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CAS No. : | 626-16-4 | MDL No. : | MFCD00000912 |
Formula : | C8H8Cl2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GRJWOKACBGZOKT-UHFFFAOYSA-N |
M.W : | 175.06 | Pubchem ID : | 12275 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.97 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.44 cm/s |
Log Po/w (iLOGP) : | 2.19 |
Log Po/w (XLOGP3) : | 2.72 |
Log Po/w (WLOGP) : | 2.86 |
Log Po/w (MLOGP) : | 3.56 |
Log Po/w (SILICOS-IT) : | 3.76 |
Consensus Log Po/w : | 3.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.95 |
Solubility : | 0.196 mg/ml ; 0.00112 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.37 |
Solubility : | 0.74 mg/ml ; 0.00423 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.43 |
Solubility : | 0.00643 mg/ml ; 0.0000367 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.27 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P260-P284-P305+P351+P338-P310 | UN#: | 2811 |
Hazard Statements: | H302-H315-H319-H330-H335 | Packing Group: | Ⅱ |
GHS Pictogram: |
* 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 |
---|---|---|
99.18% | With chlorine; 1-butyl-3-methylimidazolium chloride; at 58℃; for 3h;Irradiation; Ionic liquid; | Preparation of m-dichlorobenzyl as follows:(1) Reaction:100 mL (86.8 g) of m-xylene, 300 mL of tetrafluorohexane and 0.435 g of 1-butyl-3-methylimidazolium chloride were addedTo the reaction tank, and then in the LED light source irradiation, the reactor into the 232.44g chlorine gas at 58 reaction 3h,To obtain the m-dichlorobenzyl reaction liquid with the content of m-dichlorobenzene of 90wt%;(2) Separation:The m-dichlorobenzene reaction solution was added to a separation tank and subjected to a stratification treatment at 35 C, and the upper layer solution was introduced into the reaction tank to be relayedContinued reaction, the lower solution of m-dichlorobenzene crude;(3) Refining:The crude product of m-dichlorobenzene was added to the distillation column, vacuum distillation was carried out at 8 mmHg, the fraction of 145-149 C was collected,There was obtained 130.02 g of m-dichlorobenzyl in an amount of 99.18% and a melting point of 33.5 to 34.7C. |
116.59 g | With chlorine; 1-methyl-3-propyl-1H-imidazolium chloride; In neat (no solvent); at 60℃; for 6h;Irradiation; Green chemistry; | ( 1 ) Reaction : 100g of xylene and 0.1g 1- propyl-3-methylimidazolium chloride was added to the reaction tank, and then under LED light source, introduced into the reaction tank 106.5g of chlorine at 60 C under the reaction 6h, obtained between dichlorobenzyl content of 70wt% of inter-dichlorobenzyl reaction solution; ( 2 ) separation: The inter-dichlorobenzyl should be added to the liquid separating tank, slicing at 35 C, the upper solution into the reactor tank to continue the reaction, the solution is lower among dichlorobenzyl crude; ( 3 ) to give : The inter-dichlorobenzyl added to the crude distillation column, distillation under reduced pressure at 8mmHg, fraction collected 145-149 C, to give 116. 59g dichlorobenzyl between a level of 99%, mp 33. 5- 34. 8 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; at 80℃; under 15514.9 Torr; for 8h; | A solution of 1,3-bis(chloromethyl)benzene (15g, 85.6 mmol) and N,N-diisopropylethylamine (60 ml, 344 mmol) in methanol (107 ml) was charged to a bomb pressure reactor, which contained a magnetic stirrer bar, tetrakis(triphenylphosphine) palladium(0) (0.99g, 0.85 mmol) was added and the apparatus was purged with carbon monoxide. The apparatus was pressurized to 300psi of carbon monoxide and heated to 80C and stirred at this temperature for 8 hours. The reaction was allowed to cool to room temperature and the mixture was evaporated under vacuum. The residue was dissolved in toluene (400ml) and washed with aqueous hydrochloric acid {2N, 2 x 300ml). The toluene layer was washed with saturated aqueous sodium hydrogen carbonate solution (300ml) and saturated brine (100ml) then dried (MgSO4) and evaporated under vacuum to give dimethyl 2,2'-(1,3-phenylene)diacetate a yellow mobile oil with a few solids present (17.2g, 90%) that can be used directly in the next step. 1H NMR: when analysed by conventional proton NMR (400MHz, d6-DMSO), the compound of preparation 1a) gives the following spectrum: delta 3.62 (s, 6H), 3.67 (s, 4H), 7.16-7.17 (m, 3H) and 7.26-7.28 (m, 1H). 13C NMR: when analysed by conventional carbon NMR (100MHz, d6-DMSO), the compound of preparation 1a) gives the following spectrum: delta 40.0, 51 .7, 127.8, 128.4, 130.2, 134.4 and 171.5. MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1 a) gave a mass of 223.0966 (C12H15O4), calculated 223.0965. |
90% | With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; at 80℃; for 8h;Autoclave; | A solution of 1,3-bis(chloromethyl)benzene (15g, 85.6 mmol) and N,N-diisopropylethylamine (60 ml, 344 mmol) in methanol (107 ml) was charged to a bomb pressure reactor, which contained a magnetic stirrer bar, tetrakis(triphenylphosphine) palladium(O) (0.99g, 0.85 mmol) was added and the apparatus was purged with carbon monoxide. The apparatus was pressurized to 300psi of carbon monoxide and heated to 80C and stirred at this temperature for 8 hours. The reaction was allowed to cool to room temperature and the mixture was evaporated under vacuum. The residue was dissolved in toluene (400ml) and washed with aqueous hydrochloric acid {2N, 2 x 300ml). The toluene layer was washed with saturated aqueous sodium hydrogen carbonate solution (300ml) and saturated brine (100ml) then dried (MgSO4) and evaporated under vacuum to give dimethyl 2,2'-(1,3-phenylene)diacetate a yellow mobile oil with a few solids present (17.2g, 90%) that can be used directly in the next step. 1H NMR: when analysed by conventional proton NMR (400MHz, d6-DMSO), the compound of preparation 1a) gives the following spectrum: delta 3.62 (s, 6H), 3.67 (s, 4H), 7.16-7.17 (m, 3H) and 7.26-7.28 (m, 1 H). 13C NMR: when analysed by conventional carbon NMR (100MHz, d6-DMSO), the compound of preparation 1a) gives the following spectrum: delta 40.0, 51.7, 127.8, 128.4, 130.2, 134.4 and 171.5. MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1a) gave a mass of 223.0966 (Ci2Hi50), calculated 223.0965. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55 g | Example 1 Synthesis 1 of m-Xylylene Dithiol (Compound a-1) Containing a Small Amount of the Compound (b) In a 1 L four-neck reaction flask equipped with a stirring machine, a reflux cooling tube, a nitrogen gas purge tube and a thermometer, 74.1 g of m-xylylene dichloride, 67.2 g of thiourea and 270 g of water were mixed together, and the mixture was heated to reflux for 2.5 hours. The mixture was cooled to room temperature, and then 134.1 g of 50% aqueous solution of sodium hydroxide was added thereto under nitrogen atmosphere, and the mixture was hydrolyzed at 70 C. to 40 C. for 2 hours. Next, the reaction solution was cooled to 40 C., hydrochloric acid was added thereto until pH became 2, and subsequently the mixture was stirred for 30 minutes to carry out neutralization. After the reaction was completed, extraction was carried out with 360 mL of toluene, and then toluene and a slight amount of water were removed under reduced pressure with heating. After that, a polythiol composition containing m-xylylene dithiol obtained was purified by distillation, and then washed with water. The pressure was reduced with heating to remove water, and then filtration was carried out, thereby obtaining 55.0 g of a polythiol composition. In this polythiol composition, the content percentage of the corresponding compound (b) was 0.05% by mass. Further, the content percentage of m-xylylene dithiol was 99.6% by mass. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In butan-1-ol; at 20℃; | In a three-necked reaction flask 600 ml n-butanol and KappaOEta (1.35g24 mmol) were added respectively, 50 ml n-butanol dissolved in m-dichlorobenzyl (2.1 g, 12 mmol) and bis(2-mercaptoethyl) ether (1.66 g, 12 mmol) were added into the reaction flask. After completion of addition for an hour, the reaction mixture was stirred at room temperature overnight. The reaction mixture was vacuum-dried and chromatographed on silica gel to give white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In acetonitrile for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 96% | In N,N-dimethyl-formamide; at 100℃; for 0.05h;Microwave irradiation; | The synthesis of 3,3'-dimethyl-1,1?-(1,3-phenylenedimethylene)-bis(1H-imidazolium) dichloride can be described as follows [22].Briefly, The dicationic IL named [m-C6H4(CH2ImMe)2][Cl]2 was prepared under microwave irradiation, from the mixture: 4.26 g(4.13 ml, 50mmol) of 1-methylimidazole and 2.27 g (10mmol) of them-xylene dichloride in N,N-dimethylformamide (3 ml) at 100 C for 3 min. The resulting mixture was washed three times upon addition of diethyl ether (100 ml), and then dried in vacuo(<1mbar) for 8 h, to give a white hygroscopic solid compound in high yield (=96%).Three other dicationic ILs were synthesized by means of metathesis reactions (anion exchange) of the dichloride salts with:- [K+ PF6-] (1.2 g, 6.5 mmol) dissolved in 20 ml of demineralized water to give [m-C6H4 (CH2ImMe)+ 2] [PF6-] 2 after a separation process.- [Li+ (CF3SO2)2N-] (1.86 g, 6.5 mmol) to give [m-C6H4 (CH2ImMe+2] [(CF3SO2)2N-] 2 following the same procedure.- [NH4+ BF4-] (0.68 g, 6.5 mmol) under microwave heating to give[m-C6H4 (CH2ImMe)+ 2] [BF4-] 2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With sodium hydrogencarbonate; In N,N-dimethyl-formamide; acetonitrile; at 80℃; for 19h; | 1 (221 mg, 0.6 mmol), NaHCO3 (101 mg, 1.2 mmol), and 1,3-bis(chloromethyl)benzene (105 mg, 0.6 mmol) were suspended in ACN/DMF (1:1, 3.0 mL). The mixture was heated to 80 C for 19 hr, then cooled to rt. Solids were precipitated out with addition of diethyl ether, and collected by filtration. The crude material was further washed with diethyl ether and methanol, to give 5% yield of dimer as a pale tan-colored solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a 1.0 M solution of alkyl halide (1.0 equivalence) in N, N-dimethylformamide was added adenine (1.10 equivalence) and potassium carbonate (1.50 equivalence). The suspension was stirred at room until the completion of reaction as judged by TLC. Upon completion, reaction mixture was poured into water (20 mL), extracted with ethyl acetate (3 x 50 mL), the organic layer was washed with water (20 mL), dried over Na2SO4. The solvent was removed under reduced pressure to give the crude reaction mixture which was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride; In 1,2-dimethoxyethane; mineral oil; at 0 - 20℃; for 15h; | Reference Example 1 Synthesis of Ligand (A) (0128) (0129) To a solution of imidazole (408.7 mg, 6.0 mmol) in 10 mL of dimethoxyethane (DME), sodium hydride (60% in mineral oil, 309.3 mg, 7.73 mmol) was gradually added at 0 C. Subsequently, dichloro-m-xylene (4.87 mmol) was added, followed by stirring at room temperature for 15 hours. A 20% aqueous sodium hydroxide solution was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and then the obtained crude product was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to obtain the target product as a colorless solid in a yield of 98%. (0130) 1H NMR (500 MHz, CDCl3) delta 7.53 (s, 2H, NCHN), 7.35 (t, J=2.5 Hz, 1H, Ar), 7.10 (s, 2H, Ar), 7.09 (s, 2H, CH2NCHCH), 6.92 (s, 1H, Ar), 6.88 (s, 2H, CH2NCHCH), 5.10 (s, 4H, NCH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With silver(I) hexafluorophosphate In acetonitrile for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium azide; In water; at 70℃; for 7h;Green chemistry; | General procedure: A mixture of sodium azide (1 mmol), benzyl or alkyl halide (1 mmol), and corresponding acetylene (1 mmolof phenyl acetylene or 2 mmol of alkyl acetylene) and catalyst (5 mg of catalyst equal to 0.1 mol % of copper)was taken in a round bottomed ask containing 1 mL of H 2 O and 0.2 mL of PEG 300 and heated at 70C for3 h under vigorous stirring. After completion of the reaction (monitored by TLC), the catalyst was removedby external magnet, washed with EtOH, and dried under vacuum. The collected solvent was concentratedunder vacuum and the product was allowed to crystalize, which did not require any further purication.The obtained products were conrmed and completely characterized by physical and spectral data (see theSupporting Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: LDA / tetrahydrofuran; hexane / 1.5 h / 0 °C 1.2: 75 percent / tetrahydrofuran; hexane / 10 h / 23 °C 2.1: 68 percent / KOH / ethane-1,2-diol / 6 h / 180 °C | ||
Multi-step reaction with 2 steps 1.1: potassium carbonate / butanone / 0.08 h / 20 °C 1.2: 6 h / 60 °C 1.3: 17 h / Reflux 2.1: dihydrogen peroxide / methanol; water / 4 h / 0 - 20 °C 2.2: 16 h / 20 °C / pH 9 - 10 | ||
Multi-step reaction with 2 steps 1.1: potassium carbonate / butanone / 0.08 h / 20 °C 1.2: 6 h / Heating 1.3: 17 h / Reflux 2.1: dihydrogen peroxide / methanol; water / 4.5 h / 0 - 5 °C 2.2: 16 h / 20 °C / pH 9 - 10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine; In methanol; at 20℃; for 16h; | N,N-Di[4,5-dihydro-4(S)-isopropyl-1,3-oxazol-2-yl-methyl]amine (396.1 mg, 1.48 mmol) was dissolved in methanol (1 ml) in a 20-ml Schlenk glassware. To this solution were added triethylamine (0.2 ml, 1.43 mmol) and alpha,alpha'-dichloro-m-xylene (0.07 ml, 480 mumol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed by evaporation and the residue was purified by a silica gel column chromatography (hexane : ethyl acetate = 2 : 5 (by volume) and 3 % by volume of triethylamine) to give the title compound as a brown oil (149.9 mg). The yield was 49%.1H-NMR (300MHz, CDCl3, 35C) d: 7.42-7.25 (m, 4H, phenyl protons), 4.22(dd, J=8.2, 7.2 Hz, 4H, -CH-CHH-), 3.95(dd, J=13.8, 7.2 Hz, 4H, -CH-CHH-), 3.90-3.88(m, 4H, -CH-CHH-), 3.85(s, 4H, Ar-CH2-N-), 3.51(s, 4H, -NH-CH2-). 