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CAS No. : | 593-71-5 | MDL No. : | MFCD00001078 |
Formula : | CH2ClI | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PJGJQVRXEUVAFT-UHFFFAOYSA-N |
M.W : | 176.38 | Pubchem ID : | 11644 |
Synonyms : |
|
Num. heavy atoms : | 3 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 24.68 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.27 cm/s |
Log Po/w (iLOGP) : | 1.4 |
Log Po/w (XLOGP3) : | 1.56 |
Log Po/w (WLOGP) : | 1.62 |
Log Po/w (MLOGP) : | 1.82 |
Log Po/w (SILICOS-IT) : | 2.02 |
Consensus Log Po/w : | 1.68 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.92 |
Solubility : | 2.14 mg/ml ; 0.0121 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 11.9 mg/ml ; 0.0676 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.85 |
Solubility : | 2.5 mg/ml ; 0.0142 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.28 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 | UN#: | 2810 |
Hazard Statements: | H301-H315-H319-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
97% | With methyllithium; lithium bromide In diethyl ether at -78℃; for 0.5 h; | General procedure: To a cooled (–78°C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi–LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With methyllithium; lithium bromide In diethyl ether at -78℃; for 1 h; | General procedure: To a cooled (–78°C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi–LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 2.83333 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; ethyl acetate at 0℃; Stage #3: at 0 - 20℃; for 0.666667 h; |
(Production Example 1) Synthesis of 2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To the mixture of triisopropyl borate (15 ml, 65 mmol), chloroiodomethane (13 g, 72 mmol), and tetrahydrofuran (78 ml), n-butyllithium (a 1.6 M n-hexane solution, 41 ml, 65 mmol) was added dropwise at -78°C (an outer temperature) over 20 minutes, and then the obtained mixture was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0°C (an outer temperature), and a 4 N hydrochloric acid-ethyl acetate solution was added dropwise thereto at the same temperature until the reaction mixture became neutral. At the same temperature, pinacol (7.7 g, 65 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 40 minutes. The solvents were evaporated under reduced pressure, and then the obtained residue was distilled under reduced pressure (63-70°C, 11 mmHg), thereby obtaining the entitled compound (9.2 g, 52 mmol, 81percent). 1H-NMR Spectrum (CDCl3) δ(ppm): 1.30(12H, s), 2.97(2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 24.17 h; |
To a stirred solution of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1 1 .0 mL, 53.75 mmol) and chloroiodomethane (4.3 mL, 59.12 mmol) in anhydrous THF (100 mL), cooled to -78 °C, was added cold n-butyllithium solution (23.94 mL, 59.12 mmol) dropwise. After stirring for 30 min at this temperature, chlorotrimethylsilane (8.2 mL, 64.50 mmol) was added dropwise. After stiring for 10 min, the reaction mixture was allowed to return to room temperature and stirred for 24 h. Water (80 mL) was added and the mixture extracted with Ε∑0 (2 x 80 mL). The organic extracts were combined, washed with water (2 x 80 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (Heptane/EtOAc 99:1 to 95:5).to yield 2-(chloromethyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (4.35 g, 24.65 mmol, 46percent yield) as a colourless oil. NMR (400 MHz, DMSO-cfe, δ): 2.99 (s, 2H), 1 .32 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane at -78 - 20℃; for 2.83 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; ethyl acetate at 0℃; Stage #3: at 0 - 20℃; for 0.666667 h; |
To a mixture of triisopropyl borate (15 ml, 65 mmol), chloroiodomethane (13 g, 72 mmol) and tetrahydrofuran (78 ml) was added dropwise n-buthyllithium (1.6M n-hexane solution, 41 ml, 65 mmol) at -78°C (external temperature) over 20 minutes. Then, the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was cooled at 0°C (external temperature), to the mixture was added dropwise a 4N hydrochloric acid-ethyl acetate solution in order to neutralize at the same temperature. To the reaction mixture was added pinacol (7.7 g, 65 mmol) at the same temperature, and then, the reaction mixture was stirred at room temperature for 40 minutes. After the solvent was distilled off under reduced pressure, the resulting residue was distilled under reduced pressure (63-70°C, 11 mmHg) to obtain the title compound (9.2 g, 52 mmol, 81percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 1.30 (12H, s) , 2.97(2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: With sodium ethanolate In N,N,N,N,N,N-hexamethylphosphoric triamide at 20℃; for 24 h; Large scale Stage #2: at 20℃; for 2 h; Large scale |
To 50L reactor, add 1.9 kg intermediate 4, hexamethylphosphoric acid triamide 19L, sodium ethoxide 0.26 kg. React under the condition of room temperature for 24 hours. Add chloroiodomethane 1.4 kg. Stir for 2 hours. The reaction liquid quickly add 570L in water, separate out a large amount of yellow solid, filtering. The filter cake is added to the chloroform 5.7L dissolved, for sequentially 0.3M sodium thiosulfate solution 1.9L, 0 . 4M sodium bicarbonate solution, 1.9L saturated salt water 1.9L washing liquid, anhydrous sodium sulfate drying, decolorized with active carbon. Filtered, concentrated under reduced pressure to dryness; anhydrous ethanol is added 13.3L, heating to reflux, the solid is completely dissolved, gradually cooling crystallization, filtration. 40 °C blast drying, to obtain white solid 1.6 kg, yield 89percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at -78℃; for 1 h; | LDA (169 mL, 163 mmol) was added dropwise at 78 °C through a cannula to a mixture of iodochloromethane (9.45 mL, 130 mmol) and ethyl N-[(1,1-dimethylethyl)oxy]carbonyl}-O-(phenylmethyl)-L-tyrosinate (prepared as described in J. Med. Chem. 1990, 33, 1620) also at 78 °C. The resulting dark solution was stirred for one hour at 78 °C, then 50 mL of a 1:1 acetic acid:tetrahydrofuran solution was added slowly and the reaction was warmed to ambient temperature, poured onto a mixture of ice water and ethyl acetate, and the aqueous solution was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown solid was suspended in cold ether and filtered to give the title compound (3.17 g). The filtrate was concentrated under reduced pressure to give an additional 7.4 g of slightly impure title compound (10.57 g, 80percent yield). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.80-3.21 (m,2H), 3.87-4.25 (m, 2H), 4.42-4.72 (m, 1H), 5.03 (s, 2H), 6.81-7.17(m, 4H), 7.29-7.57 (m, 5H); LC/MS (m/z) ES+=427 (M + 23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 0.333333h;Inert atmosphere; | To methyl (R)-(+)-2,2-dimethyl-l,3-dioxolane-4-carboxylate (5 g, 30.5925 mmol, 1 eq) and chloroiodomethane (5.757 mL, 13.4898 g, 76.4812 mmol, 2.5 eq) in 70 ml of dry THF, cooled at -78C, were added lithium diisopropylamide (38.2406 mL, 76.4812 mmol, 2.5 eq) over 10 minutes and kept stirring for additional 10 minutes before addition of 20 ml a solution of acetic acid in 120ml of THF and finally 50ml of water. The mixture was poured in a stirred biphasic solution of 600ml of ethyl acetate and 350ml of sodium hydroxide IN. The pH was basified by addition of 50ml of sodium hydroxide IN.Aqueous layers were extracted by 600ml of ethyl acetate. Organic layers were washed by brine, dried (MgSC^), and concentrated in vacuo. The resulting brown oil was purified two successive chromatography on silica gel (DCM 100%) yielding the title compound as a pale yellow oil (1.6g, 30%). 