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Structure of 4693-91-8 * Storage: {[proInfo.prStorage]}
* 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.
With thionyl chloride In benzene for 1 h; Heating / reflux
16.62g (0.1 mol) of 4-methoxyphenylacetic acid was dissolved in 10ml of benzene before 29ml (0. 2 mol) of thionylchloride was added thereto. Then, the solution was heated and refluxed, and was stirred for one hour. Thionylchloride remaining in the reaction solution and the solvent was condensed to be removed to obtain 4-methoxy-phenyl-acetyl chloride (compound I), a liquid phase product, at a quantitative yield. The product was used without purification.
100%
for 2 h; Reflux
General procedure: A mixture of various carboxylic acids (1.0mmol), an excess of thionyl chrolide (5mL) was refluxed for 2h and concentrated in vacuo to give corresponding acyl chloride (quant).
88%
With thionyl chloride In <i>N</i>-methyl-acetamide; water
(i) 4-Methoxyphenylacetyl chloride Thionyl chloride (200 ml) was added to 4-methoxyphenylacetic acid (78 g, 0.47 mole) followed by one drop of dimethylformamide. The reaction was heated at 65° C. for 4 hours and the solvent was removed under vacuum. The residue was distilled in vacuo (water aspirator) at 135° C. to give the product as a red oil (75.9 g, 88percent).
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With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 23℃;
100%
With thionyl chloride In benzene for 1h; Heating / reflux;
1
16.62g (0.1 mol) of 4-methoxyphenylacetic acid was dissolved in 10ml of benzene before 29ml (0. 2 mol) of thionylchloride was added thereto. Then, the solution was heated and refluxed, and was stirred for one hour. Thionylchloride remaining in the reaction solution and the solvent was condensed to be removed to obtain 4-methoxy-phenyl-acetyl chloride (compound I), a liquid phase product, at a quantitative yield. The product was used without purification.
100%
With thionyl chloride for 2h; Reflux;
General synthetic procedure for the title compound 3a-w
General procedure: A mixture of various carboxylic acids (1.0mmol), an excess of thionyl chrolide (5mL) was refluxed for 2h and concentrated in vacuo to give corresponding acyl chloride (quant).
98%
With oxalyl dichloride In benzene for 3h; Ambient temperature;
97%
With thionyl chloride at 25℃; for 18h;
95%
With thionyl chloride
90%
With thionyl chloride 1) 3 h room temperature, 2) 25 h, 35-40 deg C;
88%
With thionyl chloride In <i>N</i>-methyl-acetamide; water monomer
1.i (i)
(i) 4-Methoxyphenylacetyl chloride Thionyl chloride (200 ml) was added to 4-methoxyphenylacetic acid (78 g, 0.47 mole) followed by one drop of dimethylformamide. The reaction was heated at 65° C. for 4 hours and the solvent was removed under vacuum. The residue was distilled in vacuo (water aspirator) at 135° C. to give the product as a red oil (75.9 g, 88%).
84%
With thionyl chloride for 4h; Heating;
84.3%
With thionyl chloride; N,N-dimethyl-formamide Reflux;
1.1-3.1 Process steps:
In a 250 ml reactor equipped with a mechanical stirrer, a reflux condenser, exhaust gas receiving device, and a thermometer, 32 g of p-methoxyphenylacetic acid, 90 g thionyl chloride and 1 g N,N-dimethylformamide were added, and the mixture was heated to reflux. The bubbler was connected to the outlet of the reflux condenser, and the bubbler stops reacting after 0.5h without bubbles.The reaction time was 8-10 hours. After the reaction, water pump was used to recover excess thionyl chloride under reduced pressure. After the kettle was cooled, the liquid was distilled under reduced pressure to obtain 31.2 g of pure product. The gas phase purity was 96%, and a yield was 84.3%.
83%
With phosphorus(V) chloride In diethyl ether for 30h; Ambient temperature;
80%
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃;
70%
With oxalyl dichloride for 5h; Reflux;
N-formyl-2-(4-methoxyphenyl) acetamide (4):
To a Stirred solution of 2-(4-methoxyphenyl) acetic acid (1.5 g,9.036 mmol) in oxalyl chloride (10 vol) at reflux temperature for5 h. The reaction mixture was concentrated under vacuum in inertatmosphere to obtain crude compound of (4-methoxyphenyl)acetyl chloride (5) was used for the next step without purification.The crude compound was diluted in acetone (3 ml, 2 volumes)under argon atmosphere and added the mixture of pyridine(610.0 mg, 13.55 mmol) and formamide (1.07 g, 13.55 mmol) inacetone (3 ml) drop wise at 0 C. The reaction mixture was allowingto room temperature and stirred for 18 h. The reaction mixturewas concentrated under vacuum at room temperature. The mixturewas diluted in ethyl acetate and washed with 1 N aqueousHCl, sat NaHCO3, water, brine, dried over anhydrous Na2SO4 andconcentrated under vacuum, crude compound was obtained. Thecrude compound was titrated with diethyl ether the solid productwas filtered and dried under vacuum to obtain N-formyl-2-(4-methoxyphenyl) acetamide (4) (1.22 g, 70%) as Light-yellow solid.Purification crude product via titrated with diethyl ether thesolid product was filtered and dried under vacuum to obtain lightyellow solid, 70% yield. MP = 118-121 C; FT-IR (KBr): mmax = 3005,2954, 2836, 1726, 1512, 1387, 1271, 1254, 1177, 1030, 751.; 1HNMR (400 MHz, DMSO): d 11.26 (d, J = 9.4 Hz, 1H), 8.96 (d,J = 9.5 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H),3.71 (s, 3H), 3.57 (s, 2H).; 13C NMR (101 MHz, DMSO d6): d173.15, 163.84, 158.70, 130.91, 126.30, 114.26, 55.48, 41.73.;LCMS: m/z 194.2 [M + H]: 211.2 [M + H2O].
