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CAS No. : | 1798-06-7 | MDL No. : | MFCD00082985 |
Formula : | C8H7IO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FJSHTWVDFAUNCO-UHFFFAOYSA-N |
M.W : | 262.04 | Pubchem ID : | 137214 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.7 |
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) : | -6.02 cm/s |
Log Po/w (iLOGP) : | 1.61 |
Log Po/w (XLOGP3) : | 2.64 |
Log Po/w (WLOGP) : | 1.92 |
Log Po/w (MLOGP) : | 2.55 |
Log Po/w (SILICOS-IT) : | 2.5 |
Consensus Log Po/w : | 2.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.4 |
Solubility : | 0.104 mg/ml ; 0.000399 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.07 |
Solubility : | 0.221 mg/ml ; 0.000843 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.13 |
Solubility : | 0.195 mg/ml ; 0.000745 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.67 |
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 |
---|---|---|
33% | Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 6 h; Stage #2: With sodium hydroxide; water In tetrahydrofuran |
To a stirred solution of 2-(4-iodophenyl)acetic acid (2.00 g, 7.63 mmol) in tetrahydrofuran (150 ml_) at room temperature was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 7.63 ml_, 7.63 mmol). The resulting solution was stirred for 6 hours prior to dilution with brine, adjustment to pH = 13 with NaOH, and extraction with ethyl εicetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford 192a (620 mg, 33percent) as a light orange solid which was used in the subsequent reaction without further purification. LRMS (ESI): (calc) 248.1 ; (found) 271.1 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; for 2h;Heating; Inert atmosphere; | A mixture of 4-iodophenylacetic acid (3 g, 11.5 mmol, 1 e.q.) and thionyl chloride (5 mL, 49 mmol, 4.5 e.q.) was heated in an 80 C oil bath under argon for 2 h. The reaction is then allowed to cool to room temperature. The excess thionyl chloride is removed in vacuum to give 6 as a dark yellow oil (3.2 g, 100%) which is used without further purification. NMR (300 MHz, CDCb) d 4.11 (2 H, s, CH2), 7.03 & 7.73(4 H, AA'XX', Ph-H). |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; | G2. DMF (5 drops) was added to a dichloromethane solution (30 mL) containing acid Gl (4.02 g, 15 mmol) and oxalyl chloride (1.61 mL, 18 mmol) at room temperature. After stirring for 1 h., excess dichloromethane was removed using reduced pressure. The remaining residue was dissolved in a dry THF and was added to a THF solution containing ethyl cuperate (23 mmol) at -20 C. After 20 min., a saturated copper sulfate solution was then added at -20 C, and the mixture was warmed to room temperature. The resulting solution was extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The remaining residue was purified on silica eluting with 30% ethyl acetate/hexane solution to give 2.29 g (56 % yield) of ketone G2: ESI (MH+) m/z 275. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;Inert atmosphere; | Under an inert atmosphere and at room temperature, 4 ml (43.8 mmol) of oxalyl chloride are added to 3.8 g (14.6 mmol) of 4-iodophenylacetic acid suspended in dichloromethane (54 ml). Two drops of DMF are introduced and the reaction mixture is heated for one hour at room temperature, and then concentrated under reduced pressure. The residue is taken up in toluene and concentrated again. The acid chloride thus obtained is dissolved in dichloromethane (10 ml) and added dropwise to 5 g (14.6 mmol) of the compound obtained from step 1.9 suspended in dichloromethane (30 ml) in the presence of 2.45 g (29.2 mmol) of NaHCO3, under cold conditions (ice bath) and under an inert atmosphere. The reaction medium is stirred overnight at room temperature, and is then filtered through Celite and concentrated under reduced pressure. 8.5 g of product are obtained in the form of a yellow foam, and are used directly in the following step without purification. MH+: 586 |
With thionyl chloride; at 100℃; for 1.5h;Inert atmosphere; | Under an argon atmosphere, to 4-iodophenylacetic acid (11) (prepared by the process described in Chen, Q.-H. et al., Bioorg. Med. Chem. 14, 7898-7909 (2006)) (1.06 g, 4.05 mmol) was added thionyl chloride (5.00 mL, 68.6 mmol) and heated to reflux (100 C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-iodophenylacetyl chloride (12) as a brown oily crude product, which was used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 20℃; for 0.166667h; | intermediate 35; yV-[2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-2-(4-iodo-phenyl)- acetamide; A solution of (4-iodo-phenyl)-acetic acid (5 g, 19.08 mmol) in MeCN was treated with CDI (3.40 g, 21 mmol) and allowed to stir at RT for 10 min after which a voluminous precipitate was produced. Triethylamine (5.80 ml_, 42 mmol) was added, followed by 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrobromide (5.56 g, 19.08 mmol) and the reaction slurry was stirred at RT for 18 h. The reaction mixture was then partitioned between water (200 ml_) and EtOAc (2 x 300 ml_). The combined organic extracts were washed with 10% aqueous Na2SO4 (2 x 100 ml_) and brine (100 ml_), dried (Na2SO4), filtered and concentrated in vacuo to afford the title product.Yield: 6.18 g (71%).LC-MS (Method 2): Rt 2.98 min, m/z 455 [M+H] 496 [M+H+MeCN]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | To a stirred solution of 2-(4-iodophenyl)acetic acid (2.00 g, 7.63 mmol) in tetrahydrofuran (150 ml_) at room temperature was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 7.63 ml_, 7.63 mmol). The resulting solution was stirred for 6 hours prior to dilution with brine, adjustment to pH = 13 with NaOH, and extraction with ethyl epsilonicetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford 192a (620 mg, 33%) as a light orange solid which was used in the subsequent reaction without further purification. LRMS (ESI): (calc) 248.1 ; (found) 271.1 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h; | To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification. |
98% | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h; | Preparation 38 Methyl 4-Iodophenylacetate To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification. |
98% | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h; | To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification. |
98% | hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h; | To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification. |
98% | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h; | To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MEOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification. |
93% | With thionyl chloride; at 0 - 20℃; for 1h; | Methyl (4-iodophenyl)acetate (13).; To a solution of <strong>[1798-06-7](4-iodophenyl)acetic acid</strong> (12) (15.0 g, 57.0 mmol) in dry methanol (50 mL) was added SOCl2 (20.7 mL, 285 mmol, 5 equiv) drop wise at 00C. After stirring for 1 h at room temperature, the solvent was removed under reduced pressure and the residue dissolved in Et2O (400 mL). The organic phase was subsequently washed with saturated aqueous NaHCO3 (400 mL), saturated aqueous NH4Cl (400 mL) and brine (400 mL) and dried over MgSO4. Concentration under reduced pressure gave 13 (14.7 g, 93%). Rf=O.57 (EtOAc/hexane, 1 :4); 1H NMR (360 MHz, CDCl3) δ 7.65 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 3.69 (s, 3H), 3.56 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 171.3, 137.6, 133.5, 131.2, 92.5, 52.0, 40.5. |
