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CAS No. : | 2012-74-0 | MDL No. : | MFCD00037763 |
Formula : | C11H13ClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VTJMSIIXXKNIDJ-UHFFFAOYSA-N |
M.W : | 212.67 | Pubchem ID : | 16197 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 57.42 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.2 cm/s |
Log Po/w (iLOGP) : | 2.06 |
Log Po/w (XLOGP3) : | 3.38 |
Log Po/w (WLOGP) : | 3.16 |
Log Po/w (MLOGP) : | 3.13 |
Log Po/w (SILICOS-IT) : | 2.91 |
Consensus Log Po/w : | 2.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.41 |
Solubility : | 0.0833 mg/ml ; 0.000392 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.84 |
Solubility : | 0.0306 mg/ml ; 0.000144 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.27 |
Solubility : | 0.116 mg/ml ; 0.000543 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.95 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
91% | With potassium hydroxide In 5,5-dimethyl-1,3-cyclohexadiene; water | EXAMPLE 22 In the xylene dispersion of fine potassium hydroxide having particle diameter of less than 100μ obtained by the process of Example 1, 26 g. (0.33 mole) of isopropyl chloride was charged, and then a solution of 37.5 g. (0.22 mole) of 4-chlorophenylacetic acid in 50 ml. of xylene was added dropwise during about 10 minutes and then, the reaction was continued at 70°-80° C. for 50 minutes. After the reaction, the reaction mixture was poured into 300 ml. of water and the organic layer was separated and concentrated to distil off xylene and the product was distilled under a reduced pressure to obtain 43 g. (yield of 91percent) of α-isopropyl-4-chlorophenylacetic acid (m.p. 88°-89° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | sulfuric acid; at 20℃; | To a solution of commercial <strong>[2012-74-0]2-(4-chlorophenyl)-3-methylbutyric acid</strong> (1 g, 4.7 mmol) in CH3OH (10 mL), few drops of cone. H2SO4 were added, and the resulting mixture was left stirring at room temperature overnight. After solvent evaporation under vacuum, CH2Cl2 (10 mL) and H2O (10 mL) were added; the two phases were separated and the organic one dried over Na2SO4, filtered and evaporated under vacuum to give the intermediate methyl 2-(4-chlorophenyl)-3-methylbutanoate as an <n="18"/>oily residue (quantitative yield). This intermediate was transformed in the related methyl 2-(4-hydroxyphenyl)-3-methylbutanoate according a known procedure3: a mixture of methyl 2-(4-chlorophenyl)-3-methylbutanoate (1.06 g, 4.7 mmol), 60% sodium hydride (0.56 g, 14.1 mmol) and H2O (85 muL, 4.7 mmol) was heated to 45C while kept at argon atmosphere for 3 days (1H-NMR analysis). The solvent was evaporated and the residue diluted with EtOAc and washed with IN HCl (2 x 5 mL); the solvent was evaporated under vacuum and the crude residue was purified by flash chromatography (CHCI3/CH3OH 85: 15) to give the pure intermediate as an oil (0.75 g, 77% yield). 1H-NMR (CDCl3) delta 7.18 (d, 2H, J = 7Hz), 6.82 (d, 2H, J = 7Hz), 5.75 (bs, IH, OH), 3.70 (s, 3H), 3.15 (d, IH, J = 14Hz), 2.55 (m, IH), 1.10 (d, 3H, J = 7Hz), 0.72 (d, 3H, J = 7Hz). The steps of insertion of the triflate group and the following hydrolysis were performed as described1 and 3-methyl-2-[4- (trifluoromethylsulfonyloxy)phenyl]butanoic acid was obtained as a colourless oil (0.91 g, 78% yield calculated from the 4-hydroxy methyl ester derivative). The optical resolution was performed as described.4 (2R)-3-methyl-2-[4- (trifluoromethylsulfonyloxy)phenyl]butanoic acid (0.32 g, 35% yield) was obtained as a white solid. [alpha]D25 (c=l, CH3OH): -50; 1H-NMR (CDCl3) delta 7.55 (d, 2H, J = 7Hz), 7.25 (d, 2H, J = 7Hz), 3.15 (d, IH, J = 14Hz), 2.55 (m, IH), 1.10 (d, 3H, J = 7Hz), 0.72 (d, 3H, J = 7Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; butan-1-ol; at 50 - 70℃; for 6.5h;Heating / reflux;Purification / work