[ CAS No. 25148-68-9 ] {[proInfo.proName]}

Name: 25148-68-9|N-Methyl-1,2-benzenediamine dihydrochloride|99%
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SKU: A359399
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Quality Control of [ 25148-68-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 25148-68-9 ]

Product Details of [ 25148-68-9 ]

CAS No. :	25148-68-9	MDL No. :	MFCD00042021
Formula :	C₇H₁₂Cl₂N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DKEONVNYXODZRQ-UHFFFAOYSA-N
M.W :	195.09	Pubchem ID :	91296
Synonyms :

Calculated chemistry of [ 25148-68-9 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	0.0
Num. H-bond donors :	2.0
Molar Refractivity :	54.08
TPSA :	38.05 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.83
Log Po/w (WLOGP) :	2.73
Log Po/w (MLOGP) :	1.8
Log Po/w (SILICOS-IT) :	0.81
Consensus Log Po/w :	1.63

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.17
Solubility :	0.132 mg/ml ; 0.000676 mol/l
Class :	Soluble
Log S (Ali) :	-3.29
Solubility :	0.101 mg/ml ; 0.000516 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.43
Solubility :	0.725 mg/ml ; 0.00372 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 25148-68-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 25148-68-9 ]

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

Upstream synthesis route of [ 25148-68-9 ]
Downstream synthetic route of [ 25148-68-9 ]

[ 25148-68-9 ] Synthesis Path-Upstream 1~2

1
[ 25148-68-9 ]
[ 152628-03-0 ]
[ 152628-02-9 ]

Yield	Reaction Conditions	Operation in experiment
77.4%	Stage #1: at 70 - 135℃; for 13.5 h; Stage #2: With ammonia In water at 30 - 90℃; for 1 h;	4-Methyl-2-n-propyl-lH-benzimidazole-6-carboxylic acid (50 gms) is suspended in Poly phosphoric acid (300 gms), temperature is raised and maintained for 30 min at 70 - 75⁰C, N-Methyl-o-phenylenediamine dihydrochloride. (45 gms) is added lot wise over 2 hrs and maintained at temperature of 70 - 75⁰C for lhr. The temperature of the reaction mass is raised and maintained for 10 hrs at 130 - 135⁰C. Mass temperature is cooled to 7O⁰C, water (600 ml) is added slowly at temperature of 60 - 9O⁰C. Temperature of the reaction mass is cooled to 3O⁰C, pH is adjusted to 8.0 - 8.5 with aqueous ammonia solution. EPO <DP n="12"/>Temperature of the reaction mass is raised, maintained at 50- 55⁰C for 1 hr, filter the solid, wet cake is washed with hot water (200 ml) and unload the wet cake. The above wet cake suspended in water (900 ml), temperature is raised and mixed for 1 hr at 50 - 55⁰C. Filtered the solid, washed with hot water (100 ml) and dried the wet cake at temperature of 70 - 75⁰C till constant weight. The above dry material is suspended in methanol (260 ml), and temperature is raised to 45 - 5O⁰C, charcoal (6.5 gms) is added and mixed for about 30 min. Insolubles are filtered through hyflow bed, washed the bed with hot methanol (60 ml), collect and cooled the filtrate to 25⁰C. Water (160 ml) is added slowly to the filtrate at temperature of 25 - 35⁰C, Mass temperature is raised, maintained for 1 hr at reflux temperature. Reaction mass temperature is cooled, maintained for 2 hrs at 0 - 5⁰C. The solid obtained is filtered, wet cake is washed with methanol (60 ml), the wet cake is dried at temperature of 70 - 75⁰C till becomes constant weight. The dry weight of 4-Methyl-6(l -methyl benzimidazol-2-yl)-2-n-propyl IH- benzimidazole is 54 gms (Yield 77.4percent). Water content by KF is 5.85percent.