1H NMR delta: 4.62 (dd, J 7.8 Hz, J 5.1 Hz, 1 H), 4.46 (dd, J22.0 Hz, J 17.1 Hz, 2 H), 4.26 (t, J 8.9 Hz, 1 H), 4.09 (dd, J 9.0 Hz, J 5.0 Hz, 1 H), 1.50 (s, 3 H), 1.39 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With lithium diisopropyl amide; at -78℃; for 1.0h; | LDA (169 mL, 163 mmol) was added dropwise at 78 C through a cannula to a mixture of iodochloromethane (9.45 mL, 130 mmol) and <strong>[127132-32-5]ethyl N-[(1,1-dimethylethyl)oxy]carbonyl}-O-(phenylmethyl)-L-tyrosinate</strong> (prepared as described in J. Med. Chem. 1990, 33, 1620) also at 78 C. The resulting dark solution was stirred for one hour at 78 C, then 50 mL of a 1:1 acetic acid:tetrahydrofuran solution was added slowly and the reaction was warmed to ambient temperature, poured onto a mixture of ice water and ethyl acetate, and the aqueous solution was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The brown solid was suspended in cold ether and filtered to give the title compound (3.17 g). The filtrate was concentrated under reduced pressure to give an additional 7.4 g of slightly impure title compound (10.57 g, 80% yield). 1H NMR (400 MHz, CDCl3) delta 1.40 (s, 9H), 2.80-3.21 (m,2H), 3.87-4.25 (m, 2H), 4.42-4.72 (m, 1H), 5.03 (s, 2H), 6.81-7.17(m, 4H), 7.29-7.57 (m, 5H); LC/MS (m/z) ES+=427 (M + 23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | at 20℃; for 4h;Inert atmosphere; | Di-tert-butyl phosphate tetrabutylammonium salt (0.826 g, 1.83 mmol) was combined with chloroiodomethane (1.6 mL, 18.3 mmol) and was stirred at r.t. for 4 h during which time a precipitate formed. Tert-butyl methyl ether was then added and the mixture was vigorously stirred for 20 min resulting in the formation of a white precipitate. The precipitate was removed by filtration through a pad of Celite and the filtrate was concentrated. The resulting yellow oil was then taken up in tert-butyl methyl ether (16 mL) to precipitate additional salts. The mixture was filtered through a pad of Celite and the filtrate was concentrated and dried under vacuum to afford di-tert-butyl (chloromethyl) phosphate (0.457 g, 97% yield) as an oil: 1H NMR (500 MHz, CHLOROFORM-d) delta 5.62 (d, J=14.5 Hz, 2H), 1.50 (s, 18H). |
91% | In benzene; at 20℃; for 20h;Darkness; | Compound 2 was prepared by using an alternative method. To a solution of compound (1) (11.1 mmol) in benzene (0.9 mL/mmol) was added chloroiodomethane (111 mmol). The reaction mixture was stirred at room temperature for 20 hours in the dark. The crude mixture was concentrated under reduced pressure and the oily residue was dissolved in diethyl ether. The precipitate was filtered off and the organic layer was washed with a saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on silica (cyclohexane/EtOAc 9:1 then 8:2) to afford the expected compound as a colorless oil in 61% yield. ?H NMR (CDC13, 400MHz) oe (ppm) 5.64 (d,J=l2Hz, 2H), 1.51 (s, 18H). |
49% | In benzene; at 20℃; for 3h; | Method 2: Tetrabutylammonium di-t-butyl phosphate is prepared by dissolving di-t-butyl phosphate [2Og, 94 mmol (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, Vol. 27, 3163 (1971)] in methanolic tetrabutylammonium hydroxide (47 mL of IM solution, 47 mmol) . The reaction mixture has a temperature of 23C and pH of 4.33. The pH of the reaction mixture is adjusted to 6.5-7.0 by addition of methanolic tetrabutylammonium hydroxide (48 mL of IM solution, 48 iranol) over 0.2 h. The reaction mixture is stirred for 0.5 h at approximately 2betaC and then is concentrated under reduced pressure at a bath temperature below 40C. The crude residue is azeotroped three times by adding toluene (3x100 mL) and then the mixture is concentrated under reduced pressure. The crude residue is then triturated in cold hexanes (0C) for 1 h and then the solid is collected by filtration, washed with a minimum amount of cold hexanes and dried to give a first crop of tetrabutylammonium di-t-butyl phosphate as a white- solid.(24.0 g) . The mother liquor is concentrated under reduced pressure and then triturated in cold hexanes (20 mL) for Ih.The solid is collected by filtration, washed with a minimum amount of cold hexanes and dried to give a second crop of tetrabutylammonium di-t-butyl phosphate as a white solid. [(8.5g), 32.5 g total (77%)]. A solution of tetrabutylammonium di-t-butyl phosphate (218 g, 480 mmol) in benzene (200 mL) is added dropwise to stirred chloroiodomethane (800 g, 4535 mmol) over 1.5 h at rt. The reaction mixture is stirred an additional 1.5 h at rt and then is concentrated under reduced pressure. The oily residue is dissolved in Et2O and filtered to remove white solids that precipitates. The organic layer is washed with saturated NaHCO3 and H2O/brine (1/1) . The organic layer is then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a red brown oil (320 g) . The red brown oil is subjected to chromatography on silica gel (800 g) eluted with 20% EtOAc/Hexanes, 25% EtOAc/Hexanes then 30% EtOAc/Hexanes. The product containing fractions are concentrated under reduced pressure to yield a golden oil. The oil is diluted with CH2C12 (30 mL) , concentrated under reduced pressure and then dried under vacuum to yield the compound 3 (61.3g, 49% yield). IH NMR (Benzene-dbeta) delta5.20 (2H, d, J=15), 1.22 (18H, s) . |
In benzene; at 20℃; for 4h;Product distribution / selectivity; | Phosphate ester A (45.1 g, 0.1 mol) and chloroiodomethane B (200 g, 1.14 mol) were combined in 100 ml of benzene and the mixture was stirred at room temperature for four hours before benzene was removed under vacuum. Then, 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate provided di-tert-butyl chloromethyl phosphate, which was utilized in the next step without any purification | |
In acetone; at 40℃; | Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) is dissolved in methanol (15 g): to this solution at 0 C. a slight excess of concentrated HCl is slowly added with efficient stirring at 0 C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetrabuthylammonium hydroxide 1 M in methanol (20.14 mmole) while keeping the reaction cooled at 0 C. with efficient stirring. The resulting clear solution is placed under reduced pressure to give the intermediate product. The <strong>[68695-48-7]tetrabuthylammonium di-tert-butyl-phosphate</strong> dissolved in acetone is then added dropwise to 53.3 grams of chloroiodomethane (302.1 mmole) and stirred at 40 C. for 1-2 hours. The solvent and excess of chloroiodomethane are distilled off, the reaction mass suspended in TBME and then filtered. The filtrate is washed by a saturated solution of sodium bicarbonate and water and then placed under reduced pressure to substitute the solvent by acetone, i.e., to remove the solvent after which it is replaced with acetone. The chloromethyl di-tert-butyl phosphate 7-20% in acetone is used in the next step without further purifications (70-80% yield): 1H-NMR (CD3OD, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) delta -11.3 (s, 1P). | |
In acetone; at 40℃; | Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole)Was dissolved in methanol (15 g) and to this solution at 0 C.,Slowly add a slight excess of concentrated HCl and perform efficient stirring at 0 C.The addition of acid causes the precipitation of potassium chloride.The solids are then filtered and washed with methanol.By adding an equimolar amount of tetrabutylammonium hydroxide 1 M (20.14 mmole) in methanol,Converting the compound in the mother liquor to the ammonium form,Meanwhile, the reaction is cooled to 0 C. and efficient stirring is carried out.The resulting clear solution is placed under reduced pressure to provide the intermediate product.Thereafter, 53.3 grams of chloroiodomethane (302.1 mmole)Tetrabutylammonium di-tert-butylphosphate dissolved in acetone was added dropwise,And stir at 40 C. for 1-2 hours.The solvent and excess chloroiodomethane were distilled off,The reaction mass is suspended in TBME and then filtered.The filtrate is washed with a saturated solution of sodium bicarbonate and water, then placed under reduced pressure and the solvent is replaced with acetone, ie the solvent is removed,Replace it with acetone.7 to 20% of chloromethyl di-tert-butyl phosphate in acetone is used in the next step without further purification (70 to 80% yield): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With diethylzinc; In n-heptane; 1,2-dichloro-ethane; at 0 - 5℃; for 3h; | Preparation 28 1-Bromo-4-(cyclopropoxy)benzene To a 0 C. solution of 1-bromo-4-vinyloxy-benzene (31.75 g, 159.51 mmol) and chloroiodomethane (101.3 g, 574.2 mmol) in 1,2-dichloroethane (410 mL), slowly add diethylzinc (1 M in heptane, 380 mL) over 1 hr while maintaining the temperature below 5 C. Stir the white mixture at 0-5 C. for 2 hours. Quench the reaction slowly at 5 C. with aqueous saturated ammonium chloride (400 mL, exothermic) and separate the layers. Extract the aqueous layer with diethyl ether (2*200 mL). Combine the organic layers, wash with saturated ammonium chloride (400 ml), dry over sodium sulfate, filter, and concentrate under reduced pressure to give the title compound (33 g, 97%) as an oil: GCMS: 212. |