up; | In a suitable reactor 566g of () CPA and 2430 g of 30% aqueous butanol was charged under stirring. A solution of 322g of (-) PEA in 966g of 30 % aqueous n-butanol was added to above solution at temperature ranging from 50-70C in about 60 minutes and the contents were heated to reflux for about 90 minutes. The reaction mixture was allowed to come to about 50C in about 240 minutes and filtered off. The filtrate was weighed (2507 g) and treated for recovery of R enriched (-) CPA isomer along with washings of wet cake (850g) as described in example (L LA). The cake (757 g) obtained was washed twice (2 x 390 g) with 30% aq. n-butanol and filtered off. The cake (680. 0g) was further recrystallised using 2430 g of 30 % aqueous n-butanol by heating to reflux temperature (Z90C) FOR about 120 minutes and then allowed to cool to 52C in about 150 minutes and filtered off. The weight of cake and filtrate being 527.7g and 2523 g respectively. The wet cake (527.7 g) was refined in 1562 g of 30% aqueous n-butanol by refluxing for 35 minutes at 90C and the contents were cooled to 52C in about 60 minutes, filtered and weighed. The weight of cake and filtrate obtained was 406. 3g and 1617g respectively. The cake was dried to a constant weight (306 g). The dried PEA salt (306g), distilled water (300g), toluene (900g) were charged into a suitable reactor successively and contents were stirred well. 250G of 40% H2S04 was added over a period of 10-30 minutes and mixed well for 20-30 minutes. The separated aqueous layer containing PEA-HS04 (641 g) was stored for recovery of S (-) PEA. The toluene layer is made free of traces of acid and concentrated to obtain (S+) CPA (197g). Dry weight OF S (+) CPA = 197.0 g. [A] D= +45.129 [CHC13, 6.01] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In propan-1-ol; water; at 20 - 88℃; for 3 - 3.16667h;Heating / reflux;Purification / work up; | In a suitable reaction vessel, 42.2g of ()-CPA and 138. Og of 30% aqueous n- propanol was charged and heated to form a solution. A solution of 14.2g (-) PEA in 42g of 30% aqueous n-propanol was added to the above solution at 52C. The mixture was heated to the reflux temperature for (88C) about 60 minutes and the contents were allowed to reach to 37C under stirring in about 120 minutes. The precipitated (+) CPA- (-) PEA salt (cake) was filtered off and washed with 50g of 30% aqueous n-propanol twice separating the filtrate each time. The wet cake was dried and weighed. The general procedure followed for liberation of the (+) CPA from its amine salt was described below. A small portion of the salt (2. 0G) was extracted with 30ML of 40% Sulphuric acid. The liberated (+) CPA, was extracted with 2 x 20 ml of DCM and concentrated to obtain (+) CPA, which was dried and analysed for its optical purity by POLORIMETRY. The same procedure was followed for all the examples described below. Dry weight = 23.16 g. aD = +41. 09 [CHC13, C = 6.00]; EXAMPLE-3; To 42.2g of () CPA was added under stirring 94. 0g of 20% aqueous n-propanol to make a solution. A solution of 14.2g of (-) PEA in 71. Og of propanol-water (20%) was added to the above solution at 50C and the mixture was heated to reflux temperature for about 60- 70 minutes, allowed to cool to 30C under stirring in about 120 minutes. Precipitated salt was filtered and cake was washed with 20% aqueous n-propanol twice, separating the filtrate each time. Cake obtained was dried and weighed. Dry weight = 23.44 G. aD = + 40.56 [CHC13 ; C=6.05]; EXAMPLE-8; To 42.8g of () CPA was added under stirring 186. 0g of 30% aqueous n-propanol to form a solution. A solution of 14.2g of (-) PEA in 71. OG OF 30% aqueous n-propanol was added to the above solution at 55C in 30 minutes. The reaction mixture was heated to reflux for about 150 minutes and the contents were allowed to reach to room temperature. The precipitated salt of (+) CPA- (-) PEA was filtered off. The cake was re-dissolved in 50g of the solvent system used for resolution of (+) CPA, heated to reflux for about 30 minutes cooled and filtered off. The same procedure was repeated again and the cake obtained was dried and weighed. Dry Weight = 21. 01 G. AD = + 42.86 [CHCL3 ; C=6.04] | |