With thionyl chloride
With chloroform; phosphorus(V) chloride
With phosphorus(V) chloride
With thionyl chloride In dichloromethane for 1h; Heating;
With thionyl chloride for 1h; Heating;
With thionyl chloride In benzene at 80℃; for 1h;
With oxalyl dichloride In benzene for 1h; Ambient temperature;
With oxalyl dichloride In benzene for 3h; Ambient temperature;
With thionyl chloride In Carbon tetrachloride at 65℃;
With thionyl chloride In benzene Heating;
With pyridine; oxalyl dichloride In dichloromethane for 2.5h;
With thionyl chloride In dichloromethane Heating;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.416667h;
With thionyl chloride In benzene for 3h; Heating;
With thionyl chloride at 60℃; for 1h;
With oxalyl dichloride In benzene at 50 - 60℃;
With thionyl chloride
With thionyl chloride In benzene at 80℃; for 1h;
With thionyl chloride for 0.25h; Ambient temperature;
With oxalyl dichloride In benzene for 5h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 18h;
With phosphorus(V) chloride In chloroform Heating;
With thionyl chloride In dichloromethane
With thionyl chloride at 80℃; for 1h;
With phosphorus trichloride
With oxalyl dichloride In dichloromethane at 20℃; for 0.333333h;
With thionyl chloride for 2h; Heating;
With oxalyl dichloride; N,N-dimethyl-formamide In benzene at 25℃; for 1.5h;
With thionyl chloride at 20℃; for 24h;
With thionyl chloride
1.a EXAMPLE 1.
a) Preparation of 4-methoxyphenylacetic acid chloride. A mixture of 20 g of 4-methoxyphenylacetic acid and 20 g of thionyl chloride is refluxed for 30 min. then evaporated at 80°C. 21.5 g of an orange fluid oil are obtained.
With thionyl chloride at 0℃; for 2h; Heating / reflux;
5
Description 5: Synthesis of λ/-[1-(hydroxymethyl)cyclohexyl]-2-[4- (methyloxy)phenyl]acetamide; SOCI2 (30 ml, freshly distilled) was added dropwise to a solution of compound [4- (methyloxy)phenyl]acetic acid (3.3 g, 19.9 mmol) in dry CH2CI2 (30 ml) at O0C under stirring. The reaction was heated to reflux for 2 hours and then concentrated under reduced pressure to give the crude product of [4-(methyloxy)phenyl]acetyl chloride as a yellow oil .(I-Aminocyclohexyl)methanol (2.2 g, 17.05 mmol, description 1 ) and Et3N (3.0 ml) were dissolved in dry CH2CI2 (20 ml) and stirred under nitrogen. After cooling to O0C, a solution of [4-(methyloxy)phenyl]acetyl chloride in dry CH2CI2 (20 ml) was added dropwise. The reaction was allowed to warm to ambient temperature and stirred for 2 hours, quenched by addition of H2O and extracted with ethyl acetate twice, dried (MgSO4), filtered and evaporated to give the crude product λ/-[1-(hydroxymethyl)cyclohexyl]-2-[4- (methyloxy)phenyl]acetamide (3.0 g, 54.5% yield for two steps) as a brown oil.
With thionyl chloride In benzene for 3h; Heating / reflux;
7 Preparation Example 7 Preparation of 3'-fluoro-4'-methoxy-2-(4-methoxyphenyl)acetophenone
Preparation Example 7 Preparation of 3'-fluoro-4'-methoxy-2-(4-methoxyphenyl)acetophenone thionyl chloride (3.57 g) was added to a solution of 4-methoxyphenylacetic acid (3.32 g, 19.98 mmol) in benzene (30 ml).. After the mixture was heated under reflux for 3 hours, the solvent was distilled off.