1.75(d, septet, J=6.6, 6.6 Hz, 2H, CH3-CH-CH3), 0.97(d, J=6.6 Hz, 6H, CH3-CH-CH3), 0.88(d, J=6.6 Hz, 6H, CH3-CH-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.7% | With N-benzyl-N,N,N-triethylammonium chloride; potassium acetate; In acetone; toluene; | REFERENCE EXAMPLE 1 Synthesis of m-xylylene glycol diacetate m-Xylylene dichloride (25.0 g, 143 mmol) and potassium acetate (34.0 g, 171 mmol) were suspended in acetone (125 ml). To the suspension was added benzyltriethylammonium chloride (4.8 g) and the mixture was refluxed for 2.5 hr. The reaction mixture was cooled and filtered. The solvent was evaporated and toluene (50 ml) was added. The toluene layer was washed with water (50 ml) and saturated brine (50 ml) and the solvent was evaporated to give m-xylylene glycol diacetate (31.3 g, 98.7%) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triphenylphosphine; In tetrahydrofuran; | REFERENTIAL EXAMPLE 66 Production of (E)-3-[2-[4-(3-thienyl)-2-thienyl]ethenyl]benzyl chloride 100 mg of 4-(3-thienyl)-2-thiophenecarboxaldehyde and 250 mg of 3-chloromethylbenzyltriphenylphosphonium chloride [prepared by refluxing a xylene solution of alpha,alpha'-dichloro-m-xylene and triphenylphosphine] were suspended in 1 ml of tetrahydrofuran, and 31 mg of 60% oily sodium hydride was added under ice cooling. The mixture was stirred for 1.5 hours at room temperature, and the solvent was evaporated. The residue was neutralized with 1 N HCl, and extracted with ethyl acetate. The extract was worked up in a customary manner, purified by silica gel column chromatography [Wakogel C-300, 5 g; eluding solvent: hexane/ethyl acetate=10/1], and recrystallized from chloroform-hexane to give 80 mg (yield 49%) of the captioned compound as a pale yellow crystalline powder, m.p. 137-138 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With hydrogenchloride; n-butyllithium; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; hexane; water; isopropyl alcohol; | EXAMPLE 1 1-[[3-[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one Hydrochloride (3:2) (CP #1) A solution of N-[2-(1-methylethoxy)phenyl]piperazine (11.95 g, 54.3 mmol, prepared as described by Martin and Scott, et. al. J. Med. Chem., 1989, 32, 1052-1056), in THF (250 mL) was treated with alpha,alpha'-dichloro-m-xylene (23.7 mL, 0.163 mol) and refluxed. After 4 h, diisopropylethylamine (10.4 mL, 55 mmol) was added and the solution was refluxed an additional 1.5 h. Treatment with 1N HCl (120 mL), water (50 mL), and ether (200 mL) caused a white solid to form which was collected by filtration. This material (7.40 g, 18.73 mmol) was partitioned into saturated aqueous NaHCO3 to give 6.0 g of an oil. A solution of this material in THF (10 mL) was added to a solution of gamma-valerolactam (1.74 g, 17.5 mmol) in THF (80 mL) which had been treated at 0 C. with 2.5 M n-BuLi/hexane (7.0 mL. 1 mol-eqiv). The resulting solution was heated at reflux for 1.5 h, treated with a suspension of gammavalerolactam (500 mg, 5.05 mmol) and 2.5 M n-BuLi/hexane (2.0 mL) in THF (10 mL) and refluxed an additional hour. The solution was cooled and partitioned between water and ether. The ether layer was separated, dried, filtered, and concentrated to give a yellow oil. This material was purified on two Waters Prep-500 silica gel columns (EtOAc/hexane; 8:2), affording 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]-methyl-piperidin-2-one as an oil, 4.80 g. A solution of this oil in i-PrOH (30 mL) was treated with conc HCI (1.15 mL) followed by ether (ca. 500 mL). A white solid was collected by filtration and recrystallized from i-PrOH/ether affording 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride (3:2) as a white crystalline solid (3.74 g, 44%), m.p. 206-208 C. Both 1 H-NMR and FAB-MS supported the assigned structure. Elemental Analysis: Calculated for C26 H35 N3 O2.1.5 HCl: C, 65.57; H, 7.72; N, 8.82; Cl, 11.17. Found: C, 65.29; H, 7.78; N, 8.68; Cl, 10.95. |
44% | With hydrogenchloride; n-butyllithium; conc HCl; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; hexane; water; isopropyl alcohol; | EXAMPLE 1 1-[[3-[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]piperidin-2-one Hydrochloride (3:2) (CP #1) A solution of N-[2-(1-methylethoxy)phenyl]piperazine (11.95 g, 54.3 mmol, prepared as described by Martin and Scott, et. al. J. Med. Chem., 1989, 32, 1052-1056), in THF (250 mL) was treated with alpha,alpha'-dichloro-m-xylene (23.7 mL, 0.163 mol) and refluxed. After 4 h, diisopropylethylamine (10.4 mL, 55 mmol) was added and the solution was refluxed an additional 1.5 h. Treatment with 1N HCl (120 mL), water (50 mL), and ether (200 mL) caused a white solid to form which was collected by filtration. This material (7.40 g, 18.73 mmol) was partitioned into saturated aqueous NaHCO3 to give 6.0 g of an oil. A solution of this material in THF (10 mL) was added to a solution of gamma-valerolactam (1.74 g, 17.5 mmol) in THF (80 mL) which had been treated at 0 C. with 2.5M n-BuLi/hexane (7.0 mL. 1 mol-eqiv). The resulting solution was heated at reflux for 1.5 h, treated with a suspension of gammavalerolactam (500 mg, 5.05 mmol) and 2.5M n-BuLi/hexane (2.0 mL) in THF (10 mL) and refluxed an additional hour. The solution was cooled and partitioned between water and ether. The ether layer was separated, dried, filtered, and concentrated to give a yellow oil. This material was purified on two Waters Prep-500 silica gel columns (EtOAc/hexane; 8:2), affording 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]-methyl-piperidin-2-one as an oil, 4.80 g. A solution of this oil in i-PrOH (30 mL) was treated with conc HCl (1.15 mL) followed by ether (ca. 500 mL). A white solid was collected by filtration and recrystallized from i-PrOH/ether affording 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride (3:2) as a white crystalline solid (3.74 g, 44%), m.p. 206-208 C. Both 1 H-NMR and FAB-MS supported the assigned structure. Elemental Analysis: Calculated for C26 H35 N3 O2.1.5 HCl: C, 65.57; H, 7.72 N, 8.82; Cl, 11.17. Found: C, 65.29; H, 7.78; N, 8.68; Cl, 10.95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; N,N-dimethylformamide, sodium carbonate; N,N-dimethyl-formamide; | EXAMPLE 6 Synthesis of 1,3-bis(2-chloro-4-carbobenzyloxyphenoxymethyl)-benzene: To a solution of 2-chloro-4-hydroxybenzoic acid benzyl ester (26.3 g, 0.1 mol) in 100 ml N,N-dimethylformamide sodium carbonate (5.3 g, 0.05 mol) was added, and stirred for 10 minutes at room temperature. Then a solution m-xylylenedichloride (8.8 g, 0.05 mol) in 50 ml N,N-dimethylformamide was added in drops to the reaction mixture in 10 minutes. The reaction mixture is stirred at 120 C. for 2 hours, cooled and blown into water to give a precipitate. The obtained precipitate was filtered, and rinsed with water. Then crued product was suspended in methanol and stirred at 60 C. for 30 minutes, cooled and filtered, and gave a white drystal of 1,3-bis(2-chloro-4-carbobenzyloxy-phenoxymethyl)-benzene (25.2 g, yield 80%): m.p. 95.8-97.0 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | In water; N,N-dimethyl-formamide; | Example 3 Synthesis of 1,3-bis(6-carbomethoxy-2-naphthoxymethyl)benzene: To sodium salt of 2-hydroxynaphthalene-6-carboxylic acid methyl ester (44.8g) N,N-dimethylformamide (200 ml) was added with stirring at room temperature. Then a solution of m-xylylenedichloride (17.5 g, 0.1 mol) in N,N-dimethylformamide was added in drops thereto in 10 minutes. The reaction mixture was stirred at 105 C. for 4 hours and then cooled to give a precipitate. The precipitate was rinsed with N,N-dimethylformamide, treated with hot water at 80 C. for 30 minutes with stirring, and then with methanol at 60 C. for 30 minutes with stirring; cooled, filtered and dried to give a white crystals of 1,3-bis(6-carbomethoxy-2-naphthoxymethyl)benzene (39.7 g, yield 77.8%): m.p. 177.3-178.0 C. NMR values: delta 3.95 (6H, s), 5.21 (4H, s), 7.20-8.52 (16H, m) Mass value: m/z=506 (M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.0% | 100 g of 4, 4 -BIPHENOL, 500 g of dimethyl sulfoxide, and 89.5 g of a 48% by weight aqueous sodium hydroxide solution and 50 g of water were charged into a 1 L four- neck flask. equipped with a thermometer, a condenser tube and a stirrer, and the mixture was heated to an inner temperature of about 80C to dissolve it. Thereafter, a solution obtained by dissolving 37.6 G of 1,3- bis (chloromethyl) benzene in 112. 