Structure of 37091-73-9
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CAS No. : | 37091-73-9 |
Formula : | C5H10Cl2N2 |
M.W : | 169.05 |
SMILES Code : | C[N+]1=C(Cl)N(C)CC1.[Cl-] |
MDL No. : | MFCD09039290 |
InChI Key : | AEBBXVHGVADBHA-UHFFFAOYSA-M |
Pubchem ID : | 10176306 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.56 |
TPSA ? Topological Polar Surface Area: Calculated from |
6.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
-1.85 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.18 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-3.59 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.23 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.28 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.63 |
Solubility | 3.95 mg/ml ; 0.0234 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.91 |
Solubility | 20.9 mg/ml ; 0.124 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.44 |
Solubility | 6.14 mg/ml ; 0.0363 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.49 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.11 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.6% | With phosgene; In tetrachloromethane; at 5 - 50℃; for 5.5h; | For 1000 ml three port in the reaction bottle, by adding 1,3-dimethyl-2-imidazolidinone (34.2 g, 0.3 mol), carbon tetrachloride (400 ml), stirring slowly dropwise solid phosgene carbon tetrachloride solution (containing solid phosgene 30 g, 0.1 mole, carbon tetrachloride 100 ml), the reaction mixture is kept below 5 C, violent mixing 0.5 hours, the reaction at room temperature 1 hour, heating to 50 C, maintain 4 hours. To be the reaction product is cooled to room temperature, filter, a small amount of carbon tetrachloride washing, get a pure white crystalline product chloropivaloyl 1,3-dimethyl-2-chlorotrifluoromethylbenzene imidazoline 49 g, yield of 96.6%, |
70.1% | With oxalyl dichloride; In benzene; at 20℃; for 5h;Inert atmosphere; | Under an inert atmosphere, 1,3-Dimethyl-2-imidazolidinone (7.0 mL, 64 mmol) was dissolved in anhydrous benzene (25 mL). To this oxalyl chloride (7.2 mL, 80 mmol) was added, and the solution was refluxed for 5 hours, and allowed to sit at room temperature overnight. The solution was filtered quickly to give 2-chloro-1,3-dimethylimidazolinium chloride (7.5815 g, 44.85 mmol) in 70.1% yield. |
53% | With Phthaloyl dichloride; at 140℃; for 5h; | 1,3-dimethyl-2-imidazolidinone 3.50g (30.7 mmol), and the mixture was heated for 5 hours and stirred at 140 of chloride phthalic acid 6.54g (32.4 mmol). After cooling, the crystal upon addition of 1,4-dioxane 25mL precipitated, filtered with a glass filter, washed twice with 1,4-dioxane 10 mL, washed once with ether 5 mL, and dried under vacuum. To give 2-chloro-1,3-dimethyl imidazolium chloride 2.72g (53% yield). |
With oxalyl dichloride; In chloroform; for 20h;Reflux; Inert atmosphere; Schlenk technique; | To a solution of 1,3-dimethyl-2-imidazolidinone (1.0 mL, 9.3 mmol) dissolved in dry CHCl3 (20 mL) was added oxalyl chloride (3.9 mL,44.7 mmol) dropwise. The yellow solution was stirred at reflux for 20 h. The solvent was removed under vacuum. The remaining solid was washed twice with Et2O | |
With oxalyl dichloride; In toluene; at 80℃; for 12h;Inert atmosphere; | General procedure: N,N?-Disubstituted cyclic urea (6 mmol) was dissolved in toluene (50 mL) and oxalyl chloride (7.6 g, 5.2 mL, 60 mmol) was added. The resulting mixture was stirred at 80 C for 12 h. The white precipitate was then filtered off under an inert atmosphere, washed with anhydrous Et2O, and dried in vacuo to give the pure chloride as a white solid. | |
With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 6h;Inert atmosphere; | General procedure: A solution of urea (50mmol) in dry CH2Cl2 (10mL) was added dropwise at 0C under an Argon atmosphere to a solution of freshly distilled oxalyl chloride (55 mmoL) in dry CH2Cl2 (25ml). The reaction mixture was allowed to reach rt. and was stirred at rt 6h. The solvent was then evaporated under reduced pressure to afford a brown solid which was washed with dry Et2O (4×20mL) to give a white solid. | |