90% | With tert.-butylnitrite; at 40℃; for 48h; | Add compound 1z (0.5 mmol, 131.1 mg) and methanol containing 40 mol% tert-butyl nitrite to the reaction tube; then react for 48 hours at 40C in air; after the reaction, add sodium thiosulfate and stir. After quenching, using a rotary evaporator to remove the solvent, silica gel adsorption, and finally column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3z, the yield is 90% |
86% | With thionyl chloride; at 20℃; for 36h; | A solution of 5 g (19 mmol) of [(4-IODO-PHENYL)-ACETIC ACID] in 50 mL of methanol [(MEOH)] was added dropwise 3.5 mL [(48] mmol) of [THIENYL] [CHLORIDE (SOCL2),] and the resulting mixture was stirred at rt for 36 h, after which time analysis by thin layer chromatography (TLC) indicated product formation. The mixture was concentrated to give 4.5 g [(86%] yield) of (4-iodo-phenyl)-acetic acid methyl ester as a pale beige oil as indicated by H NMR. A solution of 2. 88 mL (20.5 mmol) [OF DIISOPROPYLAMINE (IPR2NH)] in 50 mL of tetrahydrofuran [(THF)] was flushed with argon and cooled [TO-78 C.] To this solution was added dropwise 8.2 mL (20.5 mmol) [OF N-BUTYLLITHIUM (NBULI)] 2. 5 M solution in hexane, and the resulting mixture was stirred at-78 [C] for 20 min, after which time a solution of 4.5 g (16.3 mmol) of [(4-IODO-PHENYL)-ACETIC ACID METHYL ESTER] in 25 mL of THF was added dropwise. The mixture was allowed to warm up to rt for 40 min, then it was cooled again [TO-78 C,] and 2.62 mL (19.6 mmol) [OF CYCLOHEXANECARBONYL CHLORIDE] was added dropwise, and the resulting mixture was allowed to warm up to rt, and stirred at rt overnight under argon. The reaction mixture was quenched on ice by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated to give 7 g of a burgundy oil which was chromatographed on silica gel (Biotage; 10% ethyl acetate in hexane) to afford 5.06 g [(80%] yield) of desired [3-CYCLOHEXYL-2-(4-IODO-PHE72YL)-3-OXO-PROPIONIC ACID METHYL ESTER AS] a pale yellow solid as indicated [BY 1HNMR] (1: 2.6 keto: enol ratio). LC-MS-calcd for C16Hl9IO3 [[M++H] +] : 387.04, found: 387.0. According to a modified literature procedure (Collins, [1.] et al [J. MED. CHENA.] 2002, 45, 1887-1900) a solution of 5.06 g (13.1 mmol) of 3-cyclohexyl-2-(4-iodo-phenyl)-3-oxo- [PROPIONIC ACID METHYL ESTER] in 80 mL of dimethylsulfoxide (DMSO) was added a solution of 1.53 g (26.2 mmol) of sodium chloride (NaCI) in 5.8 mL of water (H2O), and the resulting mixture was heated at [150 C] for 3 h during which time a white solid formed. The reaction mixture was cooled to rt, poured into 500 mL of water, and extracted thoroughly with ethyl acetate. The combined organic extracts were washed with water (3 times), brine, dried over sodium sulfate and concentrated to give 4.13 g (96% yield) of desired 1-cyclohexyl-2- (4-iodo- phenyl)-ethanone as a yellow solid as indicated by 1H NMR (containing small traces of impurities). The product was used without any further purification in the next step. According to a modified literature procedure (Wasserman, H. H.; Ives, J. L. [J.] Org. Chem. 1985, 50, 3573-3580) a solution of 4.13 g (12.6 mmol) of [1-CYCLOHEXYL-2- (4-IODO-] [PHENYL)-ETHANONE] in 20 mL of toluene was flushed with argon. To this solution was added 2.7 mL (17.6 mmol) [OF METHOXY BIS (DIMETHYLAMINOQ7WLETHA7LE,] and the resulting mixture was stirred at 70C under argon overnight. The reaction mixture was concentrated to give 5.07 g of crude 1-cyclohexyl-3-dimethylamino-2-(4-iodo-phenyl)-propenone as indicated [BY'H NMR] (containing traces of starting material). The product was used without any further purification in the next step. A solution of 2.55 g (6.32 mmol max) of crude 1-cyclohexyl-3-dimethylamino-2-(4- [IODO-PHEENYL)-PROPENONE,] and 0.98 g (6.32 mmol) [OF 5-AFNINO-IH-PYRAZOLE-4-CARBOXYLIC ACID] ethyl ester in 30 mL of acetic acid [(HOAC)] was heated at reflux for 66 h, during which time a precipitate formed. The precipitate was filtered off and discarded, and the acetic acid filtrate was concentrated to a solid residue, which was washed with 1: 1 ethyl acetate: hexane and dried to give 1.67 g (55% yield) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3- carboxylic acid ethyl ester as a pale yellow [SOLID.'H] NMR (CDC13) [5] 8.57 (s, [1H),] 8. 53 (s, 1H), 7.86-7. 83 (d, J= 8.4 Hz, 2H), 7.1-7. 06 (d, J= 8.4 Hz, 2H), 4.46 (q, 2H, J= 7.2 Hz), 3.31- 3.21 [(M,] 1H), 2.62-2. 41 [(M,] 2H), 1.87-1. 82 [(M,] 2H), 1.74-1. 66 [(IN,] 3H), 1.44 (t, 3H, J= 7.2 Hz), 1.41-1. 21 [(M,] 3H). A solution of 1.66 g (4.1 mmol max) of crude 1-cyclohexyl-3-dimethylamino-2-(4-iodo- [PHENYL)-PROPENONE,] and 0.44 g (4.1 mmol) [OF 5-AMI7LO-LH-PYRAZOLE-4-CARBONITRILE IN] 20 mL of acetic acid [(HOAC)] was heated at reflux for [66 H,] during which time a finely dispersed precipitate formed. Since all attempts to filter off the precipitate were unsuccessful, the reaction mixture was concentrated to give a brown residue which was chromatographed on silica gel (Biotage; 2% ethyl acetate in dichloromethane) to afford 1.09 g (62% yield) of 7- cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid NMR (CDC13) [6] 8.49 (s, 1H), 8.39 (s, 1H), 7.88-7. 86 (d, J= 8.4 Hz, 2H), 7.07-7. 05 (d, J= 8.4 Hz, [2H),] 4.13 (q, 2H, J= 7.2 Hz), 3.28-3. 21 [(M,] 1H), 2.59-2. 47 [(M,] 2H), 1.87-1. 8... |
With sulfuric acid; at 85℃; for 16h;Inert atmosphere; | A vessel was charged with Compound Q21A (10 g, 38.1 mmol, 1.00 eq ) in MeOH (60 mL). H2SO4 (3.74 g, 38.1 mmol, 2.03 mL, 1.00 eq ) was added to the mixture under N2. The reaction was stirred at 85 C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and then reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with saturated aq NaHCCh (70, 50mL). The final organic phase was concentrated under reduced pressure to give Compound Q21B. NMR (400 MHz, CDCh) d 7.65 (d, J= 8.4 Hz, 2H), 7.04 (d, J= 8.4 Hz, 2H), 3.70 (s, 3H), 3.57 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfuric acid; for 7h;Heating / reflux; | 1. 25 ml (0. 023 mol) of concentrated sulphuric acid are added dropwise to a mixture of 6. 14 g (0. 023 mol) of 4-iodophenylacetic acid in 50 ml of ethanol. The reaction medium is then heated under reflux for 7 h, and then concentrated in a rotary evaporator under vacuum. Water is added to the residue obtained. The solution is neutralized by adding sodium bicarbonate. The desired product is extracted by adding ethyl ether. The organic phase is washed with water, dried over magnesium sulphate and concentrated in a rotary evaporator. The product is purified by filtration on a silica column, eluted with a dichloromethane 8/heptane 2 mixture. After evaporation of the solvents, 6. 2 G (96%) of the expected compound are recovered in the form of a colourless oil. |
90% | With sulfuric acid;Heating / reflux; Neat (no solvent); | [4-IODOPHENYLACETIC] acid (3 g), ethanol (20 mL) and conc. [H2SO4] (5 mL) were refluxed overnight. Ca. 15 mL ethanol was then evaporated, the residue was extracted with dichloromethane (3 x 100 mL), the combined organic extracts were washed with sat. aq. [NAHCO3,] dried over [NA2S04] and evaporated in vacuo to afford 2.97 g (90 %) of 121JP58 as a yellow oil. Characterization Data [: 1H-NMR (CDC13) ] 7.62 (d, 2H, J= 8.4), 7.02 (d, 2H, J = 8.4), 4.07 (q, 2 H, [J=] 7.0), 3.59 (s, 2H), 1.12 (t, 3H, [J=] 7.0). |
43% | With sulfuric acid;Reflux; Inert atmosphere; | To a solution of A (50 g, 0.2 mol, 1 .Oeq) in EtOH (200m1, 2.Omol, 10.0 eq) was added catalytic H2S04 and the reaction heated at ref lux under N2 overnight. The mixture was diluted with 250 mL water and extracted with 2x1 50 mL EtOAc. The combined organic fractions were concentrated and purified by column chromatography (EtOAc: PE1 :50 to 1:10) to give the title compound (24 g, 43%) as a colorless solid. |