With thionyl chloride for 1h; Reflux;
With oxalyl dichloride In benzene at 25℃; for 1.5h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 22℃;
With thionyl chloride for 1h; Reflux; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere;
With thionyl chloride In N,N-dimethyl-formamide at 20℃; Reflux;
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
With thionyl chloride In tetrahydrofuran for 1.5h; Reflux;
Diethyl 2-(2-(2-methoxyphenyl)acetamido)-4,5-dihydrothieno[2,3-c]pyridine-3,6(7H)-dicarboxylate 10i
General procedure: 2-Methoxyphenyl acetic acid (465 mg, 2.8 mmol) and thionyl chloride (204 µL, 2.8 mmol) were refluxed in anhydrous THF (1 mL) for 1.5 hours, and the resulting reaction solution was added to a solution containing 9d (200 mg, 0.67 mmol) and DIPEA (210 µL, 1.2 mmol) in THF (0.5 mL). After stirring for 1 day, the reaction mixture was taken up in EtOAc, washed with 1M aqueous HCl, washed with 5% aqueous Na2CO3, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel (hexane/EtOAc 4:1) to yield an oil (161 mg, 54%). An 81 mg sample was further purified by HPLC (4.8 mg). 1H NMR (300 MHz, CDCl3) δ 11.2 (br s, 1H, NH), 7.31 (m, 2H, Ar-H), 6.95 (m, 2H, Ar-H), 4.53 (s, 2H, 7-CH2), 4.27 (q, J = 7.1 Hz, 2H, CH2CH3), 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 3.89 (s, 3H, OCH3), 3.82 (s, 2H, CH2Ar), 3.68 (m, 2H, 5-CH2), 2.86 (m, 2H, 4-CH2), 1.30 (t, J = 7.2 Hz, 3H, CH2CH3), 1.30 (t, J = 6.9 Hz, 3H, CH2CH3). ESI-MS m/z 447.3 [M + H]+.
With thionyl chloride for 2h; Reflux;
With thionyl chloride In toluene at 60℃;
With oxalyl dichloride Reflux;
With thionyl chloride for 2h; Reflux;
With thionyl chloride In benzene at 80℃; for 3h; Heating;
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0 - 80℃; for 0.25h; Inert atmosphere;
With oxalyl dichloride In benzene at 20℃; for 24h;
With thionyl chloride In dichloromethane at 80℃; for 2h; Inert atmosphere;
With thionyl chloride; N,N-dimethyl-formamide In toluene at 40℃; for 0.5h; Inert atmosphere;
With thionyl chloride In dichloromethane for 4h; Reflux;
With thionyl chloride In dichloromethane for 0.25h;
With thionyl chloride at 90℃; for 1h;
With thionyl chloride at 80℃; for 3h;
With thionyl chloride at 80℃; for 6h;
With thionyl chloride In dichloromethane at 0 - 20℃;
With Aluminum Chloride for 3h; Reflux;
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46].
With thionyl chloride In 1,4-dioxane for 2h; Reflux;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃;
With thionyl chloride In benzene Reflux;
With thionyl chloride at 80℃; for 6h; Inert atmosphere;
1 Acid chloride formation:
General procedure: Acid chloride formation: (0087) The corresponding acid (1 eq) and SOCl2 (1.5 eq) is introduced in a flask having a coolant and under an inert atmosphere. The reaction mixture is heated at 80°C for 6 hours. After this time has elapsed, the excess SOCl2 evaporated under reduced pressure and the acid chloride obtained is used directly in the amide formation reaction.
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 21℃; Inert atmosphere;
With thionyl chloride for 3h; Inert atmosphere; Reflux;
2-(4-Methoxyphenyl)ethanethioamide (1d).
In a round bottomed flask equipped with a magnetic stirringbar and argon gas inlet, 2-(4-methoxyphenyl)acetic acid (1a, 5.0 mmol) was dissolved in thionylchloride (10.0 mL). The mixture was allowed to heat to reflux for 3 h, which was concentrated toremove the additional thionyl chloride under reduced pressure to give the 2-(4-methoxyphenyl)acetylchloride (1b). Then ammonia solution (5.0 mmol ammonia gas in 5.0 mL water) was added into theacyl chloride in ethyl acetate (5.0 mL), and the 2-(4-methoxyphenyl)acetamide (1c) was crystallizeform the mixture in 95% yield as white solids; Its spectral data were identical with those reportedwith the melting point of 169-170 °C (lit. [31] 163-165 °C). The 2-(4-methoxyphenyl)ethanethioamide(1d, 0.45 g) was synthesized and isolated by using Lawesson's reagent (5.0 mmol) in toluene (20.0 mL)under 50 °C for 2 h, and the residue was purified by flash column chromatography on silica gel(EtOAc/hexane, 1:1) to afford yellow solids with the yield of 85%. 1H-NMR (400 MHz, DMSO-d6, δ ppm): 7.66 (s, 1H), 7.26-7.17 (m, 2H), 6.92-6.71 (m, 2H), 6.70 (s, 1H), 4.05 (s, 2H), 3.81 (s, 3H).
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.16667h;
With 4-methyl-morpholine; 1,3,5-trichloro-2,4,6-triazine at 20℃; for 0.166667h;
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
General procedure: Aralkanoic acid chlorides 2 were synthesized by the reaction ofaralkanoic acids 1 (1 mmol) in the presence of 1,2edichloroethane(12 mL) solvent and phosphorous oxychloride (0.4 mL) as chlorinatingagent under reflux for 3 h. Then, the resulting solution wascooled to room temperature, and the solvent was removed underreduced pressure to afford aralkanoic acid chlorides 2, which wasdirectly used in the next step without further purification. Aralkanoicacid chlorides 2 was dissolved in acetonitrile (80 mL), addeddrop wise to a solution containing hydrazine hydrate (1 mmol), TEA(0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 h withmonitoring by TLC. After consumption of the starting material, thereaction mixture was cooled to room temperature. Evaporation ofthe solvent under reduced pressure yielded crude substituted aromaticacid hydrazides 3 as a white solid on cooling, which waspurified by column chromatography and crystallized on methanol.