8 g of dimethyl sulfoxide was added dropwise over 1 hour, and an inner temperature was raised to 120C, followed by reaction at the same temperature for 1 hour while stirring. After completion of the reaction, the resulting reaction solution was poured into 1,500 g of water, the resulting crystal was filtered, washed with 300 g of water twice and dried at an inner temperature of 80C for 12 hours to obtain 97.9 g of a crystal of 1, 3-bis [4- (4-HYDROXYPHENYL) phenoxymethyl] benzene. Apparent yield: 96. 0%. Mass spectrometric value (FD-MS): m/z = 474, melting point: 200C or higher 10 g of the above-obtained crystal of 1, 3-bis [4- (4- hydroxyphenyl) phenoxymethyl] benzene, 61 g of epichlorohydrin, 130 g of dimethyl sulfoxide, and 1.8 g of sodium hydroxide were charged into a 1 L four-neck flask equipped with a thermometer, a condenser tube and a stirrer, and an inner pressure was reduced to about 6 kPa, followed by reaction at an inner temperature about 50C while refluxing for 4 hours. An inner temperature was raised to about 70C, followed by further reaction at the same temperature for 1 hour while refluxing. After completion of the reaction, the resulting reaction solution was poured into 650 g of water, and the precipitated crystal was collected by filtration, washed with 100 g of water twice and recrystallized by using 97 g of tetrahydrofuran to obtain 2.0 g OF L, 3-bis [4- (4-OXIRANYLMETHOXY)- phenyl] phenoxymethyl] benzene. Purity: 92.3% (LC area percentage value), Apparent yield: 16. 2%. Mass spectrometric value (FD-MS): M/Z = 586, melting point : 225C. |
Yield | Reaction Conditions | Operation in experiment |
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95% | A lOOmL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (6.83 grams, 0.04 moles), with KOH (2.63 grams, 0.04 moles), and with 25 mL of DMSO. The mixture was stirred at about 35 C for about ¾ hour, then a solution of alpha,alpha' -dichloro-m-xylene (3.52 grams, 0.02 moles) in 5 mL of DMSO was added to the dark solution over about 25 minutes. After the addition, the reaction mixture was heated at 50C for about 3 hours, and then it was poured into about 400 mL of water. A sticky white solid separated. The mixture was slurried with about 75 mL of diethyl ether; the solids dissolved. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with 2 x 75 mL of diethyl ether. The ether layers were combined and were washed with 1 x 75 mL of saturated aqueous sodium chloride solution, and then they were dried over anhydrous magnesium sulfate. After filtration, the ether was removed by rotary evaporation at a bath temperature of about 60C / P=3.4 kPa to give 8.42 grams of clear, viscous brown oil. Yield = 95%. Structure was confirmed by IR, GC/MS, and JH- and 13C-NMR analyses |
Yield | Reaction Conditions | Operation in experiment |
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21.4 g | With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; at 80℃; under 15514.9 Torr; for 12h; | A solution of 1,3-bis(chloromethyl)benzene (15g, 85.6 mmol) and N,N-diisopropylethylamine (60 ml, 344 mmol) in ethanol (107 ml) was charged to a bomb pressure reactor, which contained a magnetic stirrer bar, Tetrakis(triphenylphosphine)palladium(0) (0.99g, 0.85 mmol) was added and the apparatus was purged with carbon monoxide. The apparatus was pressurized to 300psi of carbon monoxide and heated to 80C and stirred at this temperature for 12 hours. The reaction was allowed to cool to room temperature. The mixture was evaporated under vacuum. The residue was dissolved in toluene (400ml) and washed with HCl (2N, 2 x 300ml). The organic phase was washed with saturated sodium hydrogen carbonate solution (300ml) and saturated brine (100ml), dried (MgSO4) and evaporated under vacuum to give the title compound as a yellow mobile oil with a few solids present (21.4g). 1H NMR: when analysed by conventional proton NMR (400MHz, d6-DMSO), the compound of preparation 1 d) gives the following spectrum: delta 1.19 (t, J 8.0Hz, 6H), 3.64 (s, 4H), 4.08 (q, J 8.0Hz, 4H), 7.16-7.18 (m, 3H) and 7.26-7.28 (m, 1H). 13C NMR: when analysed by conventional carbon NMR (100MHz, d6-DMSO), the compound of preparation 1d) gives the following spectrum: delta 14.0, 40.2, 60.2, 127.8, 128.3, 130.1, 134.5 and 171.0. MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1d) gave a mass of 251.1277 (C14H19O4), calculated 251.1278. Subsequent conversion to 2-[3-(2-hydroxy-2-methylpropyl)phenyl]acetic acid are then similar to those described in preparation 1b) and 1c), and in WO 2007/010356. |
21.4 g | With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; at 80℃; under 15514.9 Torr; for 12h;Autoclave; | A solution of 1,3-bis(chloromethyl)benzene (15g, 85.6 mmol) and N,N-diisopropylethylamine (60 ml, 344 mmol) in ethanol (107 ml) was charged to a bomb pressure reactor, which contained a magnetic stirrer bar, Tetrakis(triphenylphosphine) palladium(O) (0.99g, 0.85 mmol) was added and the apparatus was purged with carbon monoxide. The apparatus was pressurized to 300psi of carbon monoxide and heated to 80C and stirred at this temperature for 12 hours. The reaction was allowed to cool to room temperature. The mixture was evaporated under vacuum. The residue was dissolved in toluene (400ml) and washed with HCl (2N, 2 x 300ml). The organic phase was washed with saturated sodium hydrogen carbonate solution (300ml) and saturated brine (100ml), dried (MSO4) and evaporated under vacuum to give the title compound as a yellow mobile oil with a few solids present (21.4g). 1H NMR: when analysed by conventional proton NMR (400MHz, d6-DMSO), the compound of preparation 1 d) gives the following spectrum: delta 1.19 (t, J 8.0Hz, 6H), 3.64 (s, 4H), 4.08 (q, J 8.0Hz, 4H), 7.16-7.18 (m, 3H) and 7.26-7.28 (m, 1 H). 13C NMR: when analysed by conventional carbon NMR (100MHz, d6-DMSO), the compound of preparation 1 d) gives the following spectrum: delta 14.0, 40.2, 60.2, 127.8, 128.3, 130.1, 134.5 and 171.0. MS: when analysed by mass spectrometry, using positive electrospray ionisation technique, the compound of preparation 1 d) gave a mass of 251.1277 (C14H19O4), calculated 251.1278. Subsequent conversion to 2-[3-(2-hydroxy-2-methylpropyl)phenyl]acetic acid are then similar to those described in preparation 1 b) and 1 c), and in WO 2007/010356. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Example 96. Synthesis of compound 272Compound 233 (200 mg, 0.55 mmol) and <strong>[626-16-4]3-(chloromethyl)benzyl chloride</strong> (113 mg, 0.60mmol) were dissolved in pyridine 2 mL, followed by stirring for 3 hours at room temperature.After the completion of the reaction, the reaction mixture was added with water, andextracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate,and concentrated under reduced pressure. The concentrate was dissolved in dimethylformamide, and then morpholine (0.04 mL, 0.44 mmol) and sodium iodide (cat.) were added thereto, followed by stirring for 4 hours at room temperature. After the completion of the reaction, water was added thereto, thereby forming a white solid, whichwas filtered to obtain Compound 272 (20 mg, 0.03 mmol, 32 %).?H NMR (400 MHz, DMSO-d6): oe 11.49 (m, 1H), 8.55 (s, 0.5H), 7.88 (s, 0.5H), 7.81 (m, 3H), 7.69-7.63 (m, 1.5H), 7.57-7.5 1 (m, 1.5H), 7.41 (m, 3H), 6.83 (d, J = 12.0 Hz, 2H), 6.59 (m, 1H), 6.50 (d, J = 1.80 Hz, 2H), 4.77 (s, 1H), 4.34 (s, 1H), 3.52 (m, 6H), 2.30 (m, 4H), 2.20 (m, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Example 97. Synthesis of compound 245Compound 244 (33 mg, 0.09 mmol) and <strong>[626-16-4]3-(chloromethyl)benzyl chloride</strong> (17 mg, 0.12 mmol) were dissolved in pyridine 0.2 mL, followed by stirring for 3 hours at room temperature. After the completion of the reaction, the reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesiumsulfate, and concentrated under reduced pressure. The concentrate was dissolved in dimethylformamide, and then morpholine (0.02 mL, 0.24 mmol) and sodium iodide (cat.) were added thereto, followed by stirring for 4 hours at room temperature. The reaction mixture was added with water, and extracted with ethyl acetate. The obtained organic layerwas dried over magnesium sulfate, and purified by column chromatography (ethylacetate:hexane = 1:1 2:1) to obtain Compound 245 (18 mg, 58 %).1H NMR (400 MHz, DMSO-do): oe 11.52-46 (m, 1H), 8.71-8.24 (2s, 1H), 7.89-7.76 (m, 3H),7.70-7.65 (m, 1H), 7.44-7.23 (m, 5H), 6.84 (m, 2H), 6.50 (d, J = 14.7 Hz, 2H), 4.83 (s, 1H),4.36 (s, 1H), 3.53-3.49 (m, 6H), 2.31 (m, 4H), 2.22 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; for 24h;Reflux; | 1,3-dichlorodimethylbenzene (1.38 gm) (0.01 mol) was added to <strong>[117011-70-8]4-aminophenoxyisobutyric acid</strong> (2.47 gm) (0.02 mol) and K2CO3 (2.76 gm) were dissolved in 25 ml of ethanol (anhydrous, denatured). The mixture was stirred and refluxed for 24 hrs. At the end, water was added and evaporated to remove the ethanol. 1.0 gm dithionite was added, filtered hot and acidified with acetic acid. The compound was solid and the MP 133-135. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 20h; | Tert-butyl 3,3?-azanediylbis(propane-3,1-diyl)dicarbamate (14.0 g, 0.038 mol) was dissolved in 150 mL of acetonitrile. To the solution was added 1,3-bis(chloromethyl)benzene (3.34 g, 0.019 mol), followed by diisopropylethylamine (13.2 mL, 0.076 mol). The reaction was stirred at 60 C. for 20 hours. The solvent was removed and the residue was purified by flash chromatography (silica gel, 15% methanol in dichloromethane) to give 7.56 g (52%) of pure tert-butyl-3,3?,3?,3?-(1,3-phenylenebis(methylene))bis(azanetriyl)tetrakis(propane-3,1-diyl)tetracarbamate as a brown oil. MS m/e (MH+), calculated 765.55. found 765.67. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Diphenylphosphinous acid-acetone complex (3.05 g, 0.012 mol) was kept for 3 h at 1 mmHg and 150-160C (in a bath), 10 mL of hexamethyldisilazane was added, and the mixture was kept for 3 h at 110C in a dry argon flow, next 0.87 g (0.005 mol) of m-xylylene dichloride was added, the mixture was stirred at 110C for 8 h and concentrated in a vacuum. The residue was dissolved in 15 mL of CHCl3, the solution was washed with 15% solution of Na2CO3 (2 × 15 mL), water (2 × 15 mL), and diluted (1 : 1) HCl (2 × 15 mL) and evaporated in a vacuum. The residue was chromatographed on a column with silica gel L (eluent used was HCl3 and HCl3 : iPrOH (100 : 1)). Yield 1.90 g (75.0%), mp 89-92 (benzene-hexane). 1H NMR (DCl3, delta, ppm): 3.53 (d, 4H, 2JH-P =13.80 Hz, P(O)CH2-Ar), 6.88 (m, 4H, Ar-H), 7.41-7.68 (m, 10H, Ar-H). 31P NMR (DCl3, delta, ppm): 39.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | A mixture of 3.66 g (0.016 mmol) of di(p-tolyl)phosphinous acid and 16 mL of hexamethyldisilazane was stirred for 3 h at 110C, next 1.23 g (0.007 mol) of mxylylene dichloride was added, the mixture was stirred at 110C for additional 15 h and evaporated in a vacuum. The residue was dissolved in15 mL of CHCl3, the solution was washed with 15%solution of Na2CO3 (2 × 15 mL), water (2 × 15 mL),and diluted (1 : 1) HCl and evaporated in a vacuum. The residue was chromatographed on a column with silica gel L (eluent used was HCl3 and HCl3 : iPrOH (100 : 1)). Yield 2.60 g (67%), mp 148-150C (benzene-hexane). For C36H36O2P2 anal. calcd. (%): C, 76.85; H, 6.46; P, 11.01. Found (%): C, 76.76, 76.80; H, 6.34, 6.43; P, 11.00, 10.97. 1H NMR (DCl3, delta, ppm): 2.99 (s, 6H, 2Ar-CH3), 3.50 (d, 4H, 2JH-P = 13.80 Hz, P(O)CH2Ar), 6.93 (m, 4H, Ar-H), 7.02-7.56 (m, 8H, Ar-H). 31P NMR (DCl3, delta, ppm): 39.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | 11.8 g of 1,3-bis (chloromethyl) benzene were dissolved in 160 ml N, N- dimethylformamide, warmed to 40 after 45 Zhi was added 23.3 g of anhydrous potassium carbonate, stirred for 10 minutes, slow after the NET 47.1 g was added slowly, at 43 between 48 Zhi stirred for 22 hours, cooled to room temperature, the solid was collected by filtration, the solid was dissolved in 400 ml of dichloromethane, washed twice with 150 ml each, the organic layer was separated and concentrated to dried to give the crude, the crude product is recrystallized from ethanol to obtain 44.8 g MNEPA finished product as a white solid, yield 84.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In N,N-dimethyl-formamide; at 150℃; for 1h;Inert atmosphere; | General procedure: mixture of tris(2-pyridyl)phosphine (1) (133 mg, 0.5 mmol), organic dichloride (0.25 mmol)and DMF (3 mL) was stirred at 150 for 1 h. The solvent was then removed in vacuo and Et2O(5 mL) was added to the residue. The suspension was filtered and the residue was washed threetimes with Et2O (3 × 5 mL) and dried in vacuo to give salt 4a,c,d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | A stainless autoclave, a '-dichloro [...] an interior temperature is charged into the 500 ml and methanol 10 g in 50 C reacted in the stirring time 6. Reaction in a maximum the internal essureof the reactor 4kgf/cm2(gage pressures to) was. The responses generated are to migrate to and multi function cap liquid, remove the methanol or depressurization of the fluid bag for. Obtained xylose possible with conventional stage cost for facility, hydrochloride [...] 100 ml water, NaOH aqueous solution until pH 13 and then the putter is dichloro methane by extracting the organic layer includes [...] xylose got. Xylose [...] yield is about 89%, the (HPLC) purity 99% (area) power is fed,1H-NMR data were identified structure as follows. |
Yield | Reaction Conditions | Operation in experiment |