With hydrogenchloride; for 16h;Reflux; | A solution of 2f1 (Lancaster; 4.54 g, 17.3 mmol) and concentrated HCI in EtOH (100 mL) is heated to reflux for 16 h. The cooled mixture is concentrated under reduced pressure and the residue diluted with EtOAc. The solution is washed with aqueous saturated NaHC03 solution, water and brine, dried (MgS04), filtered and concentrated under reduced pressure. The resulting ethyl ester is transformed into compound 2f2 using the procedure described in step 1 of example 2c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h; | EXAMPLE 32; <n="68"/>2-r4-riH-Pyrazol-l-vnphenyll-N-UlR)-l-r5-f2.2.2-trifluoroethoxy)pyridin-2-yl1ethvnacetamxde; To a 50 ml round bottom flask equipped with a magnetic stir bar were added 4- iodophenylacetic acid (1.048 g, 4.000 mmol), (lR)-l-{5-[(2,2,2-trifluoroethyl)oxo]pyridin-2- yl}ethylamine dihydrochloride (1.172 g, 4.000 mmol). l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.767 g, 4.000 mmol), l-hydroxy-7-azabenzotriazole (0.544 g, 4.000 mmol) and triethylamine (1.115 ml, 8.000 mmol) into 10.0 ml OfCH2Cl2. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and the two layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. The residue was dissolved into CH2C12 (20 ml). Hexanes was added while stirring until slightly cloudy. A white crystal gradually crystallized on the wall of the flask. The mixture was allowed to sit overnight. The solvent was decanted and the crystal was washed with hexanes (3 x 10 ml). Dried under vacuum to give 2-(4-iodophenyl)-N-((l R)-I- {5-[(2,2,2-trifluoroethyl)oxo]pyridin-2-yl}ethyl)acetamide as a white solid (1.700 g, 92%). 1HNMR (CDCl3, 400 MHz) δ 8.226 (d, J= 2.75 Hz5 IH); 7.657 (d, J= 8.33 Hz, 2H); 7.223 (dd, J= 2.89 Hz, J= 8.57 Hz5 IH); 7.169 (d, J= 8.51 Hz3 2H); 7.031 (d, J= 8.15 Hz, 2H); 6.736 (d, J= 6.87 Hz, IH); 5.091 (dq, J= 7.01 Hz, IH); 4.387 (dd, J= 7.97 Hz, J= 15.93 Hz, 2H); 3.513 (s, 2H); 1.400 (d, J= 6.77 Hz, 3H); MS (Electrospray): m/z 465.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h; | To a solution of 4-iodophenylacetic acid (1346 mg) in N, N- dimethylformamide (15 ML) were added tert-butyl 2- aminophenylcarbamate (1.07 g), 1-hydroxybenzotriazole (HOBT) (764 mg), 1-ETHYL-3- (3'-DIMETHYLAMINOPROPYL) carbodiimide hydrochloride (1.08 g), and the mixture was stirred at ambient temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was sequentially washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of hexane and ethyl acetate (4: 1 to 2: 1) to give Compound (1) as a pale yellow amorphous (2.03 g). 1H-NMR (300 MHz, DMSO-D6, 5) : 1.50 (3x3H, s), 3.66 (2H, s), 6.62 (1H, brs), 7.07-7. 20 (4H, m), 7.33 (1H, m), 7.47 (1H, m), 7.69 (2xlH, d, J=8.3 Hz), 8.00 (1H, brs); MASS (ES+): m/e 453. Preparation 2 To a stirred solution of Compound (1) (25.6 g) in ethanol (300 mL) was added concentrated hydrochloric acid (30 mL), and the mixture was refluxed for 1 hour. The solvent was evaporated in vacuo azeotropically with toluene. The residual solid was collected with the mixture of ethanol and ethyl acetate (1: 10) to give Compound (2) as an orange solid (20.0 g). H-NMR (300 MHz, CDC13, 8) : 4.52 (2H, s), 7.30 (2xlH, d, J=8.3 HZ), 7.49-7. 57 (2H, m), 7.73-7. 82 (4H, m); MASS (ES+): m/e 335. | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h; | To a solution of 4-iodophenylacetic acid (1346 mg) in N,N-dimethylformamide (15 mL) was added tert-butyl 2-aminophenylcarbamate (1.07 g), 1-hydroxybenzotriazole (HOBT) (764 mg), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g), and the mixture was stirred at ambient temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was sequentially washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of hexane and ethyl acetate (4:1 to 2:1) to give Compound (1) as a pale yellow amorphous (2.03 g). 1H-NMR (300 MHz, DMSO-d6, δ): 1.50 (3×3H, s), 3.66 (2H, s), 6.62 (1H, brs), 7.07-7.20 (4H, m), 7.33 (1H, m), 7.47 (1H, m), 7.69 (2×1H, d, J=8.3 Hz), 8.00 (1H, brs); MASS (ES+): m/e 453. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide;benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h; | Under nitrogen at 5 C., to a solution of 4-iodophenylacetic acid (11.6 g) in N,N-dimethylformamide (110 ml) were added (1R)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride (9.19 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (7.54 g) and 1-hydroxybenzotriazole (6.56 g), and the mixture was stirred at room temperature for 12 hours.The resulting mixture was poured into 1N sodium hydroxide and the aqueous mixture was extracted with a mixture of hexane and ethyl acetate (1:1).The organic layer was washed successively with water (two times) and brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure and dried in vacuo to give N-[(2R)-2-(3-chlorophenyl)-2-hudroxyethyl]-2-(4-iodophenyl)acetamide (16.7 g). (+)ESI-MS (m/z): 438 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride; In methanol; water; at 20℃; for 24h; | Preparation 83 methyl 4-Iodophenylacetate To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 ML) was added 4N hydrochloric acid in dioxane (10 ML).The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 5 - 20℃; for 12h; | Under nitrogen at 5C, to a solution of 4- iodophenylacetic acid (11.6 g) in N, N-dimethylformamide (110 ml) were added (lR)-2-amino-l- (3-chlorophenyl) ethanol hydrochloride (9.19 G), 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide (7.54 g) and 1-hydroxybenzotriazole (6.56 g), and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into 1N sodium hydroxide and the aqueous mixture was extracted with a mixture of hexane and ethyl acetate (1: 1). The organic layer was washed successively with water (two times) and brine, dried over anhydrous magnesium sulfate, evaporated under reduced pressure and dried in vacuo to give N-[(2R)-2- (3-CHLOROPHENYL)-2-HUDROXYETHYL]-2- (4-IODOPHENYL) acetamide (16.7 G). (+) ESI-MS (m/z): 438 (M+Na) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In toluene; at 80℃; for 2h; | A solution of 4-iodo phenyl acetic acid (Lancaster, 1. 31g, 5mmmmol) in anhydrous toluene (10mL) was heated to 80C and treated with a solution of N, N- dimethyl fonnamide di-t-butyl acetal. After 2 h the reaction mixture was cooled to ambient temperature and subjected to flash column chromatography on silica gel (23-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound (0.7g, 44%). 1H NMR (300 MHz, CDCl3) : 8 7.62 (d, 2H, J= 8.2Hz), 7.01 (d, 2H, J= 8.2Hz), 3. 45 (s, 2H), 1.43 (s, 9H). |