In propan-1-ol; water; butan-1-ol; at 20 - 70℃; for 3.33333 - 3.83333h;Heating / reflux;Purification / work up; | To 42. 1g of () CPA was added under stirring, 155g of 21% aqueous n-butanol-n- propanol to form a homogeneous solution. A solution of 14.2 g of (-) PEA in 105 G of 21% aqueous n-butanol-n-propanol was added to the above solution at 70C in about 50 minutes and the mixture was heated to reflux for about an hour, allowed to reach to room temperature under stirring in about 90-120 minutes. Crystallized (+) CPA (-) PEA salt was filtered off and cake was washed twice with 50g of same solvent system used for reaction separating the filtrate each time. Wet cake was dried and weighed. Dry WEIGHT = 21. 17 9-AD + 41. 57 [CHC13 ; C=6.06] | |
In water; butan-1-ol; at 35 - 93℃; for 1.5 - 3.58333h;Heating / reflux;Purification / work up; | To 42.26g of (+)-CPA was added under stirring 120g of 20% aqueous n-butanol to form a solution. A solution of 14.26g of (-) PEA in 40g of 20% aqueous n-butanol was added to above solution at 55C. The reaction mixture was refluxed for about 90 minutes and allowed to cool slowly to 37C in about 90-120 minutes. The precipitated CPA- (-) PEA salt (cake) was filtered off and washed with 50G of 20% aqueous butanol under stirring twice separating the filtrate each time. The wet cake was dried and weighed. Dry weight = 23.5 g. aD =+41. 14 [CHC13 ; C=6.23]; EXAMPLE-5; To 42.2g of CPA was added under stirring 45. Og of saturated solution of butanol in water to make a homogeneous solution. A solution of 14.4g (-) PEA in 114g of saturated solution of butanol in water was added to the above solution at a temperature ranging between 45-52C and the mixture was heated to reflux temperature for about 65 minutes, allowed to cool to 37C in about 150 minutes under stirring. Precipitated salt was filtered. Cake was washed with 50g of 10% aqueous butanol twice, separating the filtrate each time. Cake obtained was dried and weighed. Dry Weight = 26.71 G. aD = + 40.79 [CHC13 ; C=6. 03]; EXAMPLE-10; TO 42. 2G OF () CPA HAVING [A] D-3 was added under stirring, 138g 30% aqueous n-butanol to form a solution. A solution of 14. 2 of (-) PEA in 42.2g of above solvent system was added to the already made (+)-CPA solution at 50-60C in 30-50 minutes. The reaction mixture was refluxed for about 60-80 minutes, cooled to room temperature and filtered off. Precipitated salt (cake) was washed twice with 50g of the solvent system used for reaction, separating the filtrate each time. Wet cake was dried and weighed. Dry weight = 23. 15 g. [A] D= + 38.11 [CHCL3 ; C = 6.05]; EXAMPLE-12 The glass lined reactor equipped with stirrer, heater exchanger, dropping funnel and a thermovel is charged with 6.36kg of () CPA, 19.17kg butanol, 8.79kg water under stirring and heated to 50-60C. 2.27kg OF S (-) Phenylethylamine (PEA) is fed into the reactor over a period of 20-30 minutes. The contents are heated with steam to vigorous reflux (92-93 by circulating cold water in the heat exchanger and reflux is contd. for 60 minutes, followed by gradual cooling of the reaction mixture to 35C over a period of 120 minutes and is filtered off (28.32 kg ML-I). The (+) CPA- (-) PEA salt (cake) obtained is dried under vacuum for a period of 20-30 minutes. The cake is recharged into the reactor followed by of 6.38kg of butanol, 2.78kg of water and contents are stirred for a period of 20 minutes, filtered under vacuum to dryness to obtain 10.02kg of washings (WS-I) and 6.38kg of cake. The filtrate (ML-1) and washings (WS-1) are combined and concentrated for recovery of R