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75% | Under a nitrogen atmosphere,TolSO2SNa (5 mmol, 1.051 g, 1 equiv.) Was added to the flask,3-Chloromethyl-benzyl chloride (6mmol, 1.05g, 1.2equiv.),TBAI (0.25 mmol, 92.4 mg, 5 mol%)And MeCN (20 mL),The reaction system was reacted at 50 for 10 h,Adding silica gel,After removal of the solvent under reduced pressure,Column chromatography to obtain thiosulfonate compound.The resulting thiosulfonate compound (3 mmol, 1 equiv, 980 mg) was added to the flask,KSAc (3.9 mmol,1.3 equiv, 445 mg)And DCM (20 mL),The reaction system was reacted at room temperature for 6 hours. After the TLC detection reaction was completed, the solvent was removed under reduced pressure,Column chromatography gave the product 2h (555 mg, 75%). (Eluent polarity: PE: EA 50: 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Example 4. Synthesis of 1 ,3-bis[(2-ethoxy-5-(irans-1 -propen-1 -yl))phenoxymethyl]benzene: To a solution of 36,8 g (0,21 mol) of vanitrope in 130ml of /'so-propanol were added 23,6 g (0,21 mol) of potassium ieri-butylate, and the mixture was stirred for 15 min. 17,5 g (0, 1 mol) of m- xylylene dichloride dissolved in 30 ml of /'so-propanol were then added within a few minutes, and the mixture was stirred for 30 min. The mixture was then heated under reflux (82 C) for 4 hours. Additional 2,3 g of potassium ieri-butylate were added , and the reaction was heated under reflux for another 2 hours. 400 ml of toluene were then added, and the mixture was cooled down to room temperature. Then 350 ml of water were added, and the mixture was stirred for 30 min. The toluene phase was separated and dried over anhydrous CaCk. After separation of CaCk, 100 ml of toluene were added, the solution was heated up to 60 C, and 50 ml of methanol were added. The batch was slowly cooled down to room temperature, additional 50 ml of methanol were added, and the mixture was stirred for 1 hour. The precipitate was then filtered off, washed with methanol, and dried in a vacuum oven at 35 C. The mother liquor was concentrated in a rotary evaporator and treated as described above to afford the second crop. Combined yield was 33,0 g (72%). Purity: 96% (HPLC area-%). Melting point: 97 C. | |
72% | To a solution of 36,8 g (0,21 mol) of vanitrope in 1 30m1 of iso-propanol were added 23,6 g (0,21 mol) of potassium tert-butylate, and the mixture was stirred for 15 mm.17,5 g (0,1 mol) of m-xylylene dichloride dissolved in 30 ml of iso-propanol were then added within a few minutes, and the mixture was stirred for 30 mm. The mixture was then heated under reflux (82 00) for 4 hours. Additional 2,3 g of potassium tertbutylate were added, and the reaction was heated under reflux for another 2 hours. 400 ml of toluene were then added, and the mixture was cooled down to room temperature. Then 350 ml of water were added, and the mixture was stirred for 30 mm. The toluene phase was separated and dried over anhydrous 0a012. After separation of CaCI2, 100 ml of toluene were added, the solution was heated up to 60 00 and 50 ml of methanol were added. The batch was slowly cooled down to room temperature, additional 50 ml of methanol were added, and the mixture was stirred for 1 hour. The precipitate was then filtered off, washed with methanol, and dried in a vacuum oven at 35 00 The mother liquor was concentrated in a rotary evaporator and treated as described above to afford the second crop. Combined yield was 33,0 g (72%). Purity: 96% (HPLC area-%). Melting point: 97 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 65℃; for 1h;Inert atmosphere; | Preparation of 3,3'-(1,3-phenylene)dipropionic acid An oven dried 2 L 3-necked jacketed flask equipped with mechanical stirrer was assembled hot, and cooled under flowing N2 then charged with 67.2 g (1680 mmol) 60% sodium hydride in mineral oil. The contents were cooled to 0 C. with circulating glycol-water and 670 mL anhydrous DMF added via cannula. 360 mL (2.37 mole) diethylmalonate was added dropwise to the flask over 40 minutes. About half way through the addition, the chiller was drained and the temperature allowed to rise to 35 C. All the NaH had dissolved and the solution was clear. To this was added 102.1 g (582 mmol) 1,3-bis(chloromethyl)benzene all at once. The temperature rose to 65 C. and solid formed. After heating with steam for 1 hour, the flask was cooled to 0 C. and a solution of 37 mL concentrated HCl in 1000 mL H2O was added. The contents of the flask were then transferred to a separatory funnel, where the viscous lower layer was withdrawn as product. After removing volatiles on a rotary evaporator, the product was distilled at 125 C. 250 mTorr to produce 228 g (86%) white liquid product. |
86% | An oven dried 2 L 3 -necked jacketed flask equipped with mechanical stirrer is assembled hot, and cooled under flowing N2 then charged with 67.2 g (1680 mmol) 60% sodium hydride in mineral oil. The contents are cooled to 0C with circulating glycol-water and 670 mL anhydrous DMF added via cannula. 360 mL (2.37 mole) diethylmalonate is added dropwise to the flask over 40 minutes. About half way through the addition, the chiller is drained and the temperature allowed to rise to 35C. All the NaH had dissolved and the solution is clear. To this is added 102.1 g (582 mmol) 1 ,3-6/s(chloromethyl)benzene all at once. The temperature rose to 65C and solid formed. After heating with steam for 1 hour, the flask is cooled to 0C and a solution of 37 mL concentrated HC1 in 1000 mL H20 is added. The contents of the flask are then transferred to a separatory funnel, where the viscous lower layer is withdrawn as product. After removing volatiles on a rotary evaporator, the product is distilled at 125C 250 mTorr to produce 228 g (86%) white liquid product. |
Yield | Reaction Conditions | Operation in experiment |
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77% | A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm length) was loaded with pentane-2,4-dione (3.00 g, 30.0 mmol), acetone (30 ml), and freshly powdered potassium carbonate (4.15 g, 30.0 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then iodoethane (4.83 g, 31.0 mmol) was added at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the temperature of this was set to 60C. The mixture was allowed to stir for 6 h. After that the excess of acetone was removed by distillation until ca. 5 ml were left in the flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(chloromethyl)benzene (1.751 g, 10 mmol) in 1 ,2-dimethoxyethane (4 ml) was added, and the vessel was rinsed with more 1 ,2-dimethoxyethane (2 x 10 ml) that was added into the flask. Then freshly powdered potassium carbonate (4.15 g, 30.0 mmol) was added and the mixture was heated to reflux in an oil bath (external temp 95 C). After 17h it was allowed to cool to room temperature and diluted with diethylether:ethylacetate (1 : 1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 ml) and ethylacetate (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane: ethylacetate 7: 1 to 3: 1) affording as a white solid 3,3'-(1 ,3-phenylenebis(methylene))bis(3-ethylpentane-2,4-dione) 5 (2.54 g, 7.69 mmol, 77 % yield) (Rf = 0.33, pentane:ethylacetate 3: 1). -1H NMR (400 MHz, CDCI3) delta 7.12 (t, J = 7.6 Hz, 1 H), 6.87 (dd, J = 7.7, 1.8 Hz, 2H), 6.70 (d, J = 1.9 Hz, 1 H), 3.13 (s, 4H), 2.06 (s, 12H), 1.87 (q, J = 7.6 Hz, 4H), 0.83 (t, J = 7.5 Hz, 6H). 13C NMR (101 MHz, CDCI3) delta 207.1 , 136.7, 131.2, 128.6, 128.3, 71.8, 36.0, 27.8, 23.3, 8.5. - HRMS (ESI-TOF) calc'd for [C22H30O4 + H]+ 359.2217; found 359.2223. | |