Reference： [1] Patent: WO2007/10558, 2007, A1, . Location in patent: Page/Page column 5; 10-11
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4040 - 4051
[3] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 161 - 178

2
[ 25148-68-9 ]
[ 144701-48-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4040 - 4051

[ 25148-68-9 ] Synthesis Path-Downstream 1~82

1
[ 50-00-0 ]
[ 25148-68-9 ]
[ 1632-83-3 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 1936,1942

2
[ 849585-22-4 ]
[ 25148-68-9 ]
[ 3319-28-6 ]

Reference： [1]Journal of the Chemical Society,1929,p. 2828

3
[ 555-16-8 ]
[ 25148-68-9 ]
[ 3718-03-4 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 1936,1942

4
[ 25148-68-9 ]
[ 100-52-7 ]
[ 2622-63-1 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 1936,1942
[2]Journal of Organic Chemistry,2017,vol. 82,p. 3152 - 3158

5
[ 25148-68-9 ]
[ 123-11-5 ]
[ 2620-82-8 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 1936,1942

6
[ 25148-68-9 ]
[ 75-07-0 ]
[ 2876-08-6 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 1936,1942

7
[ 25148-68-9 ]
[ 123-38-6 ]
[ 14754-42-8 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 1936,1942

8
[ 25148-68-9 ]
[ 611-73-4 ]
[ 2048-37-5 ]

Reference： [1]Helvetica Chimica Acta,1952,vol. 35,p. 2301,2308

9
[ 25148-68-9 ]
[ 552-89-6 ]
[ 60418-14-6 ]

Reference： [1]Bollettino Scientifico della Facolta di Chimica Industriale di Bologna,1953,vol. 11,p. 42

10
[ 25148-68-9 ]
(4-chloro-3-methyl-phenyl)-phosphonic acid dichloride [ No CAS ]
[ 65463-69-6 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1977,vol. 15,p. 706 - 709

11
[ 79-14-1 ]
[ 25148-68-9 ]
2-chloromethyl-1-methylbenzimidazole hydrochloride [ No CAS ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1992,p. 3377 - 3384

12
[ 499-83-2 ]
[ 25148-68-9 ]
[ 112362-30-8 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1987,p. 2621 - 2630

13
[ 13288-40-9 ]
[ 25148-68-9 ]
[ 145533-45-5 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1993,vol. 32,p. 572 - 576

14
[ 5065-18-9 ]
[ 25148-68-9 ]
[ 92462-67-4 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1984,p. 1349 - 1356

15
[ 121-91-5 ]
[ 25148-68-9 ]
[ 141045-26-3 ]

Reference： [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,1993,vol. 32,p. 33 - 38

16
[ 5663-67-2 ]
[ 25148-68-9 ]
[ 2876-08-6 ]
[ 97272-83-8 ]

Reference： [1]Liebigs Annalen der Chemie,1985,p. 657 - 672

17
[ 25148-68-9 ]
[ 141838-50-8 ]
[ 141838-52-0 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051