94% | Diethylzinc (15 % in hexanes, 95.5 mL, 116 mmol) was added to a mixture of 1 -bromo-4-vinyloxybenzene (11.5 g, 58 mmol), chloro-iodomethane (41 g, 232 mmol) and dichloro ethane (180 mL) over 3 h at 0 0C. After 30 min NH4Cl (aq, sat, 200 mL) and of petroleum ether (300 mL) were added. The organic phase was collected and concentrated. The residue was dissolved in petroleum ether, filtered and concentrated to afford the sub-title compound (11.7 g, 94%). | |
94% | Diethylzinc (15 % in hexanes, 95.5 mL, 116 mmol) was added to a mixture of 1 -bromo-4-vinyloxybenzene (11.5 g, 58 mmol), chloroiodomethane (41g, 232 mmol) and dichloroethane (180 mL) over 3 h at 0 0C. After 30 min, NH4Cl (aq, sat, 200 mL) and petroleum ether (300 mL) were added. The organic phase was collected and concentrated. The residue was dissolved in petroleum ether, filtered and concentrated to afford the sub-title compound (11.7 g, 94%). |
94% | To mixture of 1-bromo-4-vinyloxybenzene (11.5 g, 58 imnol), chloro- iodomethane (41g, 232 mmol) and dichloroethane (180 mL) was added diethylzinc (15 % solution in hexanes; 95.5 mL, 116 mmol) over 3 h at 0C. After 30 min stirring, NH4CI solution (200 mL, aq. sat. ) and light petrol (300 mL) was added. The organic phase was separated and concentrated in vacuo (8 bar, 50 C). The residue was redissolved in light petrol and the insoluble material was filtered off. The filtrate was concentrated to afford sub-title compound (11.7 g, 94%). | |
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0℃; for 3h; | c)39.0 g (176 mmol) 1-bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled to 0 C. During 1 h 200 mL (200 mmol) diethylzinc solution (c=1 mol /1 in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2×). The organic phases are combined, washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE) C9H9BrO (M=213.1 g/mol)EI- MS: 212/214 [M]+Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In 1,2-dichloro-ethane; at 0℃; for 3h; | c) 39.0 g (176 mmol) 1 -Bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled to 0C. During 1 h 200 mL (200 mmol) diethylzinc solution (c = 1 mol/l in hexane) are added and stirring is continued for 2 h at 0C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH CI solution and extracted with TBME (2x). The organic phases are combined, washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE). C9H9BrO (M = 213.1 g/mol)EI-MS: 212/214 [M]+ Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0℃; for 3h; | c) 39.0 g (176 mmol) 1-Bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled to 0 C. During 1 h 200 mL (200 mmol) diethylzinc solution (c=1 mol/l in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2×). The organic phases are combined, washed with brine, dried over MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE). [0346] C9H9BrO (M=213.1 g/mol) [0347] EI-MS: 212/214 [M]+ [0348] Rt (TLC): 0.4 (silica gel, PE) | |
c) 39.0 g (176 mmol) of 1-bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled down to 0 C.During 1 h 200 mL (200 mmol) diethylzinc solution (c = 1 mol/l in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2x). The org. phases are combined, washed with sat. aq. NaCl solution, dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silicagel, PE).C9H9BrO (M= 213.1 g/mol)EI-MS: 212/214 [M]+ Rf (TLC): 0.4 (silica gel, PE) | ||
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0℃; for 3h; | [0507] c) 39.0 g (176 mmol) of 1-bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled down to 0 C. During 1 h 200 mL (200 mmol) diethylzinc solution (c=1 mol/l in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2×). The org. phases are combined, washed with sat. aq. NaCl solution, dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE). [0508] C9H9BrO (M=213.1 g/mol) [0509] EI-MS: 212/214 [M]+ [0510] Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In 1,2-dichloro-ethane; at 0℃; for 3h; | Example IX 1 -l3romo-4-(2-bromoethoxy)benzene 39.0 g (176 mmol) of 1-bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled down to 0 C. During 1 h 200 mL (200 mmol) diethylzinc solution (c=1 mol/L in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2×). The org. phases are combined, washed with sat. aq. NaCl solution, dried with MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE)c) 39.0 g (176 mmol) of 1-bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled down to 0 C. During 1 h 200 mL (200 mmol) diethylzinc solution (c=1 mol/L in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH4Cl solution and extracted with TBME (2×). The org. phases are combined, washed with sat. aq. NaCl solution, dried with MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE). [0407] C9H9BrO (M=213.1 g/mol) [0408] EI-MS: 212/214 [M]+ [0409] Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0℃; | a) 55.0 g (318 mmol) 4-bromophenol and 14.1 g (352 mmol) NaOH are added to 1 10 mL water. 41 .1 mL (477 mmol) dibromoethane are added slowly and the reaction mixture is stirred for 16 h under reflux. Afterwards the reaction mixture is extracted with DCM and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, CyH/EtOAc 4/1 ). b) 52.0 g (186 mmol) of 1 -bromo-4-(2-bromoethoxy)benzene is added to 300 mL THF and cooled down to 0 C. Within 30 min 25.0 g (223 mmol) KOtBu are added to this mixture in several portions. Cooling is removed and the reaction mixture is stirred at r.t. over night. The reaction is queched by the addition of water. The resulting mixture is extracted with EtOAc (2x). The org. phases are combined, washed with sat. aq. NaCI solution, dried with MgSO4, filtered and the solvent is removed in vacuo. The resulting product is used without further purification. c) 39.0 g (176 mmol) of 1 -bromo-4-vinyloxybenzene and 32.4 mL (441 mmol) chloroiodomethane are added to 500 mL dichloroethane and cooled down to 0 C. During 1 h 200 mL (200 mmol) diethylzinc solution (c = 1 mol/L in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 mL of a sat. aq. NH CI solution and extracted with TBME (2x). The org. phases are combined, washed with sat. aq. NaCI solution, dried with MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE). C9H9BrO (M= 213.1 g/mol) EI-MS: 212/214 [M]+ Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In hexane; at 0 - 20℃; for 1.75h;Inert atmosphere; | To a solution of the intermediate compound 10 (10.05 mmol, 2 g) and chloroiodomethane (60.28 mmol, 4.4 mL) under argon at 05C was slowly added diethylzinc (1 M solution in hexanes, 30.1 mmol, 30.1 mL). The reaction mixture was stirred at 05C for 15 min and allowed to warm to room temperature for 90 min. saturated NH4CI (5 mL) was added and the mixture partitioned with Et20 (50 mL), and saturated NH4CI (50 mL). The organic layer was separated and washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated to give the desired compound (2.00 g, Yield: 93%) which was used in the next step without further purification. 1 H NMR (400 MHz, CDCI3) delta 7.40-7.36 (2H, m), 6.96-6.91 (2H, m), 3.73-3.68 (1 H, m), 0.80-0.76 (4H, m) LC-MS: tR = 3.92 [M+H]+ not ion (method 3). | |