77% | A one neck round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser on top (50 cm length) was loaded with pentane-2, 4-dione (3.00 g, 30.0 mmol), acetone (30 ml), and freshly powdered potassium carbonate (4.15 g, 30.0 mmol). The mixture was allowed to stir at 400 rpm for 5 min. Then iodoethane (4.83 g, 31.0 mmol) was added at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the temperature of this was set to 60C. The mixture was allowed to stir for 6 h. After that the excess of acetone was removed by distillation until ca. 5 ml were left in the flask. The residue was allowed to cool down to room temperature and 1 ,3-bis(chloromethyl)benzene (1.751 g, 10 mmol) in 1 ,2-dimethoxyethane (4 ml) was added, and the vessel was rinsed with more 1 ,2-dimethoxyethane (2 x 10 ml) that was added into the flask. Then freshly powdered potassium carbonate (4.15 g, 30.0 mmol) was added and the mixture was heated to reflux in an oil bath (external temp 95 C). After 17h it was allowed to cool to room temperature and diluted with diethylethenethylacetate (1 :1) (20 ml). The suspension was filtered through a fritted plate and the solids were thoroughly washed with acetone (2 x 20 rn) and ethyiacetate (2 x 20 mi). The yellow fiitrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was purified by flash chromatography on silica (eluent pentane:ethylacetate 7:1 to 3:1) affording as a white solid 3,3'-(1 ,3-phenylenebis(methylene))bis(3-ethylpentane-2,4-dione) 5 (2.54 g, 7.69 mmol, 77 % yield) (Rf = 0.33, pentane:ethylacetate 3:1). H NMR (400 MHz, CDCI3) delta 7.12 (t, J = 7.6 Hz, 1 H), 6.87 (dd, J = 7.7, 1.8 Hz, 2H), 6.70 (d, J = 1.9 Hz, 1 H), 3.13 (s, 4H), 2.06 (s, 12H), 1.87 (q, J = 7.6 Hz, 4H), 0.83 (t, J = 7.5 Hz, 6H). 13C NMR (101 MHz, CDCI3) delta 207.1 , 136.7, 131.2, 128.6, 128.3, 71.8, 36.0, 27.8, 23.3, 8.5. HRMS (ESI-TOF) calc'd for [C22H30O4 + H]+ 359.2217; found 359.2223. |
Yield | Reaction Conditions | Operation in experiment |
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74% | A round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser (50 cm length) is charged at room temperature with acetylacetone (2.8 ml, 27 mmol, 2.7 equiv.), 2-butanone (13 ml) and freshly powdered anhydrous K2CO3 (3.73 g, 27 mmol, 2.7 equiv.). After 5 min under vigorous stirring (400 rpm), Me (1.74 ml, 28 mmol, 2.8 equiv) was added to the flask at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the temperature of this was set to 60C. The reaction mixture was stirred at that temperature for 6 h while progress was monitored through the analysis of aliquots by 1H-NMR. Then, the reaction was allowed to cool to room temperature and a solution of alpha,alpha'-dichloro-m-xylene (1.75 g, 10 mmol, 1.0 equiv.) in 1 ,2- dimethoxyethane (14 ml) was added at once, followed by a second loading of freshly powdered anhydrous K2C03 (3.73 g, 27 mmol, 2.7 equiv.). After that the resulting suspension was warmed up to reflux in an oil bath under vigorous stirring (800 rpm). The mixture was allowed to stir for 17 h and then it was allowed to cool to room temperature and diluted with EtiO (20 ml). The suspension was filtered through a fritted plate and the solids were thoughtfully washed with acetone (2 x 20 ml) and Et20 (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was recrystallized twice from ethanol affording 3,3'-(1 ,3- phenylenebis(methylene))bis(3-methylpentane-2,4-dione) (2.04 g, 61 %, 6.14 mmol) as a white solid. The mother liquors were concentrated and the residue recrystallized again from ethanol affording a second crop of bis-diketone 1 as a slightly yellow solid (0.421 g, 1.27 mmol, 13%). 1H NMR (400 MHz, CDCI3) delta = 7.13 (t, J = 7.6 Hz, 1 H), 6.92 (dd, J = 7.7, 1.8 Hz, 2H), 6.77 (t, J = 1.8 Hz, 1 H), 3.12 (s, 4H), 2.11 (s, 12H), 1.25 (s, 6H). 13C NMR (101 MHz, CDCI3) delta = 207.0, 136.7, 132.0, 128.8, 128.4, 67.5, 40.2, 27.3, 18.4. HRMS (ESI-TOF) calc'd for [C20H26O4 + Na]+ 331.1904; found 331.1902. | |
61% | A round bottom flask equipped with a magnetic stirrer (oval shape 40 x15 mm) and a Dimroth reflux condenser (50 cm length) is charged at room temperature with acetylacetone (2.8 ml, 27 mmol, 2.7 equiv.), 2-butanone (13 ml) and freshly powdered anhydrous K2CO3 (3.73 g, 27 mmol, 2.7 equiv.). After 5 min under vigorous stirring (400 rpm), Mel (1.74 ml, 28 mmol, 2.8 equiv) was added to the flask at once and the external joint between the reflux condenser and the flask was wrapped with Teflon tape. The flask was immersed in an oil bath and the temperature of this was set to 60C. The reaction mixture was stirred at that temperature for 6 h while progress was monitored through the analysis of aliquots by 1 H-NMR. Then, the reaction was allowed to cool to room temperature and a solution of alpha,alpha'-dichloro-m-xylene (1.75 g, 10 mmol, 1.0 equiv.) in 1 ,2- dimethoxyethane (14 ml) was added at once, followed by a second loading of freshly powdered anhydrous K2CO3 (3.73 g, 27 mmol, 2.7 equiv.). After that the resulting suspension was warmed up to reflux in an oil bath under vigorous stirring (800 rpm). The mixture was allowed to stir for 17 h and then it was allowed to cool to room temperature and diluted with Et20 (20 ml). The suspension was filtered through a fritted plate and the solids were thoughtfully washed with acetone (2 x 20 ml) and Et20 (2 x 20 ml). The yellow filtrate solution was concentrated in vacuo (rotavapor and high vacuum) affording a yellow oily solid that was recrystallized twice from ethanol affording 3,3'-(1 ,3- phenylenebis(methylene))bis(3-methylpentane-2,4-dione) (2.04 g, 61 %, 6.14 mmol) as a white solid. The mother liquors were concentrated and the residue recrystallized again from ethanol affording a second crop of bis-diketone 1 as a slightly yellow solid (0.421 g, 1.27 mmol, 13%). -1H NMR (400 MHz, CDCI3) delta = 7.13 (t, J = 7.6 Hz, 1 H), 6.92 (dd, J = 7.7, 1.8 Hz, 2H), 6.77 (t, J = 1.8 Hz, 1 H), 3.12 (s, 4H), 2.11 (s, 12H), 1.25 (s, 6H). 13C NMR (101 MHz, CDCI3) delta = 207.0, 136.7, 132.0, 128.8, 128.4, 67.5, 40.2, 27.3, 18.4. -HRMS (ESI-TOF) calc'd for [C20H26O4 + Na]+ 331.1904; found 331.1902. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Compound (III - a) is (S, S) - 1, 5 - double-(([...] butyl methylphosphonates) methylene) benzene.(IV) (3.10 g, 33 mmol) in n-hexane (33 mL) was cooled to -80 C,Then a solution of sec-butyllithium in n-hexane (34.7 mL of 1.0 M hexane solution, 34.7 mmol) was added dropwise.After the addition of sec-butyl lithium is completed, continue to -After stirring at 80 C for half an hour, a solution of (V-a) (2.69 g, 15 mmol) in n-hexane (15 mL) was added in one portion.The reaction was then slowly warmed to room temperature and stirred overnight.The reaction was transferred to a suspension of ethyl acetate (40 mL) and water (EtOAc).The organic layer was separated and the aqueous extracted with ethyl acetate (30 mL)Wash twice with saturated brine and dry over anhydrous sodium sulfate. It is then concentrated to give a viscous oil. Add n-hexane to the oil,The white solid particles were obtained by stirring, and the compound (III-a) (3.65 g, yield 72%) was obtained by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.4%; 10.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.333333h;Inert atmosphere; | (S)-methyl 4-(1-(6-(trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamido)ethyl)benzoate (387) (0.048 g, .105 mmol) and l,3-bis(chloromethyl)benzene (398) (0.037 g, .211 mmol) were mixed in DMF (0.8 ml), and to this mixture was added K2C03(0.044 g, .316 mmol) under N2. The resulting suspension was stirred at 100C for 20 min until the fully consumption of SM. The mixture was cooled to r.t., quenched with NaHCO3 solution (5 ml), extracted with EtOAc (2 x 50 ml). The organic layer was washed with water (2 x 10 ml), brine (2 x 10 ml), dried and concentrated. The residue was purified by flash chromatography to give (S')-4-(l-(1-(3-(chloromethyl)benzyl)-6-(trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxamido)ethyl)benzoate (399) as white solid (37 mg, 67.4% yield), and dimethyl 4,4'-((1S,1'S)-((1,1'-(1,3-phenylenebis(methylene))bis(6-(trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1,7-diyl-7-carbonyl))bis(azanediyl))bis(ethane-1,1-diyl))dibenzoate (400) as white solid (9.8 mg, 10.7% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In acetone; at 20℃; | Coumarin 8a (0.28 g, 1.0 mmol) was suspended in dry acetone(8 mL) before the addition of DIEA (0.17 mL, 1.0 mmol) and a,a0-dichloro-m-xylene (0.52 g, 3.0 mmol). The mixture was stirred atroom temperature overnight and then the solvent was removed under vacuum. The resulting crude was purified through columnchromatography (eluent: ethyl acetate in dichloromethane 50%).Yellow solid; yield: 0.31 g, 73%. 