18
[ 25148-68-9 ]
[ 152628-03-0 ]
[ 152628-02-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With methanesulfonic acid; In i-Amyl alcohol; at 130 - 135℃; for 18h;	1.2 kg of isoamyl alcohol was added to the reaction flask.Add <strong>[152628-03-0]2-n-propyl-4-methyl-6-carboxybenzimidazole</strong> (400 g, 1.83 mol) and stir.Methanesulfonic acid (176 g, 1.83 mol, 1.0 eq) was added and N-methyl-phenylenediamine hydrochloride (360 g, 1.85 mol) was added.The temperature was raised to 130-135 C to reflux and the reaction was carried out for at least 18 hours until no significant moisture was separated. After the reaction is completed, cool to about 70 C,Add 2000 ml of water, stir, adjust the pH to 6~7 with 30% NaOH solution, stir and cool to 20~25 C after completion, and filter to obtain the product, the yield is 93.0%, and the HPLC purity is 99.6%.
77.4%		4-Methyl-2-n-propyl-lH-benzimidazole-6-carboxylic acid (50 gms) is suspended in Poly phosphoric acid (300 gms), temperature is raised and maintained for 30 min at 70 - 750C, N-Methyl-o-phenylenediamine dihydrochloride. (45 gms) is added lot wise over 2 hrs and maintained at temperature of 70 - 750C for lhr. The temperature of the reaction mass is raised and maintained for 10 hrs at 130 - 1350C. Mass temperature is cooled to 7O0C, water (600 ml) is added slowly at temperature of 60 - 9O0C. Temperature of the reaction mass is cooled to 3O0C, pH is adjusted to 8.0 - 8.5 with aqueous ammonia solution. EPO <DP n="12"/>Temperature of the reaction mass is raised, maintained at 50- 550C for 1 hr, filter the solid, wet cake is washed with hot water (200 ml) and unload the wet cake. The above wet cake suspended in water (900 ml), temperature is raised and mixed for 1 hr at 50 - 550C. Filtered the solid, washed with hot water (100 ml) and dried the wet cake at temperature of 70 - 750C till constant weight. The above dry material is suspended in methanol (260 ml), and temperature is raised to 45 - 5O0C, charcoal (6.5 gms) is added and mixed for about 30 min. Insolubles are filtered through hyflow bed, washed the bed with hot methanol (60 ml), collect and cooled the filtrate to 250C. Water (160 ml) is added slowly to the filtrate at temperature of 25 - 350C, Mass temperature is raised, maintained for 1 hr at reflux temperature. Reaction mass temperature is cooled, maintained for 2 hrs at 0 - 50C. The solid obtained is filtered, wet cake is washed with methanol (60 ml), the wet cake is dried at temperature of 70 - 750C till becomes constant weight. The dry weight of 4-Methyl-6(l -methyl benzimidazol-2-yl)-2-n-propyl IH- benzimidazole is 54 gms (Yield 77.4%). Water content by KF is 5.85%.
	With polyphosphoric acid; at 150℃; for 14h;	General procedure: A solution of an appropriate ester (25.01mmol) in methanol (25mL) was added to a solution of NaOH (2.0g) in water (25mL), and the mixture was heated under reflux for 2h. After evaporation of methanol, the pH was adjusted to 4-5 by addition of aqueous citric acid. The precipitated solid was filtered, washed with ethanol and dried to yield carboxylic acid. The resulting compound was dissolved in polyphosphoric acid (10mL) at 150C. N-Methyl-o-phenylenediamine dihydrochloride (3.65g, 18.8mmol) was added to the mixture for 4 times in 4h. After stirring at 150C for 10h, the mixture was cooled and then poured into ice water (30mL). The pH was adjusted to 10 by addition of concentrated ammonia (ice cooling). The precipitated solid was filtered off, dried, and boiled in ethyl acetate (300mL). After cooling, the precipitated solid was filtered off, washed with diethyl ether, and dried to give the product as white solid.4.1.2.3 2-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (8c) [14] 8c was prepared by following the above general procedure. Yield: 60.1%. MP: 193-195 C. 1H NMR (400 MHz, CDCl3) delta: 7.82 (d, 2H), 7.30-7.53 (m, 4H), 3.95 (s, 3H), 2.89 (t, 2H), 2.61 (s, 3H), 1.79 (m, 2H), 0.91 (t, 3H). MS (ESI): [M + H]+ calcd 305.2; found 305.1.

Reference： [1]Patent: CN104974096,2019,B .Location in patent: Paragraph 0028-0035
[2]Patent: WO2007/10558,2007,A1 .Location in patent: Page/Page column 5; 10-11
[3]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051
[4]European Journal of Medicinal Chemistry,2016,vol. 115,p. 161 - 178

19
[ 25148-68-9 ]
[ 79-11-8 ]
[ 4760-35-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 3212 - 3228
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

20
[ 25148-68-9 ]
[ 142-73-4 ]
[ 152037-48-4 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1993,vol. 32,p. 572 - 576

21
[ 25148-68-9 ]
[ 614-75-5 ]
[ 123771-27-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 541 - 543

22
[ 111-94-4 ]
[ 25148-68-9 ]
[ 131296-87-2 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1994,p. 3203 - 3210

23
[ 59085-15-3 ]
[ 25148-68-9 ]
Tris<2-(1-methylbenzimidazol-2-yl)ethyl>nitromethane [ No CAS ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1994,p. 3203 - 3210

24
[ 99199-60-7 ]
[ 25148-68-9 ]
2-(6-fluoro-3,4-dihydro-2H-chroman-2-yl)-1-methyl-1H-benzimidazole [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2006,vol. 41,p. 599 - 604

25
[ 25148-68-9 ]
[ 88-99-3 ]
[ 178814-07-8 ]

Reference： [1]Journal of Chemical Research,2006,p. 530 - 533

26
[ 25148-68-9 ]
[ 160322-30-5 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1994,p. 3203 - 3210

27
[ 25148-68-9 ]
[ 772313-94-7 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1994,p. 3203 - 3210

28
[ 25148-68-9 ]
4'-[[2-n-propyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051

29
[ 25148-68-9 ]
[ 144701-48-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051

30
[ 25148-68-9 ]
[ 141838-54-2 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051

31
[ 25148-68-9 ]
[ 144702-26-1 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051

32
[ 25148-68-9 ]
[ 145533-48-8 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1992,p. 3377 - 3384

33
[ 25148-68-9 ]
[ 145533-50-2 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1992,p. 3377 - 3384