With diethylzinc; In 1,2-dichloro-ethane; at 0℃; for 2h; | c) 39.0 g (176 mmol) of 1-bromo-4-vinyloxybenzene and 32.4 ml (441 mmol) chloroiodomethane are added to 500 ml dichloroethane and chilled to 0 C. During 1 h 200 ml (200 mmol) diethylzinc solution (c=1 mol/l in hexane) are added and stirring is continued for 2 h at 0. The reaction is quenched by the addition of 200 ml of a sat. aq. NH4Cl solution and extracted with TBME (2×). The org. phases are combined, washed with sat. aq. NaCl solution, dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE) [0418] C9H9BrO (M=213.1 g/mol) [0419] EI-MS: 212/214 [M]+ [0420] Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0℃; for 3h; | General procedure: c) 39.0 g (176 mmol) of 1 -bromo-4-vinyloxybenzene and 32.4 ml (441 mmol) chloroiodomethane are added to 500 ml dichloroethane and chilled to 0 C. During 1 h 200 ml (200 mmol) diethylzinc solution (c = 1 mol/l in hexane) are added and stirring is continued for 2 h at 0 C. The reaction is quenched by the addition of 200 ml of a sat. aq. NH CI solution and extracted with TBME (2x). The org. phases are combined, washed with sat. aq. NaCI solution, dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE) C9H9BrO (M= 213.1 g/mol) EI-MS: 212/214 [M]+ Rf (TLC): 0.4 (silica gel, PE) | |
With diethylzinc; In dichloromethane; toluene; at 0 - 18℃;Inert atmosphere; | To a solution of 1-bromo-4- (vinyloxy) benzene (75 g, 0.376 mol) in DCM (800 mL) was added CH2ICl (264.7 g, 1.504 mol) at 18 C. Then Et2Zn (750 mL, 1M in toluene) was added slowly at 0 C under N2. The reaction was warmed to 18 C and stirred for 12 h under N2. Then the reaction mixture was added slowly to aqueous NH4Cl (500mL) , extracted with PE (3 x 800 mL) , dried over Na2SO4and filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography over silica gel (PE) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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To a solution of 4 -bromostylene (1.83g) in dichloromethane (5 mL) was added diethylzinc (1 mol/L, 30 mL) under an argon atmosphere at 0C, and the-mixture was stirred at the same temperature for 10 minutes. Chloroiodomethane (4.3 mL) was added to the mixture, and the mixture was warmed to room temperature and stirred for 9 days. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-cyclopropylbromobenzene. The obtained 4-cyclopropylbromobenzene was dissolved in tetrahydrofuran (25 mL) and cooled to -78C. To the solution was added dropwise tert-butyl lithium (1.45 mol/L pentane solution, 9.4 mL) under an argon atmosphere, and the mixture was stirred at -78C for 30 minutes. To the reaction mixture was added a solution of N,N-dimethylformamide (1.2 mL) in tetrahydrofuran (16 mL), and the mixture was warmed to 0C and stirred for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 12/1) to give 4-cyclopropylbenzaldehyde (0.72 g).1H-NMR (CDCl3) delta ppm: 0.60-0.75 (2H, m), 1.05-1.15 (2H, m), 1.80-1.95 (1H, m), 7.15-7.25 (2H, m), 7.7'0-7.80 (2H, m), 9.94 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
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at 25℃; for 3.41667h; | Method 3: Iodochloromethane (974 g, 402 mL, 5.53 mol) at 25C is treated with tetrabutylammonium di-t-butylphosphate (250 g, 0.553 mol) . The phosphate is added portionwise over 10 minutes. The heterogeneous mixture becomes a clear pink solution after approximately 15 minutes. The mixture is stirred for three hours, and the iodochloromethane is then removed by rotary evaporation with a bath temperature of <30C. ? The residue is taken up in 1 L t-butyl methyl ether and stirred for- 15 minutes to precipitate tetrabutylammonium iodide by-product. Tetrabutylammonium iodide is removed by vacuum filtration through a sintered glass funnel. The filtrate is concentrated by rotary evaporation to an oil which contains a 5:1 mixture of 3" and undesired dimer impurity:3"The mixture can be purified by a silica gel chromatography to obtain 3 as pure compound in ~60% yield as an oil. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; | EXAMPLE 25 Chloromethyl Penicillanate 1,1-Dioxide To a stirred solution of 24 g. of penicillanic acid 1,1-dioxide in 125 ml. of N,N-dimethylformamide was added 9.5 ml. of diisopropylethylamine, followed by 45 ml. of chloroiodomethane. Stirring was continued overnight and then the reaction mixture was added to 300 ml of water. The pH was adjusted to 8.5, and then the mixture was extracted with ethyl acetate. The extract was washed with water, followed by saturated sodium chloride solution, and then it was dried over sodium sulfate. The dried extract was concentrated to dryness in vacuo to give the crude product as a gum (8.9 g.). The crude product was combined with some additional material of comparable quality, and it was chromatographed on silica gel eluding with 1:1 ethyl acetatehexane. This afforded the title compound which showed only a single spot when assayed by thin-layer chromatography. The IR spectrum (KBr disc) showed an absorption at 1801 cm-1. The NMR spectrum (CDCl3) showed absorptions at 6.0 (d, 2H, J=6Hz), 5.7 (d, 1H, J=6Hz), 4.7 (t, 1H, J=3.5Hz), 4.5 (s, 1H), 3.55 (d, 2H, J=3.5Hz), 1.7 (s, 3H) and 1.5 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In N-methyl-acetamide; ethyl acetate; | PREPARATION 3 Chloromethyl penicillanate 1,1-dioxide To a solution of penicillanic acid 1,1-dioxide (1.17 g, 5 mmol) in dimethylformamide (7.5 ml) was added triethylamine (0.98 ml, 7 mmol) and chloroiodomethane (2.18 ml, 30 mmol), and the mixture was stirred at room temperature for 4 hours. After dilution with ethyl acetate (30 ml), the mixture was washed with water (3*10 ml) followed by saturated aqueous sodium chloride (5 ml), dried, and evaporated in vacuo to leave the desired compound as a yellowish oil, which crystallized from ether-petroleum ether, melting point: 94-96 C. The NMR spectrum (CDCl3) showed signals at delta=1.47 (s, 3H; 2-CH3), 1.66 (s, 3H; 2-CH3), 3.53 (d, J=3 Hz, 2H; 6alpha-H and 6beta-H), 4.46 (s, 1H; 3-H), 4.68 (t, J=3 Hz, 1H; 5-H), and 5.85 (ABq, J=6 Hz, 2H; OCH2 Cl) ppm. Tetramethylsilane was used as internal reference. |
Yield | Reaction Conditions | Operation in experiment |
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With tetra(n-butyl)ammonium hydroxide; In dichloromethane; water; ethyl acetate; | EXAMPLE 4 Chloromethyl penicillanic acid 1,1-dioxide A mixture of 4.66 g. of penicillanic acid 1,1-dioxide in 50 ml. of methylene chloride and 35 ml. of water was treated with sufficient tetrabutylammonium hydroxide (40% in water) to give a pH of 6.0. The methylene chloride layer was separated and the aqueous phase extracted with fresh methylene chloride (2*50 ml.). The organic layers were combined, dried over sodium sulfate and concentrated to give 10.1 g. of the desired intermediate. The above tetrabutylammonium penicillanate sulfone was added to 50 ml. of chloroiodomethane and the reaction mixture allowed to stir at ambient temperatures overnight. The reaction mixture was concentrated to half volume in vacuo, and chromatographed on 200 g. of silica gel using ethyl acetate/hexane as the eluent, 12 ml. cuts being taken every 30 sec. Fractions 41-73 were combined and concentrated to dryness to give 3.2 g. of the desired product. The NMR spectrum (CDCl3) showed absorption at 1.5 (s, 3H), 1.66 (s, 3H), 3.42 (d, 2H), 4.38 (s, 1H), 4.6 (t, 1H) and 5.7 (dd, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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In N-methyl-acetamide; | A. Bis-(6beta-phenylacetamido-penicillanoyloxy)-methane To a stirred suspension of <strong>[113-98-4]potassium benzylpenicillin</strong>ate (22.3 g.) in dimethylformamide (110 ml.) is added chloroiodomethane (5.3 g.). After stirring for 48 hours at room temperature the mixture is diluted with ethyl acetate (330 ml.) and extracted with water (2*60 ml.), 2% aqueous sodium bicarbonate (60 ml.) and water (2*60 ml.). The organic phase is dried and evaporated to dryness in vacuo to yield the desired compound as an amorphous powder. The IR-spectrum (CHCl3) shows strong bands at 1780, 1675, 1505, 1290, 1135 and 982 cm-1. The NMR-spectrum (CDCl3) shows peaks at delta=1.45 (s), 3.63 (s), 4.39 (s), 5.60-5.80 (m), 5.85 (s), 6.20 (d) and 7.33 (s). (TMS being used as internal standard). |
Yield | Reaction Conditions | Operation in experiment |
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71% | silver carbonate; In acetonitrile; benzene; | Preparation of di-tert-butyl chloromethyl phosphate, 2: Silver di-t-butyl phosphate (6.34 g, 20 mmol), which was prepared by mixing di-t-butyl phosphate (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163) with one equivalent of silver carbonate in 50% aqueous acetonitrile and by lyophilizing to dryness, was placed together with chloroiodomethane (35 g, 200 mmol) in benzene and stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica and eluted with 2:1 hexanes-ethyl acetate. Appropriate fractions were concentrated to dryness to obtain the subtitle compound 2 (3.7 g, 71% yield): 1H NMR (CDCl3) delta 5.63 (d, 2H, J=17), 1.51 (s, 18H); MS (MH+=259). |