With thionyl chloride; N,N-dimethyl-formamide Inert atmosphere;
With thionyl chloride at 20℃; for 4h;
With thionyl chloride at 60℃; for 5h;
2.2 4-methoxybenzeneacetyl chloride preparation
19 . 9mmol4 - methoxy acetic acid and 15 ml thionyl chloride, stirring, 60 °C reaction 5.0h, steaming and excessive thionyl chloride, to obtain the orange-yellow liquid 4 - methoxybenzene acetyl chloride, put into the refrigerator to keep spare
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
1 Synthesis of 2- (4-methoxyphenyl) acetyl chloride (Compound 1b)
12 mL of 1,2-dichloroethane solvent and 0.4 mL of chlorine-treating agent (phosphorous oxychloride) are present , 1 mmol of 2- (4-methoxyphenyl) acetic acid (Compound 1a) The reaction was carried out with refluxing for 3 hours 2- (4-methoxyphenyl) acetyl chloride (compound 1b) was synthesized. The resulting solution was cooled to room temperature, and then the solvent was removed under reduced pressure Compound 1b.The resulting solution was cooled to room temperature, and the solvent was removed under reduced pressure to obtain compound 1b, which was used directly in the next step without further purification
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h;
3.2.1. Synthesis of N-Prop-2-ynylamide (8a-8o)
General procedure: The compounds 8a-8o were all synthesized by the following general procedure. To a solutioncontaining 7a (5 g, 40.94 mmol) and DMF (0.05 mL, 0.65 mmol) dissolved in dichloromethane (100 mL)was added a solution of oxalyl chloride (3.8 mL, 45.03 mmol) dissolved in dichloromethane (10 mL)dropwise at 0 °C. After stirring the reaction mixture at r.t. for 3 h, the solution was concentrated underreduced pressure to give the corresponding acyl chloride. To a solution composed of propargylamine(3.1 mL, 45.03 mmol) and triethylamine (8.5 mL, 61.41 mmol) dissolved in dichloromethane (100 mL)was added dropwise at 0 ° C a solution of the corresponding acyl chloride previously dissolved indichloromethane (30 mL). After stirring at r.t. for 3 h, the mixture was washed with a solution ofdiluted hydrochloric acid (1 M, 100 mL) followed by an extraction with dichloromethane (3 100 mL).The combined organic layers were then dried over anhydrous sodium sulfate and then concentratedunder reduced pressure to afford the crude product 8a. The residue was then crystallized with amixture of ethyl acetate/petroleum ether to afford the pure product 8a. The spectral data for thecompounds 8a-8o are given in the Supporting-Information.
In dichloromethane at 20 - 80℃; for 1h;
With thionyl chloride In dichloromethane at 55℃; Inert atmosphere;
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; for 2h; Inert atmosphere;
With thionyl chloride In dichloromethane at 0 - 20℃; Inert atmosphere;
With thionyl chloride for 3h; Reflux;
With thionyl chloride for 2h; Inert atmosphere;
With thionyl chloride at 25℃; Inert atmosphere;
With thionyl chloride
With thionyl chloride at 65 - 70℃; for 12h;
2.3. General synthetic procedures for intermediates 4
General procedure: The substituted phenylacetic acid (3 mmol) and thionyl chloride (10 ml) were placed in a dry round-bottomed flask, and the mixture was heated to reflux at 65-70 °C for 12 h, which was detected by TLC. After the completion of reaction, the solvent was removed in vacuo and the residue was washed with CH2Cl2. The above procedure was repeated twice to obtain the crude intermediates 4, which were used for the next reaction without further purification.
With thionyl chloride; N,N-dimethyl-formamide for 3h; Reflux;
With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;
With aluminum (III) chloride; at 25℃; for 0.75h;Cooling;
General procedure: The acyl chloride 9 (1 mmol) was cooled and addeddropwise into the cooled mixture of AlCl3 (1.5 mmol) andsubstituted aromatic compounds 10 (1 mmol). The reactionmixture was stirred for 45 min at room temperature. Themixture was then quenched with cold 1M HCl aqueous solution(3 mL), and extracted with chloroform (3 x 1 mL). Thecombined organic extracts were washed with sodium bicarbonatesolution (3 mL), water (3 mL) and dried over anhydroussodium sulfate. After solvent removal, the ethanonederivatives 11 were obtained by recrystallization frommethanol.
With aluminum (III) chloride In dichloromethane at 0 - 20℃;
5.22 g
With aluminium trichloride In dichloromethane Ambient temperature;
With aluminium trichloride
With aluminium trichloride In dichloromethane at 0 - 20℃;
With aluminum (III) chloride In dichloromethane at 20℃; for 2.5h;
2
200ml of dichloromethane was added to 40g (0. 3mol) of aluminum (lll) chloride and was stirred, into which a material obtained by diluting 29. 5ml (0.33 mol) of benzene and the 18.5g (0. 1mol) of 4-methoxy-phenyl-acetyl chloride obtained from Example 1 in 100moi of dichloromethane (CH2CI2) was slowly added for about 30 minutes and then stirred at a room temperature for two hours. The resulting reaction solution was added to a 400moi of 1M hydrochloric acid aqueous solution, from which an organic layer was extracted, dried, condensed, and purified by column chromatography to obtain a light yellow solid form of 1- phenyl-2- (4-methoxyphenyl) ethanone (compound II).