44% | In toluene; at 80℃; for 2h; | 4-Iodo-tert-butyl phenvl acetate (Reagent 10); A solution of 4-iodo phenyl acetic acid (Lancaster, 1. 31g, 5mmmol) in anhydrous toluene (lOmL) was heated to 80C and treated with a solution of N, N- dimethyl formamide di-t-butyl acetal. After 2 h the reaction mixture was cooled to ambient temperature and subjected to flash column chromatography on silica gel (23-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound (0.7g, 44%). IH NMR (300 MHz, CDCl3) : 8 7.62 (d, 2H, J= 8. 2Hz), 7.01 (d, 2H, J= 8. 2Hz), 3.45 (s, 2H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | A solution of 1 g (4.7 mmol) of benzenesulfonyl-acetic acid hydrazide (example 74.1) in 4 mL of THF was treated with 391 mg (4.7 mmol) of iodophenylacetic acid, 126 mg (0.93 mmol) of 1-hydroxybenzotriazole and 2.8 g (28 mmol) of N-methylmorpholine. The mixture was stirred during 15 min at 0C, treated with 1.25 g (6.5 mmol) of EDCI and stirred during 12 hrs. The crude was treated with diluted aqueous NH4Cl and extracted twice with EtOAc. Drying of the combined organic layers over Na2SO4, filtration and evaporation gave 2 g (93%) of benzenesulfonyl-acetic acid N'- [2- (4-iodo-phenyl)-acetyl]- hydrazide as a brown oil, MS: 266 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; copper(l) iodide; In water; dimethyl sulfoxide; at 90℃; for 16h; | 3-Amino-1- [1- (3-tert-butyl-phenyl)-cyclohexylamino]-4- (3, 5-difluoro-phenyl)- butanol dihydrochloride salt (1 mmol), 4-iodophenylacetic acid (1 mmol), and potassium hydroxide (5 mmol) were added to around bottom flask equipped with stirbar. DMSO (5 mL) and H20 (5 mL) were added and the mixture dissolved. Copper iodide (10%) was added and the mixture was heated for 16 hours at 90 C. The reaction was extracted with DCM (2 x 10 mL), then neutralized with 1 M HCI and extracted with 4: 1 CHCI3/IPA. Both organic fractions were combined, dried with sodium sulfate, and concentrated to give a brown oil. This residue was purified by reverse-phase HPLC. Retention time (min) = 2.274, method [1] ;'H NMR (300 MHz, CD30D) 8 7.54 (s, 1 H), 7.46-7. 27 (m, 3H), 6.94 (d, 2H, J = 7.8 Hz), 6.76-6. 59 (m, 3H), 6.36 (d, 2H, J = 7.8 Hz), 3.58-3. 43 (m, 2H), 3. 41 (s, 2H), 3.03 (d, 1H, J = 13.7 Hz), 2.87 (d, 1H, J = 13.7 Hz), 2.76-2. 45 (m, 4H), 1.95-1. 54 (m, 4H), 1.39-1. 06 (m, 11H). 13C NMR (75 MHz, CD30D) 174.7, 162.7 (dd, 2C, J = 248. 2, 13.5 Hz), 158.2, 152.2, 146.0, 142.6 (t, 1C, J = 9.7 Hz), 133.1, 129.6, 128.9, 126.0, 124.6, 124.3, 123. 0,112. 6,111. 8 (dd, 2C, J = 17.1, 7.4 Hz), 100.9 (t, 1C, J = 25.7 Hz), 69.7, 64.0, 57.3, 45.1, 39.5, 35.9, 34.3, 32.6, 32.5, 30.0, 24.6, 21.7 ; MS (ESI) 565.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
FIG. 7 outlines the synthesis of a no-carrier-added iodine-123 labeled analogue of rofecoxib 1. Thioanisole 2 was converted to the requisite potassium trifluoroboronate salt 8 in six steps. Ketone 3 was prepared by Friedel-Crafts acylation of thioanisole 2. Oxidation of 3 using MMPP (magnesium monoperoxyphthalate hexahydrate) afforded sulfone 4 which was allowed to react with bromine in chloroform at 0 C. in the presence of a trace amount of AlCl3 to generate 5. Bromoketone 5 was then coupled with 4-iodophenylacetic acid and then cyclized in the presence of triethylamine and DBU to produce 6 (the non radioactive analogue of the target molecule 1) in 52% yield. Compound 6 was converted to boronic ester 7 using Suzuki chemistry. Addition of KHF2 then generated the trifluoroborate 8. Compound 8 was then reacted according to the method of the invention to generate the no-carrier-added radioiodinated 1. The radiochemical purity of the product exceeded 98% as revealed by radio TLC and the radiochemical yield was 42%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 10 3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 25 3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-pyridin-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 28 3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-3-yl-phenyl)-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 29 3-Cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 35 1-[3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionyl]-3-methyl Urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 36 1-[3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionyl]-3-methyl-urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 37 1-{3-Cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stiffed at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 5 8.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 5 3-Cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EL-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 8 3-Cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EL-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
70% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 9 3-Cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (17.1 mL, 122.21 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL) was cooled to -78 C. under nitrogen and then treated with a 10M solution of n-butyllithium in hexanes (12.2 mL, 122.21 mmol). The yellow reaction mixture was stirred at -78 C. for 30 min and then treated dropwise with a solution of 4-iodophenylacetic acid (15.25 g, 58.19 mmol) in dry tetrahydrofuran (55 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (18 mL). The reaction mixture turned dark in color and was allowed to stir at -78 C. for 45 min, at which time, a solution of iodomethylcyclopentane (13.45 g, 64.02 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25 C. where it was stirred for 42 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran and then quenched with a 10% aqueous hydrochloric acid solution (100 mL). The resulting aqueous layer was extracted with ethyl acetate (3*200 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1*200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.97 g, 70%) as a cream solid: mp 121-122 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 1 3-Cyclopentyl-2-(4-ethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofiran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 10 3-Cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL), a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 3 3-Cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 4 3-Cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and was acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 5 3-Cyclopentyl-2-[4-(4-hydroxy-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and was acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 6 3-Cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 7 3-Cyclopentyl-2-[4-(3-dimethylamino-prop-1-ynyl)-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS In/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 8 3-Cyclopentyl-2-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; | EXAMPLE 9 3-Cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofuran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.8% | With n-butyllithium; diisopropylamine; In tetrahydrofuran; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; | EXAMPLE 2 3-Cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-N-thiazol-2-yl-propionamide A solution of diisopropylamine (11.2 mL, 80.13 mmol) in tetrahydrofuran (120 mL) cooled to -78 C. was treated with a 2.5M solution of n-butyllithium in hexanes (32 mL, 80.13 mmol). This solution was stirred at -78 C. for 30 min and then treated with a solution of (4-iodo-phenyl)-acetic acid (9.67 g, 36.9 mmol) in tetrahydrofiran (88 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (29 mL). The reaction mixture was allowed to stir at -78 C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (8.53 g, 40.6 mmol). The reaction mixture was allowed to slowly warm to 25 C. where it was stirred at 25 C. for 18 h. At this time, the reaction mixture was quenched with water (5 mL) and then concentrated in vacuo. The residue was diluted with water (800 mL) and then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2*800 mL). The combined organic extracts were washed with water (1*600 mL) and a saturated aqueous sodium chloride solution (1*600 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (7.34 g, 57.8%) as a white solid: mp 105-107 C.; EI-HRMS m/e calcd for C14H17IO2 (M+) 344.0273, found 344.0275. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Procedure B; A mixture of 4-iodophenylacetic acid (400 mg, 1.53 mmol), 4-azabenzimidazole (273 mg, 2.29 mmol, 1.5 equiv), trans.trans-dibenzylideneacetone (17.9 mg, 0.0763 mmol, 0.05 equiv) 1,10-phenanthroline (303 mg, 1.53 mmol), copper (I) trifluoromethanesulfonate benzene complex (19.2 mg, 0.0763 mmol, 0.05 equiv), and Cs2CO3 (547 mg, 1.68 mmol) in xylene (1.5 mL) is stirred for 80 h at 125C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in a 1N NaOH aqueous solution and extracted with EtOAc. The aqueous layer is made acidic by addition of a 1 N HCI aqueous solution and extracted with CH2CI2. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by reversed phase MPLC (CH3CN/H2O/TFA) to provide the title compound. | ||