Yield | Reaction Conditions | Operation in experiment |
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50% | With diethylzinc In 1,2-dichloro-ethane at -15℃; for 19h; | 1.1 Step 1. Cyclopropanation of 4,5-dehydro-L-proline ethyl ester: 4,5-Dehydro-L-proline ethyl ester (35.0 g, 0.145 mol) was added to a solution of neat Et2Zn (35.8 g, 0.209 mol) in 1 liter of 1,2-dichloroethane at -15°C. To this mixture was added a dropwise addition of ClCH2I (102 g, 0.58 mol) over 1 h and the mixture stirred at -15°C for 18 h. The reaction was quenched with saturated aqueous bicarbonate and the solvent was evaporated and the reaction was taken up in EtOAc, washed with brine and purified by silica gel chromatography using a stepwise gradient of from 20% EtOAc/hexanes to 50% EtOAc/hexanes to give 17.5 g (50%) of diastereomerically pure step 1 title compound. |
41% | With diethylzinc In tetrahydrofuran; 1,2-dichloro-ethane at -15℃; for 18.5h; | 89.C A solution of the title compound from Step B above (3.5 g) in 1,2 dichloroethane (75 ml) was cooled to -15 0C and Et2Zn (25 mL of a 1.0 M solution in THF) was added dropwise. To this mixture was added drop wise ClCH2I (4.5 ml) over 30 minutes. After stirring for 18 h at -15 0C the mixture was quenched with saturated aqueous bicarbonate and the solvent was evaporated and the reaction was taken up in ethyl acetate and washed with brine.The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica (cyclohexane/EtOAc 4: 1) to afford the diastereomerically pure title compound (1.5 g, 41 %, MNa+ = 278). |
Yield | Reaction Conditions | Operation in experiment |
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50% | Step 6: 2-Aza-bicyclo[3.1.0]hexane-2-carboxylic acid benzyl ester To a cold (0 C.) solution of <strong>[68471-57-8]2,3-dihydro-pyrrole-1-carboxylic acid benzyl ester</strong> (example 4, step 5, 300 mg, 1.0 eq.) in diethyl ether was slowly added a solution of diethylzinc in hexanes (1M, 7 mL, 4.75 eq.), followed by chloroiodomethane (1.1 mL, 10 eq.). The reaction mixture was stirred 3 h at 0 C., allowed to warm up to room temperature and stirred an additional 3 h. The reaction mixture was partitioned between an aqueous solution of ammonium chloride and diethyl ether. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, dried over sodium sulphate and evaporated in vacuo and purified on silica, eluding with a 1:1 to 1:3 gradient of cyclohexane/dichloromethane, to yield 160 mg (50%) of the desired product as colourless oil. MS (m/e): 218.5 (MH+, 100%) |
Yield | Reaction Conditions | Operation in experiment |
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44.92% | With lithium diisopropyl amide; In tetrahydrofuran; at -78℃; for 0.666667h; | Lithium diisopropylamide (30.9 mL, 46.4 mmol) was added dropwise to a solution containing ethyl N-Boc-4-methylpiperidine-4-carboxylate (2.52 g, 9.28 mmol), and chloroiodomethane (6.55 g, 37.1 mmol) in THF (100 mL) at -78 0C over 30 minutes. After <n="84"/>addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (5 mL) in THF (45 mL) was added while keeping reaction mixture below -65 0C. The reaction was stirred for an additional 10 minutes and partitioned between ethyl acetate and brine, washed with saturated bicarbonate, concentrated and purified by silica gel (10%-20% ethyl acetate in hexanes) to afford tert-butyl 4-(2-chloroacetyl)-4-methylpiperidine-l-carboxylate (1.15 g, 44.92% yield). |
Yield | Reaction Conditions | Operation in experiment |
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Di-tert-butyl chloromethyl phosphate (3). In 50 mL of acetone was stirred (cloudy solution ) 2.68 g (12.7 mmol) of <strong>[33494-81-4]di-tert-butyl phosphate</strong> (2) on an ice bath. To the mixture was added 2.30 g (12.7 mmol) of tetramethylammonium hydroxide pentahydrate in10 mL water with stirring to give a clear solution. The solution was evaporated to a cloudy thick011 and dissolved in 50 mL of dimethoxy ethane. The cloudy dimethoxyethane was evaporated to cloudy semi-solid and placed under high vacuum until the residue formed a solid. The solid was slurried in 50 mL of refluxing dimethoxyethane and 2 g (141.7 mmol) of chloroiodomethane was added. An almost clear light yellow solution formed and refluxing was continued for 1 hour. A precipitate formed in about 5 minutes, which was yellow at first and then white in color. The hot mixture was filtered and the dimethoxyethane evaporated to give 1.90 g (58%) of a light yellow oil (3). NMR: 1H (300 MHz, CDCl3) delta 1.57 (s, 9H), 5.63 (d, 2H, J = 15 Hz); 31P NMR (300 MHz, CDCl3) delta -10.8 (s). The NMR showed about 10-15% bis-di-te/t-butyl methyl phosphate impurity that could not be removed by flash column chromatography (silica gel, ethyl acetate/hexane eluent), even with 100% ethyl acetate eluent. 1H (300 MHz, CDCl3) delta 1.5 (s, 18 H), 1.50 (s, 18H), 5.44 (t, 2H, J=12Hz); 31P NMR (300 MHz, CDCl3) delta -11.1 (s). |
Yield | Reaction Conditions | Operation in experiment |
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54% | To a solution of diethylzinc (1.1 M solution in toluene, 37.5 ml, 0.04 mmol) in 1,2-dichloroethane (80 ml) at 0 C. was added chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of <strong>[159635-22-0]3-hydroxy-4-methylene-piperidine-1-carboxylic acid tert-butyl ester</strong> (J. Org. Chem. 2001, 66, 2487) (4.19 g, 19.6 mmol) in 1,2-dichloroethane (10 ml) was added, after which time the reaction was stirred for 0.5 h at 0 C. and then allowed to reach room temperature, stirring for a further 1 h. The reaction was then quenched by addition of saturated aq. ammonium chloride solution, separated, and the organic dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 2:8-1:1) afforded the title product (2.4 g, 54%) as a crystalline solid MS: 228.2 (MH+). | |
54% | a) 4-Hydroxy-6-aza-spiro[2.5]octane-6-carboxylic Acid tert-butyl esterMethod A; To a solution of diethylzinc (1.1 M solution in toluene, 37.5 ml, 0.04 mmol) in DCE (80 ml) at 0 C. was added chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of <strong>[159635-22-0]3-hydroxy-4-methylene-piperidine-1-carboxylic acid tert-butyl ester</strong> (J. Org. Chem. 2001, 66, 2487) (4.19 g, 19.6 mmol) in DCE (10 ml) was added, after which time the reaction was stirred for 0.5 h at 0 C. and then allowed to reach RT, stirring for a further 1 h. The reaction was then quenched by addition of sat. aq. ammonium chloride solution, separated, and the organic dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/heptane 2:8?1:1) afforded the title product (2.4 g, 54%) as a crystalline solid. MS: 228.2 (MH+). | |
54% | To a solution of diethylzinc (1.1 M solution in toluene, 37.5 ml, 0.04 mmol) in 1,2- dichloroethane (80 ml) at 0C was aded chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of 3-hydroxy-4- methylene-piperidine-l-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 2487) (4.19 g, 19.6 mmol) in 1,2-dichloroethane (10 ml) was aded, after which time the reaction was stirred for 0.5 h at 0C and then allowed to reach room temperature, stirring for a further 1 h. The reaction was then quenched by adition of sat. aq.ammonium chloride solution, separated, and the organic dried (Na2S04) and concentrated. Purfication by flash column chromatography (Si02; ethylacetate/heptane 2:8-1 :1) afforded the titled product (2.4 g, 54%) as a crystalline solid. MS: 228.2 (MH+). |