enriched (-) CPA. The cake (6.38kg) obtained is charged into the reactor and recrystallized using 19.18 kg of Butanol and 8.3kg of water by heating the reaction mixture to vigorous reflux under stirring (92-93C), maintained at that temperature for 60-75 minutes and then allowed to cool to 55-60C over a period of 120minutes. RECRYSTALLIZED slurry is filtered under vacuum (120- 100mm). The filtrate obtained (27.06kg) is kept in storage tank to be used for subsequent batches of recrystallization of cake. The cake obtained (5.26kg) is further refined by charging into the reactor using 4.47kg butanol, 1.93kg of water and heating to reflux (92-93C) for 30- 40 minutes and then cooled to 45C over a period ranging from 45-60 minutes under stirring and the slurry is filtered after removing most of the solvent the cake is dried under vacuum (120-100 mm) for 10-15 minutes. The filtrate (5.3 kg) is stored and recycled to be used for refinement of further batches of the salt. The cake (3.98 kg) is dried in a jacked vacuum tray drier at 46-48C under reduced pressure till a constant wt. (3.08 kg) is obtained. |
In water; toluene; at 40℃; for 3.66667 - 3.83333h;Heating / reflux;Purification / work up; | To 42.2g of ( :) CPA was added under stirring, 85g of 3.5% aqueous toluene to form a solution. A solution of 14.2g (-) PEA in 56g of 3.5% aqueous toluene was added to above solution at 40C in 20-30 minutes and contents were heated to reflux for about 200 minutes and cooled to room temperature. Precipitated salt was filtered and cake was washed with 75g of toluene twice separating the filtrate each time. Wet cake was dried to a constant weight. Dry weight = 34. 00G. [a] D = +34. 528 [CHC13 ; C = 6. 02] | |
In 2-methyl-propan-1-ol; water; at 37 - 60℃; for 3.08333h;Heating / reflux;Purification / work up; | To 42.2g of ()-CPA was added under stirring, 80.0 g of 20% aqueous isobutyl alcohol to form a solution. A solution of 14.2 g (-) PEA in 78g of 20% aqueous isobutyl alcohol was added to above solution at 60C. The reaction mixture was heated to reflux temperature for about 65 minutes and the contents were allowed to reach to 37C under stirring in about 120 minutes. The precipitated salt was filtered and cake was washed with 50g of 20% aqueous isobutylalcohol twice. The cake obtained is dried and weighed. Dry weight: 25.60g. ap = +40.78 [CHC13 ; C = 6.06] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In N,N-dimethyl-formamide; | EXAMPLE 1 To a solution of 4.25 g (20 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid in 30 ml of ether containing one drop of N,N-dimethylformamide is added dropwise 3.81 g (30 mmol) of oxalyl chloride. The solution is stirred at RT until gas evolution ceases. The solvent and excess oxalyl chloride are removed in vacuo and the residue is taken up in 30 ml of ether. This solution is then added dropwise at 0-5 to 4.86 g (40 mmol) of a 14% w/w aqueous solution of ammonia. After stirring the mixture for 30 minutes at 0-5, the aqueous layer is removed. The ethereal solution is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-chlorophenyl)-3-methylbutyramide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 Following the methods of Example 1, 2-(4-chlorophenyl)-3-methylbutanoic acid is reacted with oxalyl chloride and aqueous methylamine to give N-methyl-2-(4-chlorophenyl)-3-methylbutyramide, which is then combined with 3-phenoxybenzyl bromide and AgBF4, yielding 3-phenoxybenzyl N-methyl-2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 407 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 5,5-dimethyl-1,3-cyclohexadiene; | EXAMPLE 4 Preparation of [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methyl-butyrate (compound No. 6). A solution of 2-chloromethyl-4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-one (13.3 g) in xylene (35 cc) is added in the course of 20 minutes to a solution of <strong>[2012-74-0]2-(4-chlorophenyl)-3-methyl-butyric acid</strong> (19 g) and triethylamine (11.7 cc) in xylene (175 cc) heated to 110 C. The reaction mixture is heated at the reflux temperature for 4 hours and, after cooling, is washed successively with water (100 cc), a 3.5% strength aqueous hydrochloric acid solution (100 cc), a 4% strength aqueous sodium carbonate solution (100 cc) and water (100 cc). After drying, decolorizing over animal charcoal and concentrating under reduced pressure, the residue obtained is purified by chromatography on a silica column and gives [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methylbutyrate (11.2 g) in the form of an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; water; | EXAMPLE 22 In the xylene dispersion of fine potassium hydroxide having particle diameter of less than 100mu obtained by the process of Example 1, 26 g. (0.33 mole) of isopropyl chloride was charged, and then a solution of 37.5 g. (0.22 mole) of 4-chlorophenylacetic acid in 50 ml. of xylene was added dropwise during about 10 minutes and then, the reaction was continued at 70-80 C. for 50 minutes. After the reaction, the reaction mixture was poured into 300 ml. of water and the organic layer was separated and concentrated to distil off xylene and the product was distilled under a reduced pressure to obtain 43 g. (yield of 91%) of alpha-isopropyl-4-chlorophenylacetic acid (m.p. 88-89 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogensulfide; triethylamine; In N-methyl-acetamide; water; | EXAMPLE 1 Three grams (14.1 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid is dissolved in approximately 50 ml of dry dimethylformamide, after which 1.43 g (14.1 mmol) of triethylamine is added in one portion. The solution is cooled to 0 and 1.59 g (14.1 mmol) of ethyl chloroformate is slowly added over 30 seconds. After 0.5 hour 3.15 g (28.2 mmol) of sodium hydrosulfide is added. The mixture is stirred overnight at room temperature. The reaction mixture is then poured into 150 ml of water and adjusted to pH 3 with 5% aqueous sulfuric acid. Extraction with 50 ml methylene chloride (3*) is followed by drying and stripping. Dimethylforamide is still present, so the product is taken up in ether and washed with 200 ml of water, dried and stripped to yield 2-(4-chlorophenyl)-3-methylbutanethioic S-acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; | Method A alpha-Isopropyl-4-chlorophenylacetic acid (1.3 g) was dissolved in ethanol (10 ml) and a solution of potassium hydroxide (0.34 g) in water (5 ml) was added to the ethanolic solution. The solvents were then removed by distillation under reduced pressure to give anhydrous potassium alpha-isopropyl-4-chlorophenylacetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With hydrogenchloride; sodium hydroxide; triethylamine; In 1,2-dichloro-ethane; acetone; | Method B A mixture of alpha-isopropyl-4-chlorophenylacetic acid (1.05 g), alpha-fluoro-3-phenoxybenzyl bromide (1.16 g), triethylamine (0.64 g) and acetone (6 ml) was heated under reflux with stirring for a period of 2 hours. Triethylamine hydrobromide was removed from the reaction mixture by filtration and the solvent was removed by distillation under reduced pressure. The product was dissolved in ethylene dichloride and the solution was washed in a sequence with 2 N HCl, water, 1 N NaOH and water. The ethylene dichloride solution was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to yield alpha'-fluoro-3'-phenoxybenzyl alpha-isopropyl-4-chlorophenylacetate (1.61 g; 87%) as a colourless oil. The product was characterised by pmr spectroscopy (see Method A above). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; triethylamine hydrochloride; triethylamine; In n-heptane; dichloromethane; carbon dioxide; | EMBODIMENT 2 (4-Chlorophenyl)isopropylketene A sample of 53.2 g of isopropyl(4-chlorophenyl)acetic acid was treated with 21.5 ml of thionyl chloride in a 500 ml flask and heated slowly to 80 C. and maintained at 80 C. for 20 minutes. The reaction mixture was allowed to stand at room temperature for 2 days. The volatiles were stripped to 75 C. at 0.5 mm Hg. The resulting yellow liquid was diluted with 250 ml of methylene chloride followed by addition of 38.0 g of triethylamine. The mixture was stirred until triethylamine hydrochloride began to precipitate after 30 minutes. After 16 hours, the reaction mixture was filtered and solid triethylamine hydrochloride was washed with heptane. Most of the solvent was stripped from the filtrate by rotary evaporation at 50 C. The residue was diluted with 75 ml of heptane and additional triethylamine hydrochloride was removed by filtration as above. The filtrate was restripped and rediluted with 75 ml heptane and refiltered with the aid of 25 ml of heptane. The filtrate was cooled in dry ice, seeded and crystallized. The resulting crystals were filtered with a filter stick and washed with chilled heptane. The filtered solids were melted, diluted with one-half volume heptane, crystallized at -80 C. and the collected solid was melted and stored at -80 C. The filtrate solution was warmed, stripped of most solvent, then distilled through a Bantam were short path head at 0.05 to 0.06 mm Hg from an oil bath at 90-120 C. Total distillate was 14.5 g collected as a bright yellow-orange liquid at a head temperature of 60-85 C. The distillate was crystallized from an equal volume of pentane at -80 C., filtered and washed twice with heptane as above to give, on warming, a second melt. The stripped filtrates totalling 5.79 g were crystallized as above in a 6-inch test tube and the melt was recrystallized immediately as described above to give a third melt. The three melts were combined and stripped to 50 C. at 5 mm Hg to give 29.4 g of the desired ketene as a yellow liquid. | |
With thionyl chloride; triethylamine hydrochloride; triethylamine; In n-heptane; dichloromethane; carbon dioxide; | Embodiment 6 (4-Chlorophenyl)isopropylketene A sample of 53.2 g of isopropyl(4-chlorophenyl)acetic acid was treated with 21.5 ml of thionyl chloride in a 500 ml flask and heated slowly to 80 C. and maintained at 80 C. for 20 minutes. The reaction mixture was allowed to stand at room temperature for 2 days. The volatiles were stripped to 75 C. at 0.5 mm Hg. The resulting yellow liquid was diluted with 250 ml of methylene chloride followed by addition of 38.0 g of triethylamine. The mixture was stirred until triethylamine hydrochloride began to precipitate after 30 minutes. After 16 hours, the reaction mixture was filtered and solid triethylamine hydrochloride was washed with heptane. Most of the solvent was stripped from the filtrate by rotary evaporation at 50 C. The residue was diluted with 75 ml of heptane and additional triethylamine hydrochloride was removed by filtration as above. The filtrate was restripped and rediluted with 75 ml heptane and refiltered with the aid of 25 ml of heptane. The filtrate was cooled in dry ice, seeded and crystallized. The resulting crystals were filtered with a filter stick and washed with chilled heptane. The filtered solids were melted, diluted with one-half volume heptane, crystallized at -80 C. and the collected solid was melted and stored at -80 C. The filtrate solution was warmed, stripped of most solvent, then distilled through a Bantam ware short path head at 0.05 to 0.06 mm Hg from an oil bath at 90-120 C. Total distillate was 14.5 g collected as a bright yellow-orange liquid at a head temperature of 60-85 C. The distillate was crystallized from an equal volume of pentane at -80 C., filtered and washed twice with heptane as above to give, on warming, a second melt. The stripped filtrates totalling 5.79 g were crystallized as above in a 6-inch test tube and the melt was