34
[ 25148-68-9 ]
[ 145533-46-6 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1992,p. 3377 - 3384

35
[ 25148-68-9 ]
[ 97272-84-9 ]

Reference： [1]Liebigs Annalen der Chemie,1985,p. 657 - 672

36
[ 25148-68-9 ]
[ 137898-62-5 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 3212 - 3228

37
[ 25148-68-9 ]
[ 137898-29-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 3212 - 3228

38
[ 25148-68-9 ]
[ 29528-19-6 ]

Reference： [1]Bollettino Scientifico della Facolta di Chimica Industriale di Bologna,1953,vol. 11,p. 42

39
[ 25148-68-9 ]
[ 25160-82-1 ]

Reference： [1]Helvetica Chimica Acta,1952,vol. 35,p. 2301,2308

40
[ 25148-68-9 ]
[ 4760-35-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With hydrogenchloride; chloroacetic acid; for 8h;Reflux;	N-Methylbenzne-1,2-diamine dihydrochloride (1.5 g,7.68 mmol) and chloroacetic acid (1.08 g, 11.52 mmol) wererefluxed in 6 M HCl (16 mL) for 8 h. After cooling to room temperatureand then in ice-bath, the mixture was neutralized by dropwiseaddition of concentrated ammonia solution. Theprecipitated product was collected by filtration and washed withcold water (5 mL). The crude product was subjected to columnchromatography on alumina (neutral) using CHCl3 as eluent. Thevolume of the solution was reduced to half of its original volume,under reduced pressure. The compound was recrystallized fromn-hexane at 298 K, followed by slow evaporation in the air. Yellowish-solid that precipitated was collected by filtration and dried inair. Yield: 1.54 g, 70%. Anal. Calc. for C9H9ClN2 (f.w. 180.63): C,59.84; H, 5.02; N, 15.51; Found: C, 60.08; H, 4.87; N, 15.46%. ESIMS(m/z): 181.04 (M+H+). 1H NMR (CDCl3, 400 MHz):deltastep 7.74 (d,J = 7.4 Hz, 1H), 7.36-7.24 (m, 4H), 4.82 (s, 2H), 3.84 (s, 3H).
	With sodium hydroxide; chloroacetic acid; In hydrogenchloride;	Step 1) Preparation of 2-Chloromethyl-1-methyl-1H-benzimidazole According to the procedure of H. Skolnik, et al., J. Chem. Soc., 65 (1943), a solution of N-methyl-o-phenylenediamine dihydrochloride (16.9 g, 0.087 mol) and chloroacetic acid (12.3 g, 0.130 mol) in 2N HCl (87 mL, 0.173 mol) was heated under reflux for 18 hours. The mixture was cooled, made basic (pH9) with 2.5N NaOH and the precipitate was collected by filtration. Recrystallization from ether/acetone gave 2.06 g of a pale green solid m.p. 143-145 C. NMR analysis showed the material to be 2-hydroxymethyl-1-methyl-1H-benzimidazole. The filtrate from the above recrystallization was concentrated and purified by flash chromatography (eluent 5% MeOH/CHCl3 to give 5.9 g (38%) of a yellow solid m.p. 95-96 C. NMR analysis showed the material to be 2-chloromethyl-1-methyl-1H-benzimidazole. NMR (DMSO-d6, 300 MHz): delta3.84 (s, 3H), 5.06 (s, 2H), 7.25 (m, 2H), 7.57 (d, J=7.3), 7.62 (d, J=7.8, 1H).

Reference： [1]Polyhedron,2019,vol. 172,p. 226 - 235
[2]Patent: US5149700,1992,A

41
[ 25148-68-9 ]
[ 116040-91-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	In hydrogenchloride;	(a) 3-(1-Methylbenzimidazol-2-yl)propan-1-ol N-Methyl-ortho-phenylenediamine dihydrochloride (4.88 g), and butyrolactone (3.22 g) were stirred at reflux for 18 hours in 4N hydrochloric acid (25 ml). The reaction mixture was cooled, the pH adjusted to 8 with concentrated aqueous ammonia and filtered. The solid was recrystallized from ethyl acetate to yield the title compound as a white solid (3.39 g 71%), m.p. 107 C. Found: C, 69.22; H, 7.38; N, 14.73. C11 H14 N2 O requires C, 69.45; H, 7.42; N, 14.72%.