54% | Method ATo a solution of diethylzinc (1.1 M solution in toluene, 37.5 ml, 0.04 mmol) in 1,2-dichloroethane (80 ml) at 0 C. was added chloroiodomethane (5.99 ml, 0.08 mmol) under Ar. This mixture was stirred for 15 minutes before a solution of <strong>[159635-22-0]3-hydroxy-4-methylene-piperidine-1-carboxylic acid tert-butyl ester</strong> (J. Org. Chem. 2001, 66, 2487) (4.19 g, 19.6 mmol) in 1,2-dichloroethane (10 ml) was added, after which time the reaction was stirred for 0.5 h at 0 C. and then allowed to reach room temperature, stirring for a further 1 h. The reaction was then quenched by addition of sat. aq. ammonium chloride solution, separated, and the organic dried (Na2SO4) and concentrated. Purfication by flash column chromatography (SiO2; ethyl acetate/heptane 2:8-1:1) afforded the titled product (2.4 g, 54%) as a crystalline solid. MS: 228.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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42% | [00313] Step E: To a solution of (S)-methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate(1.3 g, 8.1 mmol) and chtorotodomethane (4.3 g, 24 mmol) in THF (50 mL) at -78 C was added a solution of LDA (16.2 mL, 24 mmol) in portions over 10 minutes. The reaction was stirred at -78 C for 10 minutes. To this mixture was added a 10% solution of acetic acid (50 mL) in THF at -78 C. After addition, the slurry was warmed to ambient temperature. The reaction was poured into EtOAc (200 mL) and the aqueous layer basified using 1 N NaOH. The organics were separated and washed with brine, dried over MgSO4 and concentrated in vacuo. The material was purified by chromatography using DCM as eluent to give (S)-2- chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.60 g, 3.4 mmol, 42% yield) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
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81% | (Production Example 1) Synthesis of 2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To the mixture of triisopropyl borate (15 ml, 65 mmol), chloroiodomethane (13 g, 72 mmol), and tetrahydrofuran (78 ml), n-butyllithium (a 1.6 M n-hexane solution, 41 ml, 65 mmol) was added dropwise at -78C (an outer temperature) over 20 minutes, and then the obtained mixture was stirred at room temperature for 2.5 hours. The reaction mixture was cooled to 0C (an outer temperature), and a 4 N hydrochloric acid-ethyl acetate solution was added dropwise thereto at the same temperature until the reaction mixture became neutral. At the same temperature, pinacol (7.7 g, 65 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 40 minutes. The solvents were evaporated under reduced pressure, and then the obtained residue was distilled under reduced pressure (63-70C, 11 mmHg), thereby obtaining the entitled compound (9.2 g, 52 mmol, 81%). 1H-NMR Spectrum (CDCl3) delta(ppm): 1.30(12H, s), 2.97(2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | To a stirred solution of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1 1 .0 mL, 53.75 mmol) and chloroiodomethane (4.3 mL, 59.12 mmol) in anhydrous THF (100 mL), cooled to -78 C, was added cold n-butyllithium solution (23.94 mL, 59.12 mmol) dropwise. After stirring for 30 min at this temperature, chlorotrimethylsilane (8.2 mL, 64.50 mmol) was added dropwise. After stiring for 10 min, the reaction mixture was allowed to return to room temperature and stirred for 24 h. Water (80 mL) was added and the mixture extracted with Epsilon?0 (2 x 80 mL). The organic extracts were combined, washed with water (2 x 80 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (Heptane/EtOAc 99:1 to 95:5).to yield 2-(chloromethyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (4.35 g, 24.65 mmol, 46% yield) as a colourless oil. NMR (400 MHz, DMSO-cfe, delta): 2.99 (s, 2H), 1 .32 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | To <strong>[151907-79-8](1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-enecarboxylic acid</strong> (2.70 g, 11.8 mmol, Preparation No.17) in DCM (170 mL) was slowly added diethylzinc (1.1 M in toluene, 54.0 mL, 59.4 mmol). The mixture was stirred for about 10 min at ambient temperature, cooled to about 0 C., and treated drop-wise with a solution of chloroiodomethane (4.30 mL, 59.4 mmol) in DCM (24 mL). The reaction mixture was allowed to warm to room temperature and was stirred for about 18 h. Saturated aqueous NH4Cl (10 mL) was added and the mixture was stirred for about 20 min. The layers were separated and the aqueous layer was further extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to afford (1R,2S,4R,5S)-methyl 4-(ethoxycarbonylamino)bicyclo[3.1.0]hexane-2-carboxylate (0.95 g, 35%): LC/MS (Table 2, Method a) Rt=1.88 min; MS m/z: 228 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(a). Synthesis of bis-[5-oxy-adamantan-2-one]methane: Into 1 L three neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and reflux condensor under nitrogen atmosphere, 12.7 parts of sodium hydride (60% dispersion in mineral oil) was mixed with 125 mL of hexane and stirred for 3 mins. Stirring was stopped for 5 min and hexane decanted off. This process was repeated with additional 2*125 mL hexane and suspended in 125 mL of anhydrous tetrahydrofuran. Then 43 parts of 5-hydroxy-2-adamantanone was added portion wise over 2 min and the reaction mixture was heated at reflux for 90 mins. After the reaction mixture was cooled to room temperature and 62 parts of chloroiodomethane was added at once and the reaction mixture was heated at reflux for 22 hrs. The reaction mixture was cooled to 30 C. and 23.8 parts chloroiodomethane was added at once and heated at reflux for 48 hrs. The solution was cooled to room temperature and concentrated under reduced pressure and residue was extracted with 350 mL of dichloromethane. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the mixture was purified by chromatography on silica gel with 20% ethyl acetate-hexanes. The product fractions (TLC) were combined and solvent was evaporated under reduced pressure to give 12.72 parts of a white solid of the following structure confirmed by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | To a mixture of triisopropyl borate (15 ml, 65 mmol), chloroiodomethane (13 g, 72 mmol) and tetrahydrofuran (78 ml) was added dropwise n-buthyllithium (1.6M n-hexane solution, 41 ml, 65 mmol) at -78C (external temperature) over 20 minutes. Then, the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was cooled at 0C (external temperature), to the mixture was added dropwise a 4N hydrochloric acid-ethyl acetate solution in order to neutralize at the same temperature. To the reaction mixture was added pinacol (7.7 g, 65 mmol) at the same temperature, and then, the reaction mixture was stirred at room temperature for 40 minutes. After the solvent was distilled off under reduced pressure, the resulting residue was distilled under reduced pressure (63-70C, 11 mmHg) to obtain the title compound (9.2 g, 52 mmol, 81%). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.30 (12H, s) , 2.97(2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0 - 20℃; for 19h; | Cap N-8 At 0 C., to a solution of ethyl 4-methylenecyclohexanecarboxylate (0.08 g) in DCE (1 mL) was added chloroiodomethane (0.110 mL, 1.522 mmol), followed by the addition of 1 N diethylzinc in hexane (0.761 mL, 0.761 mmol). The reaction was stirred at 0 C. for 1 hr, then stirred at rt for 18 hrs. The reaction mixture was diluted with EtOAc and 1 N HCl, the organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was charged to a 25 g silica gel cartridge which was eluted with a 20 min gradient of 0-6% EtOAc in hexane to yield ethyl spiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) delta ppm 4.08-4.18 (2H, m), 2.32 (1H, tq, J=11.01, 3.53 Hz), 1.85-1.93 (2H, m), 1.53-1.74 (4H, m), 1.28-1.35 (2H, m), 1.22-1.28 (3H, m), 0.28 (2H, ddd, J=8.53, 5.52, 1.51 Hz), 0.17-0.25 (2H, m). | |
With diethylzinc; In hexane; 1,2-dichloro-ethane; at 0 - 20℃; for 19h; | At 0 C, to a solution of ethyl 4-methylenecyclohexanecarboxylate (0.08 g) in DCE (1 mL) was added chloroiodomethane (0.110 mL, 1.522 mmol), followed bythe addition of 1 N diethylzinc in hexane (0.76 1 mL, 0.76 1 mmol). The reaction was stirred at 0 C for 1 hr, then stirred at rt for 18 hrs. The reaction mixture was diluted with EtOAc and 1 N HC1, the organic phase was washed with sat. NaC1, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was charged to a 25 g silica gel cartridge which was eluted with a 20 mm gradient of 0-6% EtOAc inhexane to yield ethyl spiro[2.5]octane-6-carboxylate. ?H NMR (400 MHz, CDC13) ppm 4.08-4.18(2 H, m), 2.32 (1 H, tq, J=11.01, 3.53 Hz), 1.85 - 1.93 (2 H, m), 1.53- 1.74 (4 H, m), 1.28 - 1.35 (2 H, m), 1.22 - 1.28 (3 H, m), 0.28 (2 H, ddd, J=8.53, 5.52, 1.51 Hz), 0.17 - 0.25 (2 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With methyllithium lithium bromide In diethyl ether at -78℃; | |