A mixture of 400 mg of 4-ιodophenylacetιc acid, 273 rng of 4-azabenzιmιdazole, 17 9 mg of trans, trans-dibenzylideneacetone, 303 mg of 1 ,10-phenanthrolιne, 19 2 mg of copper (I) tϖfluoromethanesulfonate benzene complex and 547 mg of Cs2CO3 in 1 5 ml of xylene is stirred for 80 hours at 125C The mixture obtained is allowed to cool to rt and concentrated in vacuo The concentration residue obtained is dissolved in aqueous 1 N NaOH solution and extracted with EtOAc To the aqueous layer aqueousi N HCI is added in order to obtain an acidic pH and the mixture obtained is extracted with CH2CI2 The organic phase obtained is dried (Na2SO4), filtered and concentrated The concentration residue obtained is subjected to reversed phase MPLC (CH3CN/H2O/TFA) (4-lmιdazo[4,5-b]pyrιdιn-3-yl-phenyl)-acetιc acid is obtained |
Yield | Reaction Conditions | Operation in experiment |
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Procedure C; A mixture of 4-iodophenylacetic acid (4.4 g, 16.8 mmol), benzoimidazole (2.98 g, 25.2 mmol, 1.5 equiv), trans.trans-dibenzylideneacetone (197 mg, 0.840 mmol, 0.05 equiv) 1,10- phenanthroline (3.33 g, 16.8 mmol), copper (I) trifluoromethanesulfonate benzene complex (211 mg, 0.840 mmol, 0.05 equiv), and Cs2CO3 (6 g, 18.5 mmol) in xylene (12 mL) is stirred for 88 h at 125C. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is dissolved in a 1N NaOH aqueous solution and extracted with EtOAc. The aqueous layer is made acidic by addition of a 1N HCI aqueous solution. The resulting precipitate (batch 1 ) is collected by vacuum filtration. The aqueous phase is extracted with CH2CI2 . The organic phase is dried (Na2SO4), filtered and concentrated. The residue (batch 2) is combined with batch 1 and triturated in Et2O to afford 3.58 g of the title compound. | ||
A mixture of 4 4 g of 4-ιodophenylacetιc acid, 2 98 g of benzoimidazole, 197 mg of trans, trans-dibenzylideneacetone, 3 33 g of 1 ,10-phenanthrolιne, 211 mg of copper (I) tϖfluoromethanesulfonate benzene complex and 6 g of Cs2CO3 in 12 ml of xylene is stirred for 88 hours at 1250C The mixture obtained is allowed to cool to rt and concentrated in vacuo The concentration residue obtained is dissolved in 1 N NaOH aqueous solution and the mixture obtained is extracted with EtOAc The pH of the aqueous layer obtained is adjusted to acidic pH by addition of 1 N HCI aqueous solution A precipitate forms and is collected by vacuum filtration (batch 1 ) is collected by vacuum filtration The aqueous phase from the filtrate obtained is extracted with CH2CI2 The organic phase is dried (Na2SO4), filtered and concentrated The concentration residue obtained (batch 2) is combined with batch 1 and triturated in Et2O 3 58 g of (4-benzoιmιdazol-1-yl-phenyl)-acetιc acid are obtained |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide; In water; | EXAMPLE 5 [p-(p-Chlorophenylthio)phenyl]acetic Acid A solution of 6.0 g of 4-chlorothiophenol and 8.0 g of potassium hydroxide in 80 ml of water is heated to 50 C and 0.8 g of copper powder and 10.4 g of 4-iodophenylacetic acid are added. The mixture is heated to reflux and maintained at reflux overnight. The mixture is then cooled and filtered. The filtrate is acidified with concentrated HCl to give a white solid which, on recrystallization from methanol, yields cream colored plates, mp 135-140 C. A sample is recrystallized frm chloroform-hexane to give white plates, mp 144.5-148 C. | |
With potassium hydroxide; In water; | EXAMPLE 5 [p-(p-Chlorophenylthio)phenyl]acetic Acid A solution of 6.0 g of 4-chlorothiophenol and 8.0 g of potassium hydroxide in 80 ml of water is heated to 50 C. and 0.8 g of copper powder and 10.4 g of 4-iodophenylacetic acid are added. The mixture is heated to reflux and maintained at reflux overnight. The mixture is then cooled and filtered. The filtrate is acidified with concentrated HCl to give a white solid which, on recrystallization from methanol, yields cream colored plates, mp 135-140 C. A sample is recrystallized from chloroform-hexane to give white plates, mp 144.5-148 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; | The 4-iodophenylacetamide used as starting material was obtained as follows. Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of 4-iodophenylacetic acid (26.2 g), in dichloromethane (150 ml). The reaction mixture was stirred at ambient temperature for 18 hours and the solvent removed by evaporation to give 4-iodophenylacetyl chloride as an oil (23 g) which was purified by vacuum distillation; b.p. 118-119 C. (0.35 mmMg) |
Yield | Reaction Conditions | Operation in experiment |
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99% | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | 4-Iodophenylacetic acid (2.Og, 7.6 mmol, 1 eq) in CH2Cl2 (30 mL) was treated with diisopropylethylamine (1.32 mL, 7.6 mmol, 1 eq) and the mixture was cooled to 0 0C with stirring under an atmosphere of Ar. 9- Fluorenylmethyl chloroformate (2.16g, 8.36 mmol, 1.1 eq) dissolved in CH2Cl2 (7.6 mL) was added followed by the addition of dimethylaminopyridine (0.14g, 1.14 mmol, 0.1 eq). The reaction was stirred at ambient temperature for 30 min and was then diluted with CH2Cl2 (15 mL) and washed successively with 30 mL portions of IM HCl, saturated NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was used without further purification 3.34g (99%). |
Yield | Reaction Conditions | Operation in experiment |
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To a stirred solution of 4-iodophenylacetic acid (20.96 g, 8 mM) in THF (120 ml) at -70 C. under argon, was slowly added 1.85 M lithium diisopropylamide in THF (91 ml, 168 mM). There was a moderate exotherm and an intense green colour developed as the dianion formed. The solution was warmed to ambient temperature for 15 minutes then cooled back to -70 C. A solution of 4S-iodomethyl-2,2-dimethyl-(1,3)-dioxolane (J. Med. Chem. 35, 4415 (1992)) (24.2 g, 100 mM) in THF (25 ml) was added and the solution was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was quenched into ice/water and adjusted to about pH4 with dilute hydrochloric acid. This was extracted with ethyl acetate and the organic phase was washed with saturated NaCl, dried (over MgSO4) and evaporated to give 4S-(2-carboxy-2-(4-iodophenyl)ethyl)-2,2-dimethyl-(1,3)-dioxolane, which was used without purification. |
Yield | Reaction Conditions | Operation in experiment |