Reference： [1]Patent: US4801598,1989,A

42
[ 25148-68-9 ]
[ 127099-85-8 ]
[ 13038-85-2 ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; water;	EXAMPLE 1 2-guanidino-1-methylbenzimidazole A mixture of N-methyl-o-phenylenediamine dihydrochloride (10.80g. 0.005 mol) and cyanoguanidine (9.30g, 0.11 mol) was heated under reflux in water (80 ml) for 21/2 hours. The reaction mixture was cooled, basified with excess 40% sodium hydroxide, and the resulting precipitate filtered, washed with water and dried in vacuo. (7.19g; m.p. 142-146C). This was dissolved in excess dilute hydrochloric acid and evaporated in vacuo. The crude hydrochloride was recrystallized from ethanol/ether to yield 2-guanidino-1-methylbenzimidazole dihydrochloride (600g; 42%) as off-white micro-crystals m.p. 228-238C. A solution of the dihyrochloride in water was basified with excess dilute ammonia to give off-white microcrystals (4.31g). Recrystallisation from benzene/petrol-ether (b.p. 40-60C) gave 2-guanidino-1-methylbenzimidazole (4.19g) as off-white microcrystals m.p. 178-179C.

Reference： [1]Patent: US3935314,1976,A

43
[ 25148-68-9 ]
[ 4865-84-3 ]
[ 854019-04-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,2007,vol. 44,p. 685 - 691

44
[ 959987-48-5 ]
[ 25148-68-9 ]
[ 959987-49-6 ]

Yield	Reaction Conditions	Operation in experiment
61%		Example 1 Preparation of N-(2-aminophenyI)-4-(butyramido)-N,3-dimethyl-5-nitrobenzamide (compound 7):To the mixture of 3.9 g (20 mmol) N-methylbenzene~l,2-diamme dihydrochloride and 10 ml 1.6 ml pyridine (20 mmol) was added and stirred at room temperature to obtain free N~methylbenzene-l,2-diamine solution. The resulted solution was added to the mixture of 2.66 g (10 mmol) of compound 8, 3.24 g (20 mmol) CDI and 60 ml THF, stirred for 3 h and filtered off. The wet cake was dried in an oven to obtain 2.26 g solid of compound 7 (yield: 61 %).1H NMR (300 MHz. DMSOd6): delta 8.33(s, IH), 8.19(s, IH), 7.i l(d, 2H, J=6.9 Hz), 6.63(d, 2H, J=7.8 Hz), 2.70(s, 3H), 2.30~2.36(m, 5H), 1.60(m, 2H), 0.93(t, 3H, J=7.5 Hz): ESI- MS: 369 [M-I]".

Reference： [1]Patent: WO2009/4064,2009,A1 .Location in patent: Page/Page column 8; 38

45
C₂₆H₂₂ClN₃O [ No CAS ]
[ 25148-68-9 ]
[ 1098100-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In dichloromethane; water; at 10 - 15℃; for 1h;	Example 11Preparation of 4'-[(2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yI)-benzimidazol- l-yl)-methyI]-biphenyl-2-nitrile (compound 3) from compound 9:445g (1.09 mol) of compound 9 was added into 1.5 L of CH2Cl? and then 5 Dg (4.35 mol) of SOCI2 was added. The mixture was heated under reflux temperature for 5h and the mixture was evaporated under reduced pressure to obtain a light-yellow foamy residue. The residue was dissolved in 5.5 L of CH2CI2 and added dropwise during a period of 10 h to a mixture consisting of 425 g (2.18 mol) of N-methylbenzene-l,2-diamine dihydrochloride, 916 g of NaHCO3. 3 L of water and 2 L of CH2Cl2 at 10 to 15 0C. The mixture was stirred at this temperature for Ih. Then stirring was stopped and the layers were separated. The organic layer was washed with water (2x5 L) and evaporated under reduced pressure to a residue volume of about 3-4 L. To this residue 3L of petroleum ether was added dropwise during a period of Ih at 30 0C. The formed solid was filtered and dried to obtain 560g (yield: 90%, HPLC purity: 90%) of l-((2'-cyanobiphenyl-4- yl)methyl)-4-methyl-N-(2-(methylamino)phenyl)-2-propyl-lH-benzo[d]imidazole-6- carboxamide.