98% | With methyllithium; lithium bromide In diethyl ether at -78℃; for 0.5h; chemoselective reaction; | Chemoselective Addition of Lithium Carbenoids to Isocyanates; General Procedure 1 (GP1) General procedure: To a cooled (-78°C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi-LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With methyllithium; lithium bromide; In diethyl ether; at -78℃; for 0.5h; | General procedure: To a cooled (-78C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi-LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With methyllithium lithium bromide In diethyl ether at -78℃; | |
97% | With methyllithium; lithium bromide In diethyl ether at -78℃; for 1h; chemoselective reaction; | Chemoselective Addition of Lithium Carbenoids to Isocyanates; General Procedure 1 (GP1) General procedure: To a cooled (-78°C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi-LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With methyllithium; lithium bromide; In diethyl ether; at -78℃; for 1h; | General procedure: To a cooled (-78C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi-LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylzinc; In n-heptane; dichloromethane; at -5 - 20℃; for 19.5h; | A. Cyclopropanation to Prepare 2 [0133] To a solution of DCM (1.5 L) and n-heptane (0.32 L) at ambient temperature was added diethyl zinc (800 mL, 1.0 M in n-heptane). The reaction mixture was cooled to 0 C., and a solution of compound 1 (45.0 g) in DCM (250 mL) was added over 10 min. Upon completion of the addition, the reaction mixture was cooled to -5 C. and chloroiodomethane (176 g) was charged via syringe pump over 3.5 h. The reaction mixture was stirred at -5 C. for an additional 16 h and was quenched by the slow addition (1 h) of 1N aqueous HCl (1.4 L). After warming to 20 C., the phases were separated, and the aqueous layer was back extracted with DCM (0.5 L). The combined organic layers were washed with 10% aqueous NaCl (1.2 L), the phases were separated, and the organic layer was concentrated in vacuo to provide a crude oil that was purified by flash chromatography on silica gel (50 ethyl acetate/n-heptane). The desired product was isolated as a mixture of compounds 2 and 3 (46.6 g, 67.5 wt % compound 2, 62% corrected yield.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Hydrolysis/Iodolactonization to Prepare 4: [0137] A mixture of compounds 2 and 3 (161.80 g, 59 wt % compound 2) was dissolved in MeOH (1.2 L). Water was added, the mixture was cooled to 15 C. and solid LiOH.H2O (32.8 g) was charged. The reaction mixture was warmed to 25 C. and stirred for 13.5 h. The reaction mixture was then concentrated in vacuo to remove the MeOH, and DCM (1 L) and water (200 mL) were added. The resulting mixture was cooled to 10 C., and 2 N aqueous HCl (375 mL) was added. Following separation of the phases, the aqueous layer was extracted with DCM (2×500 mL, then 250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to 1.2 L. To this solution was added water (305 mL), NaHCO3 (136 g) and I2 (90.7 g). The reaction mixture was stirred at 25 C. for 40 h and diluted with 8% aqueous NaHCO3 (750 mL), water (750 mL) and DCM (300 mL). Following phase separation, the combined organic layer was extracted water (1 L). The combined aqueous layers were then washed with isopropyl acetate (300 mL), cooled to 0 C. and acidified by the addition of 2 N aqueous HCl (1.1 L). The aqueous phase was extracted with DCM (3×1 L), and the combined organic layer was washed with 10% aqueous NaHSO3 (2 L) and 10% aqueous NaCl (1.5 L). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The resulting solid was twice dissolved and re-concentrated from isopropyl acetate (1 L). Additional isopropyl acetate (100 mL) was charged to the solid, the solution was heated to 50 C. and n-heptane (800 mL) was added. After cooling to 20 C. over 4 h, the slurry was cooled to 5 C. aged for 2 h. The product was collected by filtration, washed with n-heptane (2×150 mL) and dried to afford compound 4 as a light yellow solid (66.5 g, 74% yield from compound 2). 1H NMR (400 MHz, d6-DMSO, delta): 12.5 (s, 1H) 4.23-4.17 (m, 1H), 3.32-3.16 (m, 2H), 2.28-2.22 (m, 1H), 1.74 (dd, J=12.7, 4.3 Hz, 0.6H rotamer 1), 1.67 (dd, J=12.7, 3.7 Hz, 0.4H rotamer 2), 1.39 (s, 4H rotamer 1), 1.35 (s, 5H rotamer 2), 0.59-0.45 (m, 4H). 13C NMR (100 MHz, d6-DMSO, delta): 173.9, 173.5, 153.4, 153.0, 78.7, 78.6, 59.1, 58.8, 53.7, 53.4, 38.2, 37.5, 28.1, 27.9, 20.5, 19.9, 12.2, 11.5, 8.8, 8.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran; diethyl ether at -100℃; for 0.366667h; Inert atmosphere; | General Procedure A for the Preparation of Vinyl Oxirane Substrates General procedure: To a 50 mL round bottom flask equipped with a magnetic stir bar, sequentially wasintroduced THF (5 mL), Et2O (5 mL), the corresponding enone (197 mg, 1.23 mmol, 1.0eq) and chloroiodomethane (0.13 mL, 1.84 mmol, 1.5 eq). The reaction mixture wascooled to -100 °C (isopropanol / liquid nitrogen bath) for 10 min. nBuLi (1.6 M, 1.15 mL,1.94 mmol, 1.5 eq) was added dropwise via a syringe (c.a. 2 min), and the reactiontemperature was maintained at -100 °C for 20 min and quenched with saturated NH4Cl (2mL). The product was extracted with EtOAc (3 x 5 mL), and the organic layers werecombined, washed with DI water (2 mL) and brine (2 mL). The organics were collected,dried with anhydrous MgSO4, filtered and concentrated in vacuo. In most cases, thealcohol intermediates were pure enough and were used in the next step without furtherpurification.To a 10 mL round bottom flask equipped with a magnetic stir bar, sodium hydride (60%in mineral oil, 34 mg, 0.84 mmol, 2.0 eq) and freshly distilled DMSO (1 mL) were addedand the slurry was stirred at room temperature. The allylic alcohol (90 mg, 0.42 mmol,1.0 eq) in freshly distilled DMSO (2.0 mL) was added dropwise (c.a. 2 min), and thereaction was stirred at room temperature until all of the allylic alcohol was consumed(TLC, 2 to 4 hours on average). The reaction was carefully quenched by slow addition ofsaturated NaHCO3 (1mL). The vinyl oxirane was extracted with Et2O (4 x 5 mL), and the organic layers were combined, washed with DI water (4 x 1 mL) and brine (1 mL). Theorganics were collected, dried with anhydrous MgSO4, filtered and concentrated in vacuo.The crude vinyl oxirane was purified by flash column chromatography. Note: It isessential to saturate the silica gel with triethylamine (TEA) prior to use as many of thevinyl oxiranes are sensitive to acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With methyllithium; lithium bromide; In diethyl ether; at -78℃; for 1.0h; | General procedure: To a cooled (-78C) solution of isocyanate (1.0 equiv) in dry Et2O (1 M concentration) was added the dihalomethane derivative (1.5 equiv). After 2 min, an ethereal solution of 1.5 M MeLi-LiBr (1.25equiv) was added dropwise over 5 min. The resulting solution was stirred for the appropriate time (see Table 1 and Scheme 2) at that temperature. Sat. aq NH4Cl was added (2 mL/mmol substrate) and the cooling bath was removed, the mixture was stirred till it reached r.t., and then it was extracted with additional Et2O (2 × 5 mL) and washed with water (5 mL) and brine (10 mL). The organic phase was dried (anhyd Na2SO4), filtered, and the solvent removed under reduced pressure to give pure samples of haloacetamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 1h;Reflux; | In one embodiment, the present invention can include a method of preparing the POM reagent dibenzyl(choloromethyl)phosphate, as shown in reaction Scheme 5 of FIG. 5. Briefly, CH2ClI (5 mL; 68.6 mmol) is reacted with silver dibenzyl phosphate (2 g, 52 mmol) in about 25 mL toluene and refluxed for about 1 hour before the solvent is removed and processed through a separation column with 1/1EA/H in order to produce dibenzyl(choloromethyl)phosphate as confirmed via TLC. | |