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3-Amino-1- [1- (3-tert-butyl-phenyl)-cyclohexylamino]-4- (3, 5-difluoro-phenyl)- butanol dihydrochloride salt (1 mmol), 4-iodophenylacetic acid (1 mmol), and potassium hydroxide (5 mmol) were added to round bottomed flask equipped with stirbar. DMSO (5 mL) and H20 (5 mL) were added and the mixture dissolved. Copper iodide (10%) was added and the mixture heated for 16 h at 90 C. The reaction was extracted with DCM (2 x 10 mL), then neutralized with 1 M HCI and extracted with 4: 1 CHCI3/IPA. Both organic fractions showed potential product so they were combined, dried with sodium sulfate, and rotovapped to dryness yielding brown oil. This residue was purified by reverse-phase HPLC. Retention time (min) = 2.274, method [1]; 1H NMR (300 MHz, CD30D) ; 5. 7.54 (s, 1H), 7.46-7. 27 (m, 3H), 6.94 (d, 2H, J = 7. 8 Hz), 6.76-6. 59 (m, 3H), 6.36 (d, 2H, J=7. 8Hz), 3. 58-3.43 (m, 2H), 3.41 (s, 2H), 3.03 (d, 1H, J = 13.7 Hz), 2.87 (d, 1H, J = 13.7 Hz), 2. 76-2. 45 (m, 4H), 1.95-1. 54 (m, 4H), 1.39-1. 06 (m, 11H). 13C NMR (75 MHz, CD30D) ; a 174.7, 162.7 (dd, 2C, J = 248.2, 13.5 Hz), 158.2, 152.2, 146.0, 142.6 (t, 1C, J = 9.7 Hz), 133.1, 129.6, 128.9, 126.0, 124.6, 124.3, 123.0, 112.6, 111.8 (dd, 2C, J = 17.1, 7.4 Hz), 100.9 (t, 1C, J = 25.7 Hz), 69.7, 64.0, 57. 3, 45.1, 39.5, 35.9, 34.3, 32.6, 32.5, 30.0, 24.6, 21.7 ; MS (ESI) 565.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 18h; | To a solution of 2-amino-4-methylthiophene-3-carboxamide (Ig, 6.4mmol) and 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> (1.83g, 7.0mmol) in methylene chloride (1OmL) was added Hunig's base (i.e., N,N-diisopropylethylamine) (3. ImL, 18mmol) and HATU (2.66g, 7.0mmol). The heterogeneous mixture was stirred for 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the biphasic mixture was extracted with additional methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to provide a pale brown solid. LCMS method [2]: rt = 2.02 min; M+Na 423.0. Material was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a solution of 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> 53-1 (816 mg, 3.14 mmol), 5- phenylpyridin-2-amine 53-2 (534mg, 3.14 mmol) and HATU (1.19 g, 3.14 mmol) in DMF (1 mL) was added DIEA (1.57 mL, 9.42 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 aqueous solution, water and brine, dried over Na2SO4, and concentrated by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in hexane to give 2-(4-Iodophenyl)-N-(5-phenylpyridin-2-yl)acetamide 53-3 as pale yellow solid. MS m/z 415.2 (M + 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | To a mixture of 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> 177-1 (524 mg, 2.0 mmol), l-(4- (6-aminopyridin-3-yl)piperazin-l-yl)ethanone 111-4 (440 mg, 2.0 mmol) and O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluroniumhexaflurophosphate (HATU) (798 mg, 2.1 mmol) in DMF (10 mL) was added DIEA (1.04 mL, 6.0 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give N-(5-(4-acetylpiperazin-l-yl)pyridin-2-yl)-2-(4- iodophenyl)acetamide 177-2 as tan solid. MS m/z 465.2 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); diisopropylamine; In N,N-dimethyl acetamide; water; at 100℃; for 0.166667h;Microwave irradiation; | Copper (I) iodide (0.1 mmol, 19 mg) and tetrakis(triphenylphosphine)palladium(0) (0.06 mmol, 69 mg) were added to a solution of 4-iodophenylacetic acid (31) (1.16 mmol, 304 mg) and alkyne 1 (1 mmol, 134 mg) in degassed dimethylacetamide (DMAc) (1 mL), iPr2NH (200 μL) and water (40 μL) and the resultant mixture heated under microwave irradiation at 100 C for 10 min. After cooling the reaction mixture was added to CH2Cl2/water (1:1, 200 mL), the layers separated and the aqueous layer extracted with CH2Cl2 (3 × 50 mL). The combined CH2Cl2 layers were dried over MgSO4, filtered and the solvent removed under reduced pressure to give a brown tar, which was purified by silica flash column chromatography (MeOH/CH2Cl2 0:100-20:80) to give the product as its iPr2NH salt. The salt was partitioned between 1 N aqueous HCl/EtOAc (1:1, 10 mL), the layers separated, the EtOAc layer dried over MgSO4, filtered and evaporated under reduced pressure to give the free acid as a brown solid (29 mg, 11%). 1H NMR (500 MHz, CD3OD) δ = 3.52 (s, 2H, CH2), 6.06-6.10 (m, 2H, AA'BB', 2 × CH), 6.93-6.96 (m, 2H, AA'BB', 2 × CH), 7.17-7.19 (m, 2H, AA'BB', 2 × ArH), 7.28-7.31 ppm (m, 2H, AA'BB', 2 × ArH); LRMS (LC-MS ES+): m/z 251 (M-OH+, 100%), 269 (M+H+, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
171 mg | With copper atom; In dimethyl sulfoxide; at 60℃;Sealed tube; | To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol) and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) in a sealed tube was added ethyl bromodifluoroacetate (196 mg, 1.52 mmol). The reaction mixture was stirred overnight at 60 C. The mixture was cooled to RT, quenched with aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to obtain 171 mg of the titled product; 1H NMR (300 MHz, DMSO-i δ 1.22 (t, = 6.0 Hz, 3H), 3.67 (s, 2H), 4.31 (q, = 7.2 Hz, 2H), 7.44 (d, = 8.1 Hz, 2H), 7.53 (d, = 8.1 Hz, 2H), 12.45 (s, 1H). |
171 mg | With copper atom; In dimethyl sulfoxide; at 60℃;Sealed tube; | To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol) and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) was added ethyl bromodifluoroacetate (196 mg, 1.52 mmol). The reaction mixture was stirred overnight at 60 C in a sealed tube. The reaction mixture was cooled to the RT and quenched with aqueous ammonium chloride solution (30 mL). The aqueous mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under the reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 171 mg of the desired product. H NMR (300 MHz, DMSO-d6) δ 1.22 (t, = 6.0 Hz, 3H), 3.67 (s, 2H), 4.31 (q, = 7.2 Hz, 2H), 7.44 (d, = 8.1 Hz, 2H), 7.53 (d, = 8.1 Hz, 2H), 12.45 (s, 1H). |
171 mg | With copper atom; In dimethyl sulfoxide; at 60℃;Sealed tube; | To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol) and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) was added 2-bromo-2,2-difluoroacetate (196 mg, 1.52 mmol). The mixture was stirred overnight at 60 C in a sealed tube. The reaction mixture was cooled to RT and quenched with aqueous ammonium chloride solution (30 mL). The aqueous mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 171 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, J = 6.0 Hz, 3H), 3.67 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 12.45 (s, 1H). |
171 mg | With copper atom; In dimethyl sulfoxide; at 60℃;Sealed tube; | To a stirred suspension of 4-iodophenylacetic acid (203 mg, 0.76 mmol) and copper powder (193 mg, 3.05 mmol) in DMSO (8.0 mL) was added ethyl bromodifluoroacetate (196 mg, 1.52 mmol) at RT. The reaction mixture was stirred overnight at 60 C in a sealed tube. The mixture was cooled to RT and quenched with aqueous ammonium chloride (30 mL). The aqueous mixture was further diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 171 mg of the titled product. 1H NMR (300 MHz, DMSO- d6) δ 1.22 (t, / = 7.2 Hz, 3H), 3.67 (s, 2H), 4.31 (q, = 7.2 Hz, 2H), 7.44 (d, = 8.1 Hz, 2H), 7.53 (d, = 8.1 Hz, 2H), 12.44 (s, 1H). |
645 g | With copper atom; In dimethyl sulfoxide; at 25 - 45℃;Large scale; | 4-Iodophenylacetic acid (1.0 Kg, 3.8182 mol) was taken in dimethyl sulfoxide (6.0 L) in a 10 L four neck flask. Ethyl bromo difluoroacetate (1.55 Kg, 7.6770 mol) and copper powder (0.97 Kg, 15.3637 mol) were added to the reaction mixture at 25-30 C under stirring. The temperature was controlled and maintained to 45 C during the addition. The reaction mass was stirred at 25-30 C for 10-12 h. The mixture was cooled to RT and quenched by addition of water and ethyl acetate and filtered through celite. Ammonium chloride (500 g) was added to the filtrate under stirring over a period of 10-15 min. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. Neutral alumina (500 g) was added to the organic layer and stirred for 30-45 min followed by addition of sodium sulfate. The suspension was filtered through celite and the filtrate was distilled under vacuum at 35-40 C followed by stripping with MTBE (500 mL). The residue was evacuated for 30-45 min at 35-40 C. MTBE (10 L) was added to the residue. The solution was cooled to 10-15 C before A-(+)-phenyl ethyl amine (692.74 g) was slowly added over a period of 15-20 min. The mixture was stirred for 3-4 h and the solid obtained was filtered. The wet cake was transferred to a flask and stirred in water (6.0 L) at 15 C. The pH of the solution was adjusted to 2-3 by using dil. HC1. The aqueous mixture was extracted thrice with ethyl acetate. The combined organic layers were washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off completely under vacuum. The oily residue was stripped with hexane (500 mL) and dried under vacuum for 1-2 h. Yield: 645 gm. ‘H NMR (400 MHz, CDCh) > 1.28-1.35 (m, 3H), 3.723 (s, 2H), 4.307-4.325 (d, J = 7.2 Hz, 2H), 7.393-7.413 (d, J= 8.0 Hz, 2H), 7.596-7.617 (d, J= 8.4 Hz, 2H), APCLMS (m/z) 258.21 (M-H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.5% | With tetra(n-butyl)ammonium hydrogensulfate; palladium diacetate; triethylamine; triphenylphosphine; In acetonitrile; at 20℃; | Iodo-acid 2 (10 g, 38.2 mmol), but-3-ynylbenzene 4 (5.37 mL, 38.2 mmol), triphenylphosphine (2.002 g, 7.63 mmol), palladium(II)acetate (0.857 g, 3.82 mmol), Et3N (13.30 mL, 95 mmol) and tetrabutylammonium hydrogen sulphate (1.296 g, 3.82 mmol) were dissolved in a degassed mixture of acetonitrile (170 mL) and water (17 ml) to give a brown solution. The reaction mixture was stirred at room temperature for 4 h. More but-3-ynylbenzene (0.537 ml, 3.82 mmol) was added and the reaction mixture was stirred overnight and concentrated to dryness. IN solution of NaOH was then added (pH=T 3) and the alkaline solution was shaken with MTBE to form a tri-layer system. The upper layer was discarded and the remaining two layers were combined, treated with 2N HCl solution (pH 2) and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2S04, filtered and concentrated to dryness. The residue was purified using dry column vacuum chromatography, eluent 20% EtAOc in hexanes then 30% EtOAc in hexanes to afford the title compound 14 (2.67 g, 26.5% yield), MS calcd: 264.3; found: 287.3 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | A solution of N4,N4-diisobutyl-2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-3,4- diamine (0.1 g, 0.274 mmol) in DMF (2 mL) was treated with triethylamine (0.076 mL, 0.549 mmol) followed by BOP (0.133 g, 0.302 mmol). This solution was stirred at RT for 3h then purified by flash chromatography (gradient elution with EtOAc- hexanes). Concentration of the appropriate fractions afforded N-(4-(diisobutylamino)-2'-(lH- tetrazol-5-yl)-[l, l'-biphenyl]-3-yl)-2-(4-iodophenyl)acetamide as an off-white powder. LCMS (M + H)+: 609 HPLC Tr: 1.20 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (2,3,4,5,6-pentafluorophenyl)ammonium triflate; In 5,5-dimethyl-1,3-cyclohexadiene; for 2h;Inert atmosphere; Reflux; | General procedure: To a flame-dried flask was added HS-SiPh3 (0.20 mmol), R’COOH (0.20 mmol), PFPAT (0.02 mmol),and dry xylenes (1 mL). The flask was purged with argon, and a reflux condenser was attached. The solution was refluxed under argon with stirring for 2 hours. The reaction was then cooled to room temperature and an aliquot was taken for IR analysis. Solvent was then removed under vacuum, and the oil was dissolved in CDCl3. The crude reaction mixture was then analyzed without additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | EXAMPLE A.5. A solution of 4-iodophenyl acetic acid (6.5 mg, 0.048 mmol), EDC (10.5 mg, 0.055 mmol), NHS and 600 mu DMF was stirred for 30 min at room temperature. After this time, the 4-(4-fluoro-3- (piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol) was added to the solution and the mixture was stirred at room temperature overnight. H20 (500 mu) was added, the mixture extracted with DCM (2 x 500 mu), and the combined extracts dried under vacuum. The crude mixture was purified by silica column chromatography (100% DCM), and the product obtained as a white solid (8.8 mg, 61%). 1H NMR (CDCI3) delta = 9.82 (s, 1H), 8.40-8.38 (m, 1H), 7.83-7.81 (d, 1H), 7.77- 7.75 (d, 1H), 7.70-7.69 (m, 2H), 7.63-7.56 (m, 3H), 7.00-6.89 (m, 3H), 4.20 (s, 2H), 3.63-3.11 (m, 8H), 2.84 (s, 2H). LC-ESI-MS (+) m/z = 632.9 [M+Na+]+. HRMS-ESI [M+H+]+ m/z calculated for [C28H24FIN403]+ 611.0955, found 611.0971. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | General procedure: Acetamides (1a-1x, 1ab, 1ac and 1ba-1bc). To a solution of 2-phenylacetic acid (7.0mmol), <strong>[1535-75-7]2-(trifluoromethoxy)aniline</strong> (7.7mmol) in anhydrous CH2Cl2 (25mL) were added EDCI (1.745g, 9.1mmol) and DMAP (256.6mg, 2.1mmol). The reaction mixture was stirred at room temperature overnight, diluted with HCl (1M) aqueous solution, and extracted with CH2Cl2 (3×25mL). The combined organic phase was washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. Purification by flash chromatography (Silica gel, petroleum ether: ethyl acetate=50: 1 as eluent) gave the corresponding 2-phenyl-N-[2-(trifluoromethoxy)phenyl]acetamide compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1h;Inert atmosphere; | To a solution of (3R)-5-chloro-3-(2,2-dimethylchroman-6-yl)-3-methyl-indolin-2-one (60 mg, 0.18 mmol), 4-iodophenylacetic acid (92 mg, 0.35 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (10 mg, 0.07 mmol), and potassium carbonate (97 mg, 0.70 mmol) in dimethylformamide (3.0 mL) was added copper iodide (20 mg, 0.10 mmol). The mixture was purged with nitrogen and heated to 110 C. After 1 h, the mixture was cooled to room temperature and diluted with EtOAc (20 mL). The organic layer was washed with 1 M HCl (1*20 mL), water (1*20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude material by reverse-phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) gave the titled compound. 1H NMR (400 MHz, Chloroform-d) δ 7.49-7.41 (m, 2H), 7.41-7.34 (m, 2H), 7.20 (dq, J=4.3, 2.1 Hz, 2H), 7.04 (d, J=2.3 Hz, 1H), 6.96 (ddd, J=8.6, 1.9, 1.2 Hz, 1H), 6.85 (d, J=8.9 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H), 3.71 (s, 2H), 2.74 (t, J=6.7 Hz, 2H), 1.84 (s, 3H), 1.78 (t, J=6.7 Hz, 2H), 1.31 (d, J=1.8 Hz, 6H); MS: (ES) m/z calculated for C29H27ClNO4 [M+H]+ 476.2, found 476.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | To a 500 mL three-neck reaction flask A was added 200 mL of ethyl acetate and 28.64 g of N, N'-carbonyldiimidazole at room temperature,25.00 g 4-iodophenylacetic acid was added to the reaction flask A in batches to control the gas generation rate. After the addition, the reaction solution was warmed to45 reaction 3h, cooling to 20 ~ 30 , vacuum vacuum 1h, spare. At room temperature, 1 mL of reaction flask B was added with 280 mL of ethyl acetateEster, 28.06 g of EtO2CCH2COOK and 15.70 g of magnesium chloride (MgCl2) at a temperature of 20 to 30C and 19.07 g of triethylAmine (TEA), and the mixture was stirred for 1 h. The contents of the reaction flask A were fed to the reaction flask B at room temperature, the temperature was raised to 45 C,Insulation reaction 16h. The reaction solution was cooled to 20 to 30 C, and 180 mL of 4N hydrochloric acid solution was slowly added dropwise. The organic phase was washed with 6.5% carbonSodium bicarbonate solution three times, each time the amount of 250mL, collecting organic phase, 45 C under reduced pressure to remove the solvent yellowish brown oil.To the resulting oil was added 150 mL of n-hexane, stirred at 20 to 30 C for 18 h, filtered, and the filter cake was washed with n-hexane, 40 to 50 CAnd dried in vacuo for 5 h to give 27.4 g of ethyl 4 - ([4-iodophenyl] -4-yl) -3-oxobutanoate in a yield of 86.5%. | |