With oxalyl dichloride; In toluene; at 60℃; for 20h;Inert atmosphere; Cooling with ice; | General procedure: 1 ml urea derivatives dissolved in 400 ml toluene. 1.2 mol oxalyl chloride dissolved in toluene and then instilled to previous system in ice bath, protected by nitrogen and with strongly stirred. Then stirred in room temperature for 2h and heated in 60 for 20h. The mixture was cooled and filtered in reduced pressure, washed by ethyl acetate to get white solid. Needle-like crystal was harvested with 95%-97% yields after crystallization via ethyl acetate and acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 20℃; for 5h;Inert atmosphere; | General procedure: To a solution of a 2-chloro-4,5-dihydroimidazolium chloride in CH2Cl2 was added Et3N followed by a primary amine at r.t. and the mixture was stirred at r.t. After the addition of ice-water and then 20percent aq NaOH solution, the mixture was extracted with toluene. The combined organic solution extracts were washed with H2O and brine to give a guanidine that was purified by column chromatography (silica gel or NH-silica gel) if necessary. An alkyl bromide was added to a solution of the guanidine in MeCN at r.t. and then the mixture was stirred at r.t. After evaporation of the solvent the residue was isolated either as the bromide by successively washing with hexane and Et2O or after purified by column chromatography (silica gel) if necessary as the hexafluorophosphate by treatment with aq NH4PF6 solution at r.t. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In tetrahydrofuran; dichloromethane; for 6h;Heating / reflux; | A mixture of lambda/-[1-(3,4-diaminophenyl)ethyl]-2-methylpropane-2-sulfiotanamide and GDI (569 mg, 3.51 mmol) in THF - DCM (10 ml - 10 ml) was refluxed for 6 hours. After cooling to the room temperture, water (10 mL) was added to the mixture. The mixture was extracted with EtOAc (150 ml) and organic layer was washed with brine (30 ml), dried over sodium sulfate and concentrated. The residue was recrystaliized from EtOAc to afford 430 mg (65percent) of the title compound as a pale brown solid. 1H NMR (300MHz,DMSO-d6) delta ppm 1.11 (9H, s), 1.38 (3H, d, J = 7.3 Hz), 4.37-4.28 (1H, m), 5.53 (1H, d, J = 6.6 Hz), 6.84(1H, d, J = 7.3 Hz), 6.93 (1 H, d, J = 8.1 Hz), 6.99 (1H, s), 10.54 (1H, br.s), 10.60 (1H, br.s). MS (ESI) m/z282 (M + H)+, 280 (M - H)". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid; | Example 9 A dichloromethane solution containing 400 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid described in Example 1 was cooled with ice followed by addition of 0.20 ml of 1-methylpiperazine, 2 ml of triethylamine and 301 mg of <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the dichloromethane-methanol elude in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid 4-methylpiperazylamide (264 mg, yield: 50percent). The physicochemical properties of this compound are described in Table 5, Compound No. 20. (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid cyclohexylester was produced in the same manner from (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With formic acid; triethylamine; In chloroform; | EXAMPLE 1 Preparation of (2RS)-2-[N-(carboxymethyl)-N-{(1R,2R)-2-(2-fluoro-4-biphenylyl)-1-methyl-4-phenylbutyl}carbamoyl]cyclopropane- 1,1-dicarboxylic acid 73 mg of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-2-(2-fluoro-4-biphenylyl)-1-methyl-4-phenylbutyl}amine obtained in Reference Example 1, 140 mg of 2,2-di-tert-butyl 1,2,2-cyclopropanetricarboxylate obtained in Reference Example 2 and 1.0 ml of triethylamine, were dissolved in 1 ml of chloroform, and a solution of 91 mg of <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> in 1 ml of chloroform, was added under cooling with ice, followed by stirring at the same temperature for 20 minutes and then stirring at room temperature for two hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to obtain 114 mg (yield: 98percent) of a tri-tert-butyl ester of the above identified compound as a colorless oily substance. 