1H NMR (300 MHz, CDCl3) d:1.24e1.33 (m, 2H),1.71e1.74 (m, 3H),1.81e1.85 (m, 2H), 2.04 (s, 3H),2.32 (s, 3H), 2.76e2.82 (m, 2H), 3.39 (s, 2H), 3.90e3.94 (m, 2H), 4.71(s, 2H), 6.91e6.95 (m, 2H), 7.39e7.43 (m, 3H), 7.50 (s, 1H), 7.68 (d,J 8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; potassium iodide; In acetone; at 130℃; for 0.5h;Microwave irradiation; | General procedure: The appropriate 7-hydroxycoumarin 1a-g (2.0 mmol for 2a-gand 2i-r; 3.0 mmol for 1h) was suspended in anhydrous acetone(10 mL) before adding potassium carbonate (for 2a-g and 2i-r: 0.83 g, 6.0 mmol; for 1h: 1.2 g, 9.0 mmol), the suitable monohalide(for 1h: 2-[4-(bromomethyl)phenyl]ethanol, 3.0 mmol) or dihalide(for 2a-g and 2i-r: 6.0 mmol of alpha,alpha'-dibromo(chloro)-xylenes or trans-1,4-dibromo-2-butene; 10 mmol of 1,omega-dibromoalkanes) anda catalytic amount of KI in a Pyrex vessel charged with a magnetic stirring bar and aWeflon bar. The vessel was placed in a microwave apparatus and irradiated at 130 C for 30 min. After cooling to room temperature, the inorganic residue was filtered off after thorough washing with CH2Cl2. The solutionwas concentrated to dryness andthe resulting crude was purified as detailed below. |
65% | With potassium carbonate; In acetonitrile; for 8h;Reflux; | 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one [28] (4b, 0.38 g,2.0 mmol) was refluxed in dry acetonitrile (15 mL) in the presenceof potassium carbonate (0.41 g, 3.0 mmol) and a,a0-dichloro-mxylene(1.8 g, 10 mmol) for 8 h. After cooling to room temperature,the solvent was removed under rotary evaporation and the residuewas purified through column chromatography (gradient eluent:ethyl acetate in n-hexane 10%/30%). White solid; yield: 0.43 g,65%. 1H NMR (500 MHz, DMSO-d6) d: 2.06 (s, 3H), 2.35 (s, 3H), 4.77(s, 2H), 5.21 (s, 2H), 7.01 (dd, J 8.8, 2.4 Hz, 1H), 7.04 (d, J 2.4 Hz,1H), 7.39e7.45 (m, 3H), 7.53 (s, 1H), 7.70 (d, J 8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In acetonitrile; for 5h;Reflux; | 7-Hydroxy-4-(hydroxymethyl)-2H-chromen-2-one [56] (4a,0.38 g, 2.0 mmol) was refluxed in dry acetonitrile (15 mL) in thepresence of potassium carbonate (0.41 g, 3.0 mmol) and a,a0-dichloro-m-xylene (1.8 g, 10 mmol) for 5 h. After cooling to roomtemperature, the mixture was filtered and the solid was thoroughlywashed with chloroform. The solutionwas concentrated to drynessand the crude residue was washed several times with n-hexane/diethyl ether 2/1 v/v mixture until removal of excess startinghalide, thus yielding the desired 5b. Off-white solid; yield: 0.58 g,88%. 1H NMR (300 MHz, DMSO-d6) d: 4.71 (s, 2H), 4.77 (s, 2H), 5.22(s, 2H), 5.60 (s, 1H, dis. with D2O), 6.28 (s, 1H), 6.99 (dd, J 8.8,2.4 Hz, 1H), 7.08 (d, J 2.4 Hz, 1H), 7.33e7.46 (m, 3H), 7.54 (s, 1H),7.61 (d, J 8.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; potassium iodide; In acetone; at 130℃; for 0.5h;Microwave irradiation; | General procedure: The appropriate 7-hydroxycoumarin 1a-g (2.0 mmol for 2a-gand 2i-r; 3.0 mmol for 1h) was suspended in anhydrous acetone(10 mL) before adding potassium carbonate (for 2a-g and 2i-r: 0.83 g, 6.0 mmol; for 1h: 1.2 g, 9.0 mmol), the suitable monohalide(for 1h: 2-[4-(bromomethyl)phenyl]ethanol, 3.0 mmol) or dihalide(for 2a-g and 2i-r: 6.0 mmol of alpha,alpha'-dibromo(chloro)-xylenes or trans-1,4-dibromo-2-butene; 10 mmol of 1,omega-dibromoalkanes) anda catalytic amount of KI in a Pyrex vessel charged with a magnetic stirring bar and aWeflon bar. The vessel was placed in a microwave apparatus and irradiated at 130 C for 30 min. After cooling to room temperature, the inorganic residue was filtered off after thorough washing with CH2Cl2. The solutionwas concentrated to dryness andthe resulting crude was purified as detailed below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In 1,4-dioxane; at 100℃; for 4h;Reflux; | General procedure: A mixture of compound a (2 g, 10.6 mmol) and 1,4-dibromobutane(0.6 mL, 5.3 mmol) was refluxed in 1,4 dioxane(30 mL) at 100 C until the reaction was complete (as monitored by GC-MS). After 4 h, white precipitates of L1 appeared; these were filtered off, washed with water(3 × 5 mL), and dried at ambient temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In neat (no solvent); at 100℃; for 24h;Reflux; | General procedure: A mixture of compound b (1.51 g, 7.5 mmol) and 1,5-dibromopentane (0.5 mL, 3.7 mmol) in 1,4 dioxane(30 mL) was refluxed at 100 C, and the progress of the reaction was monitored by GC-MS. After 24 h, the sticky material was allowed to settle, decanted, washed with fresh 1,4-dioxane and dried until a shiny crystalline material L5 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.6 g | With potassium carbonate; potassium iodide; In acetonitrile; at 20℃; for 24h; | 0.5 g of the crude compound 5 was dissolved in 100 ml of acetonitrile.Add n-dichlorobenzyl 0.7g (4mmol), K2CO30.2g (1.4mmol),A catalytic amount of KI was stirred at room temperature for 24 h, the precipitate was filtered off and the filtrate was concentrated to oil.Column chromatography [PE/EA=3:1 (v:v) elution],After treatment, yellowish white oilE-4-(3-chloromethyl)benzyloxyphenylacrylic acid-4'-(nitrooxy)butyl acrylate(7) 0.6g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.6 g | With potassium carbonate; potassium iodide; In acetonitrile; at 20℃; for 24h; | 0.5 g of the crude compound 5 was dissolved in 100 ml of acetonitrile, and then 0.7 g (4 mmol) of m-chlorobenzyl chloride, K2CO30.2 g (1.4 mmol) was added, and the catalytic amount of KI was stirred at room temperature for 24 h, and the precipitate was filtered off. , column chromatography [PE/EA=3:1 (v:v) elution],After workup, 70.6 g of a yellowish white oil was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tetrabutylammomium bromide; potassium hydroxide; In dichloromethane; water; at 20℃; for 7h; | The reaction is carried out under air conditions. To a solution of RP-1a (300mg, 1.136mmol) and tetra-n-butylammonium bromide (36mg, 0.1136mmol, 10% mol) in dichloromethane (1.2mL), add 1,3-dichloromethylbenzene ( 0.33ml, 2.27mmol). After potassium hydroxide aqueous solution (50%, 3 mL) was added, the reaction mixture was stirred at room temperature for 7 hours while monitoring the reaction by thin layer chromatography (2a, Rf = 0.7; 3a, Rf = 0.3, petroleum ether / ethyl acetate = 1 / 1). After the reaction is completed, the mixture is extracted three times with dichloromethane, 10 ml each time. The combined extract was washed three times with 5 ml each time, dried over anhydrous magnesium sulfate, and after removing the solvent under reduced pressure, the residue was purified by thin layer chromatography (silica gel, petroleum ether / ethyl acetate = 1/1) to obtain pure White solid 2a (300 mg, 66%). |
Tags: 626-16-4 synthesis path| 626-16-4 SDS| 626-16-4 COA| 626-16-4 purity| 626-16-4 application| 626-16-4 NMR| 626-16-4 COA| 626-16-4 structure
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