In toluene; for 1h;Reflux; | [0101] In one embodiment, the present invention can include a method of preparing the POM reagent dibenzyl(choloromethyl)phosphate, as shown in reaction Scheme 5 of Figure 5. Briefly, CH2CII (5 mL; 68.6 mmol) is reacted with silver dibenzyl phosphate (2 g, 52 mmol) in about 25 mL toluene and refluxed for about 1 hour before the solvent is removed and processed through a separation column with 1/lEA/H in order to producedibenzyl(choloromethyl)phosphate as confirmed via TLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: Chloroiodomethane; methyl (2S)-3-methyl-[(benzyloxy)carbonylamino]butanoate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2.5h; Inert atmosphere; Stage #2: With acetic acid In tetrahydrofuran at -70 - 20℃; | 38.3 Step 3 Step 3. To the solution of compound 38-3 (10 g, 37.7 mmol) in THF (20 mL) was added C1CH2I (26.6 g, 151 mmol). After it was cooled to -78°C, LDA was added slowly in 2 h. After it was stirred at -78°C for 30 min under N2, HO Ac (21 mL, 377 mmol) in THF was added under -70°C. It was warmed to r.t, and EtOAc (30 mL) was added and the mixture was poured to brine. It was extracted with EtOAc (80 mL x 3), dried over Na2S04, concentrated, and purified by column chromatography on silica gel (PE: EtOAc= 5: 1) to give compound 38-4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | To 50L reactor, add 1.9 kg intermediate 4, hexamethylphosphoric acid triamide 19L, sodium ethoxide 0.26 kg. React under the condition of room temperature for 24 hours. Add chloroiodomethane 1.4 kg. Stir for 2 hours. The reaction liquid quickly add 570L in water, separate out a large amount of yellow solid, filtering. The filter cake is added to the chloroform 5.7L dissolved, for sequentially 0.3M sodium thiosulfate solution 1.9L, 0 . 4M sodium bicarbonate solution, 1.9L saturated salt water 1.9L washing liquid, anhydrous sodium sulfate drying, decolorized with active carbon. Filtered, concentrated under reduced pressure to dryness; anhydrous ethanol is added 13.3L, heating to reflux, the solid is completely dissolved, gradually cooling crystallization, filtration. 40 C blast drying, to obtain white solid 1.6 kg, yield 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: Chloroiodomethane; N-methoxy-N-methyl-4-trifluoromethylbenzamide In tetrahydrofuran at -78℃; for 0.0333333h; Inert atmosphere; Stage #2: With methyllithium lithium bromide In tetrahydrofuran; diethyl ether at -78℃; for 0.75h; Inert atmosphere; Stage #3: 1-(Trimethylsilyl)imidazole Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | To a cooled solution (-78C) of 0.42 g (2.2 eq.) chloro-iodo-methane in 10 mL THF, 1.58 mL (2.2 eq.) of LDA 1.5 M solution in THF was added dropwise in a nitrogen atmosphere. The temperature was maintained below -72C. After stirring for additional 10 min at -78 C a solution of 0.3 g (1 eq.) of 1- benzyl 2-methyl 1,2-piperidinedicarboxylate in 3 mL THF was added dropwise. The internal temperature was maintained not higher than -72 C. After stirring for additional 5 min 1.08 mL (1.5 eq.) of LDA 1.5 M solution in THF was added dropwise. The internal temperature was maintained below - 72C. After stirring for further 30 min at -78C the reaction mixture was quenched with a solution of 1.2 g acetic acid in lOmL THF. The reaction mixture was allowed to warm to ambient temperature and 20 mL of water was added. The organic and aqueous phases were separated and the aqueous phase 3 times extracted with 25 mL of ethyl acetate. The combined organic washings were dried over magnesium sulphate, filtered, the solvents evaporated in vacuum and flashed chromatographed using heptane/dioxane 4: 1 mixture to give 0.15 g of the title product as almost colorless oil (Rf 0.12, yield 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate; In dimethyl sulfoxide; at 65℃; for 8h; | 1.0 g of telmisartan was added to 20 mL of dimethyl sulfoxide, 0.67 g of sodium carbonate and 1.07 g of chloroiodomethane were added, and the mixture was heated to 65 C for 8 hours, followed by filtration to remove insoluble matter, and the filtrate was frozen. The dryer was lyophilized, and the obtained residue was subjected to column chromatography [HP-Silica normal phase silica gel, eluent was n-hexane: ethyl acetate = (12:1, V/V)] to separate the target product. The telmisartan methylene dimer was obtained in an amount of 1.82 g, and the HPLC purity was 99.2%, and the yield was 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.31 g | 2 g of <strong>[632-85-9]wogonin</strong>, dissolved in 20 ml of tetrahydrofuran, Add 20 ml of chloroiodomethane at 30 C. Stir the reaction for 16 hours, Evaporated at 60 C under reduced pressure. Add 20 ml of acetonitrile to dissolve the residue as an intermediate. Another 9 ml of triethylamine was dissolved in 10 ml of acetonitrile. Add 3.6ml of phosphoric acid, After the drop is over, Slowly drip into the intermediate with stirring. Continue to stir the reaction at 60 C for 12 hours. Evaporate the solvent, The residue was dissolved in 20 ml of water. Add 10 ml × 3 wash water layers of ethyl acetate. Water layer filtration clarification, Lyophilization gave Compound B 0.31 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.6% | With caesium carbonate In N,N-dimethyl-formamide at 110℃; | 40.1 Step 1: Synthesis of 8-chloro- [1,3] dioxolene [4,5-g] quinoline 4-chloroquinoline-6,7-diol (2.67g, 13.0mmol, 1.0eq) was dissolved in DMF (10mL), and cesium carbonate (6.67g, 20.0mmol, 1.5eq) and chloroiodomethane (3.61g) were added. , 20.0 mmol, 1.5 eq), and reacted at 110 ° C overnight.The reaction was monitored for completeness by TLC, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the product (746.6 mg, yield: 28.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: Chloroiodomethane With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -20℃; Flow reactor; Stage #2: bis(p-methylphenyl)-methanone In tetrahydrofuran; n-heptane; ethylbenzene at -20℃; Flow reactor; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: (+/-)-2-N-tert-butoxycabonylpiperidine-3-carbonitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: Chloroiodomethane In tetrahydrofuran at -78 - 20℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.63% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: Chloroiodomethane; 2-(trifluoromethoxy)benzaldehyde With methyllithium lithium bromide In tetrahydrofuran at -78℃; for 0.75h; Inert atmosphere; Stage #2: With hexylsilane; tris(pentafluorophenyl)borate In dichloromethane at 20℃; for 1h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: Chloroiodomethane; Cyclohexyl phenyl ketone With methyllithium lithium bromide In tetrahydrofuran at -78℃; for 0.75h; Inert atmosphere; Stage #2: With hexylsilane; tris(pentafluorophenyl)borate In dichloromethane at 20℃; for 1h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: Chloroiodomethane; o-fluorobenzophenone With methyllithium lithium bromide In tetrahydrofuran at -78℃; for 0.75h; Inert atmosphere; Stage #2: With hexylsilane; tris(pentafluorophenyl)borate In dichloromethane at 20℃; for 1h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: S-Phenyl benzenethiosulfonate; Chloroiodomethane In tetrahydrofuran at -78℃; for 0.0833333h; Inert atmosphere; Stage #2: With methyllithium lithium bromide In tetrahydrofuran; diethyl ether for 1h; Inert atmosphere; Stage #3: 2,6-dichlorothiophenol With sodium iodide In tetrahydrofuran; diethyl ether; N,N-dimethyl-formamide at 0 - 20℃; for 6h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: methanethiosulfonic acid S-methyl ester; Chloroiodomethane In tetrahydrofuran at -78℃; for 0.0833333h; Inert atmosphere; Stage #2: With methyllithium lithium bromide In tetrahydrofuran; diethyl ether for 1h; Inert atmosphere; Stage #3: 2,6-dichlorothiophenol With sodium iodide In tetrahydrofuran; diethyl ether; N,N-dimethyl-formamide at 0 - 20℃; for 6h; Inert atmosphere; chemoselective reaction; |
Tags: 593-71-5 synthesis path| 593-71-5 SDS| 593-71-5 COA| 593-71-5 purity| 593-71-5 application| 593-71-5 NMR| 593-71-5 COA| 593-71-5 structure
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P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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