With pyridine In dichloromethane 1.) 0 deg C, 1 h, 2.) r.t., 2 h; Yield given;
With pyridine In dichloromethane at 0 - 20℃; for 2h;
With triethylamine In dichloromethane at 20℃; for 3.5h; Cooling with ice;
4.1.6 General synthetic procedure for compounds 29a-h
General procedure: Appropriate phenylacetyl chloride (1equiv) was added dropwise into a solution of Meldrum's acid (1equiv) and TEA (2.4equiv) in DCM (1M) under ice bath. The reaction mixture was then allowed to warm to room temperature and stirred for 3.5h. The reaction mixture was extracted with a mixture of CH2Cl2 and 1N HCl solution. The organic layer was washed with brine, dried over MgSO4, and concentrated. To the residue was added absolute ethanol (1M), and the reaction mixture was heated at reflux for 2h. The solvent was removed in vacuo, and to the resulting ethyl-4-aryl-3-oxobutanoate ( 27) in xylene (1M) was added DMF-DMA (2.5equiv). The resulting mixture was heated at reflux for 4h and then concentrated in vacuo. To the solution of residue in MeOH (1M) was added ammonium acetate (5equiv), and the resultant mixture was heated at reflux for 4h. The crude ethyl ester of appropriate 29 was saponified by 10% (w/v) NaOH (10mL) in MeOH (20mL) at reflux for 2.5h. The mixture was then adjusted to pH 1 by titrating with 3N HCl. The precipitate was collected by filtration, washed with MeOH, water, and diethyl ether, and dried to give appropriate analogs of 29.
Stage #1: cycl-isopropylidene malonate With pyridine In dichloromethane at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-methoxyphenyl-acetic chloride In dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere;
With aluminium trichloride In dichloromethane at 25℃; for 1h;
74.8%
With hydrogenchloride In dichloromethane
15.A A.
A. 1-(2,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)-ethanone (14) P-Methoxyphenylacetyl chloride (33.2 g, 0.18 mol) in CH2 Cl2 (100 ml) was added dropwise to a solution of AlCl3 (28.8 g, 0.21 mol) and m-dimethoxybenzene (24.9 g, 0.18 mol) in CH2 Cl2 (400 ml). The reaction wad complete (by TLC) after 1 hour and was poured over 10% HCl:ice slurry. The organic layer was washed with H2 O and brine, dried over MgSO4, and the solvent was removed under reduced pressure. The crude solid was recrystallized from ether/methanol to afford 14 (38.5 g, 74.8%), m.p. 78.5°-79.5° C.
52%
With aluminium trichloride In dichloromethane at 20℃; for 1h;
With aluminium trichloride In carbon disulfide Ambient temperature;
With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux;
General procedure: Aralkanoic acid chlorides 2a-g were synthesized by the reaction of aralkanoic acid 1a-g (1 mmol) in the presence of 1,2-dichloroethane (12 mL) solvent and phosphorous oxychloride(0.4 mL) chlorinating agent under reflux for 3hours. Then, the resulting solution was cooled to room temperature, and the solvent was removed under reduced pressureto afford aralkanoic acid chloride 2a-g, which was directly used in the next step without further purification. Acid chloride 2a-g was dissolved in acetonitrile (80 mL), addeddropwise to a solution containing hydrazine hydrate(1 mmol), TEA (0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 hours with monitoring by TLC. After consumption of the starting material, the reaction mixture was cooled to room temperature. Evaporation of the solvent under reduced pressure yielded crude acid hydrazide 3a-g as a white solid on cooling, which was purified by column chromatography and crystallized in methanol [46].
86%
With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux;
Compound 1b was dissolved in 80 mL of acetonitrile and added dropwise to a solution containing 1 mmol of hydrazine hydrate, 0.5 mL of TEA and 20 mL of acetonitrile. The compound 1b was monitored by TLC (thin layer chromatography) And refluxed for 3 hours. The Rf value of the TLC was calculated using an aluminum plate coated with silica gel (Kieselgel 60 F254, Merck (Germany)), and the developed TLC was confirmed using a UV lamp (VL-4 LC, France) . After the reactants were exhausted, the reaction mixture was cooled to room temperature. Subsequently, the solvent was evaporated under reduced pressure to give As a white solid To obtain 2- (4-methoxyphenyl) acetohydrazide (Compound 1c) which was purified by column chromatography and crystallized from methanol to obtain a white solid product (Compound 1c) (86%).
