At 800 °C the weight loss (91.5 %, calc.; 91.6 %, exp.)represents the formation of CuO that was characterized by FTIR spectroscopy.
  • 64
  • [ 866946-42-1 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / acetone / 24 h / 25 - 32 °C 2.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 2.2: 1.5 h / 20 - 25 °C
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / acetone / 24 h / 25 - 32 °C 2.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 2.2: 0.17 h / 25 - 30 °C / pH 9 3.1: sodium azide; tributyltin chloride / o-xylene / 25 °C / Heating / reflux 3.2: 2.25 h / 20 - 25 °C 3.3: 2 h / 20 - 25 °C / pH 4.5 - 4.8
Multi-step reaction with 4 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / acetone / 24 h / 25 - 32 °C 2.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 2.2: 0.17 h / 25 - 30 °C / pH 9 3.1: pyridine; p-toluenesulfonyl chloride / 1 h / 70 - 75 °C 4.1: sodium azide; tributyltin chloride / o-xylene / 60 h / 25 - 137 °C 4.2: 1 h / 10 - 15 °C / pH 11.5 - 12 4.3: 10 - 30 °C / pH 4.6 - 4.8
  • 65
  • 2-(4'-aminomethylphenyl)benzonitrile hydrogen chloride [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: ammonia / dichloromethane; water / 25 - 30 °C / pH 9.0 - 9.5 2.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 25 - 32 °C 3.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 3.2: 1 h / 20 °C
Multi-step reaction with 4 steps 1.1: ammonia / dichloromethane; water / 25 - 30 °C / pH 9.0 - 9.5 2.1: potassium hydroxide; <i>tert</i>-butyl alcohol / 70 - 75 °C 2.2: 1 h / 2 - 5 °C / pH 1.2 - 1.4 3.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 4.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 4.2: 1.5 h / 20 - 25 °C
Multi-step reaction with 5 steps 1.1: ammonia / dichloromethane; water / 25 - 30 °C / pH 9.0 - 9.5 2.1: potassium hydroxide; <i>tert</i>-butyl alcohol / 70 - 75 °C 2.2: 1 h / 2 - 5 °C / pH 1.2 - 1.4 3.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 4.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 4.2: 0.17 h / 25 - 30 °C / pH 9 5.1: sodium azide; tributyltin chloride / o-xylene / 25 °C / Heating / reflux 5.2: 2.25 h / 20 - 25 °C 5.3: 2 h / 20 - 25 °C / pH 4.5 - 4.8
Multi-step reaction with 6 steps 1.1: ammonia / dichloromethane; water / 25 - 30 °C / pH 9.0 - 9.5 2.1: potassium hydroxide; <i>tert</i>-butyl alcohol / 70 - 75 °C 2.2: 1 h / 2 - 5 °C / pH 1.2 - 1.4 3.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 25 - 33 °C 4.1: trifluoroacetic acid / o-xylene / 15 h / 25 - 140 °C 4.2: 0.17 h / 25 - 30 °C / pH 9 5.1: pyridine; p-toluenesulfonyl chloride / 1 h / 70 - 75 °C 6.1: sodium azide; tributyltin chloride / o-xylene / 60 h / 25 - 137 °C 6.2: 1 h / 10 - 15 °C / pH 11.5 - 12 6.3: 10 - 30 °C / pH 4.6 - 4.8

  • 66
  • [ 15026-80-9 ]
  • [ 133690-92-3 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide / dichloromethane / 25 - 32 °C 2.1: sodium azide; tributyltin chloride; N,N-dimethyl-formamide / o-xylene / 1 h / 15 - 155 °C 2.2: 1 h / 20 °C
  • 67
  • [ 15561-72-5 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: bis(1,5-cyclooctadiene)nickel (0); triphenylphosphine; cesium fluoride / toluene / 8 h / 80 °C / Inert atmosphere; Sealed tube 2.1: phosphorus pentachloride / dichloromethane / -12 - 17 °C 2.2: -10 - 25 °C 3.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 20 °C / Reflux 3.2: -10 - 20 °C 4.1: / isopropyl alcohol; water / 6 h / 55 °C
  • 68
  • [ 5720-05-8 ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: bis(1,5-cyclooctadiene)nickel (0); triphenylphosphine; cesium fluoride / toluene / 8 h / 80 °C / Inert atmosphere; Sealed tube 2.1: phosphorus pentachloride / dichloromethane / -12 - 17 °C 2.2: -10 - 25 °C 3.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 20 °C / Reflux 3.2: -10 - 20 °C 4.1: / isopropyl alcohol; water / 6 h / 55 °C
  • 69
  • N-benzyl-4'-methyl-[1,1'-biphenyl]-2-carboxamide [ No CAS ]
  • [ 138402-11-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: phosphorus pentachloride / dichloromethane / -12 - 17 °C 1.2: -10 - 25 °C 2.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 20 °C / Reflux 2.2: -10 - 20 °C 3.1: / isopropyl alcohol; water / 6 h / 55 °C
  • 70
  • [ 768-56-9 ]
  • [ 138402-11-6 ]
  • C35H40N6O [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With N,N'-bis[(E)-(3,5-di-tert-butyl)-2-hydroxyphenylmethylene]-[(1R,2R)-1,2-diphenylethylenediamino]cobalt(II); phenylsilane; 1-fluoro-2,4,6-trimethylpyridin-1-ium tetrafluoroborate In toluene at 20℃; for 24h;
  • 71
  • [ 5394-13-8 ]
  • [ 138402-11-6 ]
  • 3-((2'-(2-(2-bromobenzo[b]thiophen-3-yl)-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With 2,2,2-trifluoroethanol; tetrabutylammonium tetrafluoroborate In dichloromethane at 23℃; for 6h; Electrochemical reaction;
  • 72
  • [ 99655-68-2 ]
  • [ 138402-11-6 ]
  • 3-((2'-(2-(3-bromo-1-(phenylsulfonyl)-1H-indol-2-yl)-2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ No CAS ]
  • C39H36BrN7O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 23% 2: 31% With 2,2,2-trifluoroethanol; tetrabutylammonium tetrafluoroborate In dichloromethane at 23℃; for 6h; Electrochemical reaction; Overall yield = 56 percent;
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