86.5% | To a 500 mL three neck flask A were added 200 mL of ethyl acetate and 28.64 g of N,N'-carbonyldiimidazole at room temperature, and 25.00 g of 4-iodophenyl acetic acid was added in portions to flask A, the generation rate of gas was controlled. After the addition, the reaction liquid was heated to 45 C. and reacted for 3 hours, and then cooled to a temperature of 20 C. to 30 C., the flask was evacuated for pressure reduction for 1 hour, and ready for use. To a 1 L flask B were added 280 mL of ethyl acetate, 28.06 g of EtO2CCH2COOK and 15.70 g of magnesium chloride (MgCl2) at room temperature, the temperature was controlled at a temperature of 20 C. to 30 C., and then 19.07 g of triethylamine (TEA) was added dropwise slowly. After the addition, the mixture was further stirred for 1 hour. To flask B was added the materials in flask A at room temperature, the mixture was heated to 45 C. and reacted for 16 hours. The reaction liquid was cooled to a temperature of 20 C. to 30 C., and 180 mL of 4 N hydrochloric acid solution was added, and the mixture was partitioned, the organic layer was washed three times with 250 mL of 6.5% sodium bicarbonate aqueous solution each time, the organic layers were combined, the solvent was then stripped off in vacuo at 45 C. to give a yellow brown oil. | |
41% | To a solution of 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> (2.62 g, 10 mmol, 1.0 eq) in EtOAc (30 mL) was added CDI (2.92 g, 18 mmol, 1.8 eq) portion-wise at 0 C. The resulting mixture was stirred at room temperature overnight. Then potassium 3-ethoxy-3-oxopropanoate (1.87 g, 11 mmol, 1.1 eq), MgCl2 (1.05 g, 11 mmol, 1.1. eq) and TEA (1.34 g, 13.2 mmol, 1.3 eq) was added. The resulting mixture was stirred at 45 C. overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with 1N HCl, dried over Na2SO4 and concentrated to give a crude, which was purified by silica gel column chromatography (PE:EtOAc=5:1) to give the desired (1.35 g, yield: 41%) as a colorless oil. MS (ESI) m/z 333.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | A solution of 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> (786 mg, 3.0 mmol) and EDC-HCl (671 mg, 3.5 mmol) in 57 CH2Cl2 (20 mL) was stirred for 15 min at room temperature under argon. Then N-hydroxysuccinimide (368 mg, 3.2 mmol) and 129 NEt3 (0.56 mL, 4.0 mmol) were added and the reaction was stirred for 7 h. It was then washed with saturated NaCl solution, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (0-100% 59 EtOAc in 60 hexane), and the NHS ester 217 was isolated as a white solid (760 mg, 70%). 1H NMR (500 MHz, CDCl3) δ=7.69 (d, 2H, J=7.9 Hz), 7.09 (d, 2H, J=7.9 Hz), 3.88 (s, 2H), 2.83 (s, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | (((S)-1-Carboxy-5-(2-(4-iodophenyl)acetamido)pentyl)carbamoyl)-L-glutamic acid (RPS-027) To a solution of 2-(p-iodophenyl)acetic acid (81 mg, 0.308 mmol), HOAt (0.6M in THF, 0.51 mL, 0.308 mmol) and HATU (175 mg, 0.461 mmol) in DMF (1 mL) cooled to 0 C. under Ar was added a solution of EuK.3OtBu (1) (150 mg, 0.308 mmol) in DMF (1 mL). The mixture was stirred for 10 min, then (0.107 mL, 0.615 mmol) DIPEA was added. The reaction was stirred for 20 min at 0 C., and then for a further 3 h while warming to rt. The mixture was diluted with EtOAC (25 mL) and washed with 1N HCl, saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (0%-100% EtOAc in hexanes) and EuK-IPPA.3OtBu (10) was isolated as a yellow oil (167 mg, 74%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, 2H, J=8.4 Hz), 7.09 (br s, 1H), 6.98 (d, 2H, J=8.4 Hz), 6.00 (d, 1H, J=8.4 Hz), 5.70 (d, 1H, J=7.9 Hz), 4.25 (m, 1H), 4.10 (m, 1H), 3.41 (d, 2H, J=5.4 Hz), 3.13-3.07 (m, 2H), 2.23 (m, 2H), 1.97 (m, 1H), 1.76 (m, 1H), 1.61 (m, 1H), 1.41-1.23 (m, 3H), 1.37 (s, 9H), 1.33 (s, 18H), 1.21 (m, 2H). ESI(+)=722.4 [M+H]+. Calculated mass: 721.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃;Inert atmosphere; | To a stirred suspension of 2-(p-iodophenyl)acetic acid (26 mg, 0.10 mmol) and HBTU (50 mg, 0.13 mmol) in CH2C12 (3 mE) was added a solution of EuO.3OtBu (2) (50 mg, 0.11 mmol) and NEt3 (19 pL, 0.13 mmol) in CH2C12 (0.5 mE), and the resulting mixture was stirred overnight at it under Ar. The solvent was removed under reduced pressure and the crude residue was purified by silica chromatography (33% EtOAc in hexane to 100% EtOAc). EuOIPAA.3OtBu (7) was isolated as a clear oil (48 mg; 67%). ‘H NMR (500 MHz, MeOD) ö 7.58 (d, 2H, J=8.4 Hz), 7.02 (d, 2H, J=8.4 Hz), 4.14 (m, 1H), 4.09 (m, 1H), 3.39 (s, 2H), 3.14 (t, 2H, J=6.7 Hz), 2.26 (m, 2H), 1.99 (m, 1H), 1.77 (m, 1H), 1.69 (m, 1H), 1.50 (m, 3H), 1.42 (s, 9H), 1.41 (s, 18H). ESI(+)=718.4 [M+H]. Calculated mass: 717.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | With pyridine; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 14h; | 0.34 g (1 mmol) of tetraaminoadamantane hydrochloride at 0 C,0.35 g (4.4 mmol) of pyridine was mixed with 10 mL of dichloromethane, and 0.82 g (4 mmol) of DCC and 0.54 g (4 mmol) of HOBt were added and stirred.Then, 1.15 g (4.4 mmol) of 4-iodophenylacetic acid was added, and the reaction was kept for 2 hours, and the temperature was raised to room temperature for 12 hours.Concentrated under reduced pressure, 15 mL of ethyl acetate was added, stirred, filtered, and the filtrate was concentrated to a volume, slowly added 30 mL of methanol, stirred, filtered, washed and dried to give the formula (IIIa, n = 1), yield 85.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(I) oxide; 1D-1-O-Methyl-muco-inostol; sodium hydroxide; In water; at 100℃; for 6h; | In the l00mL hydrothermal synthesis reactor,Add sodium hydroxide (3 mmol), water (5 mL), stir and dissolve,Add <strong>[1798-06-7]p-iodophenylacetic acid</strong> (0.5 mmol), cuprous oxide (0.05 mmol),White lignan (0.05 mmol), the reaction was stirred at 100 C for 6 hours.After cooling, the pH was adjusted to 2 with dilute hydrochloric acid and extracted with ethyl acetate.The extract is concentrated and subjected to column chromatography to obtain p-hydroxyphenylacetic acid.63.8 mg, yield 84%. |
84% | With copper(I) oxide; 1-D-O-Methyl-chiro-inositol; sodium hydroxide; In water; at 100℃; for 6h; | A 100 mL hydrothermal synthesis reactor equipped with a magnetic stirring bar was charged with sodium hydroxideand water, and then stirred at ambient temperature. After the dissolution of sodium hydroxide, cuprous oxide, L-Queand aryl iodides were added. The reaction mixture was stirred at appropriate temperature until the hydrolysis of aryliodides completes by TLC analysis. Then the reaction mixture was cooled to ambient temperature, acidified by theaddition of 2 M hydrochloric acid, and extracted with ethyl acetate. The combined organic phase was dried overanhydrous magnesium sulfate and the solvent was removed under reduced pressure. The crude products were purifiedby flash column chromatography on silica gel to afford the desired product. The identity of the products was confirmedby comparison with literature melting point and spectroscopy data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dipotassium peroxodisulfate; silver(l) oxide; In acetone; at 35℃; | Add 4-iodophenylacetic acid (131 mg, 0.5 mmol), diphenylphosphine (101 mg, 0.5 mmol), potassium persulfate (270 mg, 1.0 mmol), and silver oxide (10 mg, 0.08 mmol) to the reaction flask. ) And acetone (5 mL), 35 oC;TLC follows the reaction to completion;The crude product obtained after the reaction was separated by column chromatography (dichloromethane: methanol = 95: 5) to obtain the target product (yield 77%). |
Tags: 1798-06-7 synthesis path| 1798-06-7 SDS| 1798-06-7 COA| 1798-06-7 purity| 1798-06-7 application| 1798-06-7 NMR| 1798-06-7 COA| 1798-06-7 structure
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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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