With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux;
General procedure: Aralkanoic acid chlorides 2 were synthesized by the reaction ofaralkanoic acids 1 (1 mmol) in the presence of 1,2edichloroethane(12 mL) solvent and phosphorous oxychloride (0.4 mL) as chlorinatingagent under reflux for 3 h. Then, the resulting solution wascooled to room temperature, and the solvent was removed underreduced pressure to afford aralkanoic acid chlorides 2, which wasdirectly used in the next step without further purification. Aralkanoicacid chlorides 2 was dissolved in acetonitrile (80 mL), addeddrop wise to a solution containing hydrazine hydrate (1 mmol), TEA(0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 h withmonitoring by TLC. After consumption of the starting material, thereaction mixture was cooled to room temperature. Evaporation ofthe solvent under reduced pressure yielded crude substituted aromaticacid hydrazides 3 as a white solid on cooling, which waspurified by column chromatography and crystallized on methanol.
With hydrazine hydrate; triethylamine; In acetonitrile; for 3h;Reflux;
The obtained aralkanoic acid chloride (2) was dissolved in 80 ml of acetonitrile, and then 1 mmol of hydrazine hydrate,It added dropwise to a solution containing TEA and acetonitrile 0.5 20 and, while monitoring by thin layer chromatography (TLC) was refluxed for 3 hours.After all the starting material had been consumed, the reaction mixture was cooled to room temperature and then the solvent was evaporated under reduced pressure to give crude substituted aromatic acid hydrazide 3 as a white solid.It was purified by column chromatography and crystallized from methanol
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran for 1h; Heating;
Stage #2: 2-(4-methoxyphenyl)acetyl chloride In tetrahydrofuran
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil for 1h; Reflux; Inert atmosphere;
Stage #2: 2-(4-methoxyphenyl)acetyl chloride In tetrahydrofuran; mineral oil Inert atmosphere;
With pyridine; magnesium(II) chloride In dichloromethane at 0℃; for 1.25h;
Dimethyl 2-(2-(4-methoxyphenyl)acetyl)malonate (20).
Dimethylmalonate (1.74 g, 0.0132 mol, 1.0 equiv.) was added to a suspensionof magnesium chloride (1.26 g, 0.0132 mol, 1.0 eq) in dry DCM(40 mL). The suspension was cooled to 0 C and pyridine (2.13 mL,0.0264 mol, 2.0 eq) was added. After stirring for 15 min, freshlyobtained (from the corresponding acid) 2-(4-methoxyphenyl)acetyl chloride (2.44 g, 0.0132 mol, 1.0 eq) was slowly added, andthe reaction mixture was stirred for 1 h at 0 C, and then allowed tostir at room temperature overnight. The reaction mixture wasquenched in cooled 2 M HCl solution (100 mL) and the layers wereseparated. The aqueous layer was extracted with DCM (2x 700 mL).The combined organic layers were washed with brine, dried overNa2SO4and concentrated under reduced pressure.The crude product was purified using flash chromatography(eluent: petroleum ether/EtOAc 8/2 v/v) to give 20 as a pale yellow]oil (yield 60%). MS (ESI) 303 [MNa], 319 [M K].
With pyridine; magnesium(II) chloride In dichloromethane at 0℃; for 1.25h;
Dimethyl 2-(2-(4-methoxyphenyl)acetyl)malonate (20).
Dimethylmalonate (1.74 g, 0.0132 mol, 1.0 equiv.) was added to a suspensionof magnesium chloride (1.26 g, 0.0132 mol, 1.0 eq) in dry DCM(40 mL). The suspension was cooled to 0 C and pyridine (2.13 mL,0.0264 mol, 2.0 eq) was added. After stirring for 15 min, freshlyobtained (from the corresponding acid) 2-(4-methoxyphenyl)acetyl chloride (2.44 g, 0.0132 mol, 1.0 eq) was slowly added, andthe reaction mixture was stirred for 1 h at 0 C, and then allowed tostir at room temperature overnight. The reaction mixture wasquenched in cooled 2 M HCl solution (100 mL) and the layers wereseparated. The aqueous layer was extracted with DCM (2x 700 mL).The combined organic layers were washed with brine, dried overNa2SO4and concentrated under reduced pressure.The crude product was purified using flash chromatography(eluent: petroleum ether/EtOAc 8/2 v/v) to give 20 as a pale yellow]oil (yield 60%). MS (ESI) 303 [MNa], 319 [M K].
Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium In tetrahydrofuran at -78℃;
Stage #2: 4-methoxyphenyl-acetic chloride In tetrahydrofuran at -78 - 20℃;
Stage #3: With ammonium chloride In tetrahydrofuran; water
11.A
Example 11(2S)-N-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)-2-(4-methoxyphenyl)-propanamideStep A: Preparation of (S)-4-Benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one. n-Butyllithium (15.4 ml, 24.7 mmol, 1.6 M) was added to a solution of (S)-4-benzyl oxazolidinone (4.00 g, 22.5 mmol) in dry THF (100 ml) at -78° C. and stirred for 30 min. Then p-methoxyphenyl acetyl chloride (6.50 ml, 29.3 mmol) in THF (50 ml) was added to the reaction mixture at -78° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. It was then quenched with saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×50 ml). The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (7%) in petroleum ether as eluent to afford 6.0 g (82.5%) of (S)-4-benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one as an off-white color solid.