recrystallized immediately as described above to give a third melt. The three melts were combined and stripped to 50 C. at 5 mm Hg to give 29.4 g of the desired ketene as a yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In water; benzene; | EXAMPLE II 3-BENZYL-5-[2-(4-CHLOROPHENYL)3-METHYL BUTOXYMETHYL]1,2,4-OXADIAZOLE This example teaches the synthesis of a representative compound of reaction step 2 using the intermediate prepared in Example I. First, 2.1 grams (0.01 mole) of the intermediate of Example I, 2.3 grams (0.011 mole) of 2-(4-chlorophenyl)3-methyl butyric acid, 1.0 grams (0.01 mole) of triethylamine, and 100 milliliters of methylethylketone were combined and heated under reflux for 2 hours. The mixture was then cooled and poured into 200 milliliters of benzene. The benzene mixture was then washed in turn with 100 milliliters of H2 O, 100 milliliters of 5% K2 CO3 solution, and 100 milliliters of H2 O. The benzene phase was then dried with MgSO4 and evaporated in vacuo to yield 3.0 grams (78% of theory) of the desired product. nD30 1.5210. The following is a table of certain selected compounds that are preparable according to the procedure described hereto. Compound numbers are assigned to each compound and are used throughout the remainder of the specification. |
Yield | Reaction Conditions | Operation in experiment |
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3.54% | EXAMPLE II 4-Chloro-alpha-(1-methylethyl)benzeneacetic acid:(6-phenoxy-2-pyridinyl)methyl ester STR5 A solution was prepared by admixing 3.0 grams (0.014 mole) of 6-(phenoxy)picolinalcohol, 3.5 grams (0.015 mole) of 2-isopropyl-2-(4-chlorophenyl)acetic acid chloride 10 milliliters of triethylamine and 100 milliliters of dry ether. The reaction mixture was agitated at room temperature for 1 hour. The resulting reaction product mixture was successively washed with dilute hydrochloric acid, dilute sodium hydroxide, dried over anhydrous magnesium sulfate, filtered through silica gel and concentrated to give 5.3 grams of the desired 4-chloro-alpha-(1-methylethyl)benzeneacetic acid:(6-phenoxy-2-pyridinyl)methyl ester. The product, a viscous yellow oil, had a refractive index of 1.5664 and the structure of the product was confirmed by NMR. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 68.83, 5.19 and 3.10 percent, respectively, as compared with the theoretical contents of 69.78, 5.60 and 3.54 percent, respectively, as calculated for the above named compounds (Compound No. 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In water; | EXAMPLE IV 4-Chloro-alpha-(1-methylethyl)benzeneacetic acid:cyano(6-(3-methoxyphenoxy)-2-pyridinyl)methyl ester STR7 To a solution of 2.56 grams (0.01 mole) of cyano(6-(3-methoxyphenoxy)-2-pyridine)methanol and 2.31 grams (0.01 mole) of 2-isopropyl-2-(4-chlorophenyl)acetic acid chloride in 25 milliliters of anhydrous ether was added 3 milliliters of triethylamine. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with 50 milliliters of water and extracted thoroughly with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under vacuo. The crude oily residue of 4-chloro-alpha-(1-methylethyl)benzeneacetic acid:cyano(6-(3-methoxyphenoxy)-2-pyridinyl)methyl ester product was purified by distillation at 140 C. at 0.1 millimeters of mercury (mm Hg) to give 4.0 grams of the product. The oil had a refractive index of n 25/D=1.5666. The structure of the product was confirmed by its nuclear magnetic resonance spectrum (NMR). Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 66.45, 5.23 and 6.21 percent, respectively, as compared with the theoretical contents of 66.59, 5.14 and 6.21 percent respectively, as calculated for the above compound. (Compound No. 4). |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
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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