2 ml of formic acid was added to 78 mg of the above ester, followed by stirring at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain 60 mg (yield: quantitative) of the above identified compound as a colorless oily substance. 1 H-NMR(CD3 OD) delta:0.80-1.05(3H, m), 1.50-1.90(2H, m), 2.00-3.40(6H, m), 3.60-4.60(3H, m), 6.95-7.50(13H, m). FAB-MS:548(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium bicarbonate; triethylamine; trifluoroacetic acid; In chloroform; | EXAMPLE 3 Preparation of 4-[N-(carboxymethyl)-N-{(1R,2R)-2-(2-fluoro-4-biphenylyl)-1-methyl-4-phenylbutyl}carbamoyl]phthalic acid 61 mg of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-2-(2-fluoro-4-biphenylyl)-1-methyl-4-phenylbutyl}amine obtained in Reference Example 1, 39 mg of trimellitic anhydride and 85 mul of triethylamine, were dissolved in 3 ml of chloroform, and a solution of 91 mg of <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> in 1 ml of chloroform, was added under cooling with ice, followed by stirring at room temperature for two hours. To the reaction solution, 1 ml of a saturated sodium hydrogen carbonate aqueous solution was added, followed by vigorously stirring at room temperature for one hour. Then, it was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract solution was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To the residue, 2 ml of trifluoroacetic acid was added, followed by stirring at room temperature for one hour. Then, the reaction solution was concentrated under reduced pressure. The residue was purified by medium pressure liquid chromatography (Lobar column.(TM)., Size A, RP-8, manufactured by Merck Co.; acetonitrile/0.1percent trifluoroacetic acid aqueous solution=1/1), followed by treatment with chloroform-hexane to obtain 33 mg (yield: 42percent) of the above identified compound as white powder. 1 H-NMR(CD3 COCD3) delta:1.08(3H, d, J=6.3 Hz), 1.80-3.30(5H, m), 3.90-4.40(3H, m), 6.95-7.90(16H, m). FAB-MS:584(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; triethylamine; In tetrahydrofuran; methanol; chloroform; | EXAMPLE 8 Preparation of trisodium (4R,5R)-4-[N-(carboxylatomethyl)-N-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}carbamoylhydroxymethyl]-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate 11.6 mg of N-(methoxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine obtained in Example 51, 9.6 mg of dimethyl 2-(1-acetoxycarboxymethyl)-2,3-O-isopropylidene-L-tartarate obtained in Reference Example 6 and 20 mul of triethylamine, were dissolved in 0.5 ml of chloroform, and a solution of 9.7 mg of <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> in 0.5 ml of chloroform, was added under cooling with ice, followed by stirring at room temperature for 4 hours. The reaction solution was purified by silica gel thin layer chromatography (Kieselgel.(TM).60F254, Art.(TM).5744; hexane/acetone=2/1), to obtain 11.0 mg (yield: 53percent) of a condensate as a colorless foam. 10.0 mg of the above condensate was dissolved in 0.6 ml of tetrahydrofuran, and 60 mul of a 1N sodium hydroxide aqueous solution was added, followed by stirring at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and then, methanol was added to the residue. Precipitated crystals were collected by filtration to obtain 5.7 mg (yield: 65percent) of the above identified compound as white powder. 1 H-NMR(CD3 OD) delta:0.79-1.00(3H, m), 1.32, 1.38, 1.49 and 1.68(total 6H, each s), 1.80-3.20(5H, m), 3.50-4.05(3H, m), 4,50-5.35(2H, m), 6.93-7.40(14H, m). |