Reference： [1]Patent: WO2009/4064,2009,A1 .Location in patent: Page/Page column 42

46
[ 1098100-87-8 ]
[ 25148-68-9 ]
[ 144702-27-2 ]

Yield	Reaction Conditions	Operation in experiment
		Into a reaction vessel 159g (0.375mol) of l-((2'- cyanobiphenyl-4-yl) methyl) -4 -methyl-2 -propyl-lH-benzo [d] imid- azole-6-carboxylic acid, 0.77 ml of dimethylformamide and 636ml of CH2Cl2 were added. Then, 88.5g (0.75mol) of SOCl2 were added at 00C. The reaction mixture was heated to reflux for 7 to 8 hours and concentrated to dryness. Then, 318ml of ethyl acetate were added, the reaction mixture was filtrated and the wet product was used directly in the next step.Into a reaction vessel 179g (1.69mol) of Na2CO3, 4Og of NaCl, 636ml of H2O and 636ml of ethyl acetate were added. The solution was cooled to 0-5C and 219g (1.13mol) of N- methylbenzene-1, 2-diamine dihydrochloride were added. The reaction mixture was stirred for 30min, cooled to -15 to -200C and then the product obtained in the previous step was added. After stirring for 30min the temperature slowly rose to 0-50C and after filtration the obtained product was dried at 600C for 24 hours and isolated (173g, yield 90%) .Into a reaction vessel 173g (0.317mol) of the product obtained in the previous step, 0.97g (0.015mol) of H3BO3 and 1304ml of toluene were added. The reaction mixture was heated to reflux for 3-5hours and then cooled to 10-150C and stirred for 2 hours. After filtration the wet product was dried at 600C for 24 hours and cyanotelmisartan was isolated (143g, yield 86%) . lOOg of the crude product and 200ml of ethyl acetate were heated to reflux for lhour, then cooled to room temperature and stirred for lhour. After filtration the wet product was dried at 600C for 24 hours and then isolated (95g, yield 95%) .

Reference： [1]Patent: WO2010/146187,2010,A2 .Location in patent: Page/Page column 40-41

47
[ 4546-95-6 ]
[ 25148-68-9 ]
[ 1389396-26-2 ]

Reference： [1]Inorganic Chemistry Communications,2012,vol. 23,p. 37 - 40

48
[ 25148-68-9 ]
[ 109029-13-2 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

49
[ 25148-68-9 ]
[ 1413429-75-0 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

50
[ 25148-68-9 ]
[ 1413429-76-1 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

51
[ 25148-68-9 ]
[ 109029-43-8 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

52
[ 25148-68-9 ]
[ 118001-75-5 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069
[3]Journal of Chemical Sciences,2013,vol. 125,p. 1555 - 1571

53
[ 25148-68-9 ]
[ 1413429-73-8 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

54
[ 25148-68-9 ]
[ 1413429-74-9 ]

Reference： [1]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

55
[ 79-14-1 ]
[ 25148-68-9 ]
[ 7467-35-8 ]

Reference： [1]Journal of Chemical Sciences,2013,vol. 125,p. 1555 - 1571
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069

56
[ 35274-53-4 ]
[ 25148-68-9 ]
[ 1444017-99-5 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 2954 - 2958
Angew. Chem.,2013,vol. 125,p. 3026 - 3030

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[ 4546-95-6 ]
[ 25148-68-9 ]
[ 1389396-26-2 ]

Yield	Reaction Conditions	Operation in experiment
43%	With hydrogenchloride; In water; at 120℃;	3.14 g (20 mmol) 1H-[1,2,3]triazole-4,5-dicarboxylic acid and 4.88 g (25 mmol) N-methyl-o-phenylenediamine dihydrochloride were dissolved in 50 mL 4 M HCl solution. Then the mixture was stirred at 120 C for 7-8 h. After having been cooled overnight, the precipitate was filtered and washed by hot water (50 mL×3) and ethanol (50 mL×3). White powder of HL was obtained in 43 % yield. The white powder was dissolved in DMF and colourless crystals were isolated two weeks later. Elemental analyses for HL (C11H9N5O2): Cal. (%): C, 54.32; H, 3.73; N, 28.79; Found (%): C, 54.65; H, 3.67; N, 28.92. IR (KBr, cm-1): 3244-2295(s), 2718(m), 1580(s), 1460(m), 1375(s), 1204(m), 994(m), 885(m), 756(m).

Reference： [1]Inorganic Chemistry Communications,2014,vol. 43,p. 78 - 80

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[ 25148-68-9 ]
methyl 2-{4-[(1-methyl-1H-benzimidazol-2-yl)methoxy]benzylidene}-3-oxobutanoate [ No CAS ]