76%
Stage #1: (S)-4-Benzyl-2-oxazolidinone With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: 4-methoxyphenyl-acetic chloride In tetrahydrofuran at -78 - 20℃; Further stages.;
237 g
With n-butyllithium In tetrahydrofuran; hexane at -65 - 20℃;
With n-butyllithium; triphenylmethane In tetrahydrofuran at -78℃;
With n-butyllithium In tetrahydrofuran at -65 - -45℃; for 2h; Inert atmosphere;
With triethylamine In N,N-dimethyl-formamide at 5 - 7℃; for 1.5h;
11
A solution of (R)-2-amino-2-(4-methoxyphenyl)acetamide (200 g, 1.11 mol), triethylamine (124 g, 1.22 mol) in dimethylformamide (2 L) is cooled to 5° C. in an ice bath and (4-methoxyphenyl)acetyl chloride (225 g, 187 mL, 1.22 mol) is added dropwise at a rate which maintains the temperature in a range from 5° C. to 7° C. After 1.5 hours the additional stirring in the cold, the reaction solution is transferred to a vessel containing water (12 L). The solid which forms upon standing is collected and rinsed several times with water. The material collected is dried to a constant weight affording 323.9 g (89% yield) of the desired product. Analysis by chiral HPLC indicates 98.6% enantiomeric purity. Preparation of 1-(R)-(4-methoxyphenyl)-N1-[2-(4-methoxyphenyl)ethyl]ethane-1,2-diamine:
With 4-methyl-morpholine In dichloromethane at 0 - 23℃; for 18h;
94%
With 4-methyl-morpholine In dichloromethane at 0 - 20℃; for 18.0667h;
48.F 8-(4-Methoxy-phenyl)-6-methyl-3-(4-piperidin-1-yl-but-1-ynyl)-5,6,7,8-tetrahydro-[1,6]naphthyridine trifluoroacetic acid salt
Step F. N-(5-Bromo-2-chloro-pyridin-3-ylmethyl)-2-(4-methoxy-phenyl)-N-methyl-acetamide. A 0° C. solution of (5-bromo-2-chloro-pyridin-3-ylmethyl)-methyl-amine (3.07 g, 13.0 mmol) and N-methylmorpholine (4.40 mL, 39.1 mmol) in DCM (130 mL) was treated with (4-methoxy-phenyl)-acetyl chloride (2.40 mL, 15.6 mmol) dropwise over 4 min. The resulting bright yellow solution was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with DCM, washed with H2O (2*), brine, dried (MgSO4), and concentrated to a yellow oil. Chromatographic purification (SiO2; EtOAc/hexanes) gave the title compound (4.71 g, 94%) as a pale-yellow oil. MS (ESI): mass calcd. for C16H16BrClN2O2, 382.01; m/z found, 383.3 [M+H]+. 1H NMR (acetone-d6, mixture of rotamers): 8.36 (d, J=2.3, 0.75H), 8.32 (d, J=2.1, 0.25H), 7.59-7.58 (m, 0.75H), 7.25-7.23 (m, 1.75H), 7.11 (d, J=8.5, 0.5H), 6.92-6.89 (m, 1.5H), 6.73 (d, J=8.6, 0.5H), 4.70 (s, 0.5H), 4.61 (s, 1.5H), 3.80-3.72 (m, 5H), 3.16 (s, 2.25H), 2.93 (s, 0.75H).
With aluminum (III) chloride; In dichloromethane; at 20℃; for 2.5h;Cooling with ice;
Preparation Example 7 Preparation of 3'-fluoro-4'-methoxy-2-(4-methoxyphenyl)acetophenone thionyl chloride (3.57 g) was added to a solution of 4-methoxyphenylacetic acid (3.32 g, 19.98 mmol) in benzene (30 ml).. After the mixture was heated under reflux for 3 hours, the solvent was distilled off.. To the residue, methylene chloride (50 ml) and <strong>[321-28-8]2-fluoroanisole</strong> (2.10 g) were added.. Under ice cooling, aluminum chloride (13.32 g) was added, followed by stirring for 30 minutes.. The mixture was then stirred at room temperature for 2 hours.. The reaction mixture was added to ice water, followed by extraction with methylene chloride.. The extract was dried over anhydrous sodium sulfate.. The solvent was distilled off under reduced pressure.. The residue so obtained was separated and purified by chromatography on a silica gel column and was then crystallized form ethyl acetate-hexane, whereby the title compound (2.27 g, 49.6%) was obtained as colorless prisms. Melting point: 141.7-142.7 C. Mass (m/Z): 274 (M+).. 1H-NMR (CDCl3) delta: 3.78(3H,s), 3.94(3H,s), 4.15(2H,s), 6.86(2H,d,J=8.7 Hz), 6.98(1H,dd,J=8.5 Hz,J=8.5 Hz), 7.17(2H,d,J=8.7 Hz), 7.73(1H,dd,J=12.0 Hz,J=2.2 Hz), 7.79(1H,ddd,J=8.5 Hz,J=2.2 Hz,J=1.0 Hz). IR (KBr) cm-1: 1681,1613,1516,1436,1286,1254,1223,1177, 1132,1034,1014,889,809,787.
N-{1-[2-(1,3-dioxan-2-yl)ethyl]piperidin-4-yl}-N-(4-fluorobenzyl)-2-(4-methoxyphenyl)-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 20h;
[) ELH- (4-FLUOROBENZYL-2- (4-METHOXYPHGNYL)-] acetamide, [TARTRATE (118AF60-96 ..]
A solution of triethylamine (0.57 mL, 4.09 mmol) and 118AF52-95 (328 mg, 1.02 mmol) in dry THF (5 mL) was cooled to [0°C.] A solution of 4-methoxyphenylacetyl chloride (376 mg, 2.04 mmol) was added dropwise to the cold reaction mixture and stirring was continued for 20 h at rt. The reaction mixture was partitioned between 2M [NAOH] and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 0-6 % methanol in dichloromethane. Final purification of the product by acidic ion-exchange SPE cartridge afforded the desired compound (153 mg, [33 %),] which was converted to its tartrate form as described above. Rf = 0.40 [(MEOH/CH2CL2,] 4: 96). LCMS [M/Z] 471 [M+H] [+. LU] NMR [(CDC13,] rotamers 0.4 : 0.6) 8 7.24-6. 79 (m, 8H, Ar-H), 4.63-4. 54 (m, 0.6H, pip-H), 4.52 (t, [1H,] [J=] 5.2, dioxane-H), 4.49 & 4.44 (2s, 2H, benzyl-H), 4.09-4. 01 (m, 2H, dioxane-H), 3.79-3. 68 (m, 6.2H, dioxane-H, benzyl-H, pip-H, OCH3), 3.50 (m, 1.2H, benzyl-H), 2.91-2. 80 (m, 2H, pip-H), 2.43-2. 36 (m, 2H, NCH2), 2.10-1. 98 (m, 2.2H, dioxane-H, pip-H), 1.86-1. 51 (m, 6H, pip-H, NCH2CH2), 1.34-1. 26 (m, 1.8H, pip-H, dioxane-H). HPLC tR= 7.0 min.
33%
With triethylamine In tetrahydrofuran at 0 - 20℃; for 20h;
203
A solution of triethylamine (0.57 mL, 4.09 mmol) and 1 18AF52-95 (328 mg, 1.02 mmol) in dry THF (5 mL) was cooled to 00C. A solution of 4- methoxyphenylacetyl chloride (376 mg5 2.04 mmol) was added dropwise to the cold reaction mixture and stirring was continued for 20 h at rt. The reaction mixture was partitioned between 2M NaOH and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 0-6 % methanol in dichloromethane. Final purification of the product by acidic ion-exchange SPE cartridge afforded the desired compound (153 mg, 33 %), which was converted to its tartrate form as described above.[0675J R/ = 0.40 (MeOH/CH2Cl2, 4:96). LCMS m/z Al [M+H]+. 1H NMR (CDCl3, rotamers 0.4:0.6) δ 7.24-6.79 (m, 8H, Ar-H), 4.63-4.54 (m, 0.6H3 ρip-H), 4.52 (t, IH, J= 5.2, dioxane-H), 4.49 & 4.44 (2s, 2H, benzyl-H), 4.09-4.01 (m, 2H5 dioxane-H), 3.79-3.68 (m, 6.2H5 dioxane-H, benzyl-H, piρ-H, OCH3), 3.50 (m, 1.2H, benzyl-H), 2.91- 2.80 (m, 2H5 ρiρ-H), 2.43-2.36 (m, 2H, NCH2), 2.10-1.98 (m, 2.2H, dioxane-H, pip-H), 1.86-1.51 (m, 6H, pip-H, NCH2CH2), 1.34-1.26 (m, 1.8H, pip-H, dioxane-H). HPLC /R = 7.0 min.
Stage #1: 5-bromo-pyridine-2,3-diamine; 4-methoxyphenyl-acetic chloride at 170℃; for 1.5h;
Stage #2: With sodium hydroxide In tetrahydrofuran; water; ethyl acetate
14 Reference Example 14
Reference Example 14 A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.32 g) and 4-methoxyphenylacetyl chloride (1.29 g) was stirred in the absence of solvent at 170°C for 1.5 hour.. The mixture was distributed with ethyl acetate - tetrahydrofuran (3: 1, v/v) and water (at that time, the water layer was neutralized with 1 N sodium hydroxide).. The organic layer was washed with water, dried over MgSO4, and the solvent was distilled off under reduced pressure.. The resulting crystals were collected by filtration to obtain 6-bromo-2-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine (1.22 g, 55 %).1H NMR (CDCl3) δ 3.82 (3H, s), 4.30 (2H, s), 6.90 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 9.2 Hz), 7.82 (1H, s), 8.10 (1H, s), 12.14 (1H, broad s) ppm IR (KBr) ν 3007, 1512, 1433, 1254 cm-1HPLC (220 nm) Purity 100 % (Retention time 2.57 minutes) MS (APCI+, m/e) 318 (M+1)
With triethylamine;dmap; In dichloromethane; at 20℃;
Example of Method B; To a solution of acid chloride, for example 4-methoxyphenylacetyl chloride (1.00 g, 5.42 MMOL) in CH2CI2 (30 mL) was added amine, such as 2-amino-4, 6-dimethylpyridine (661 mg, 5.42 MMOL), followed by DMAP (catalytic amount) and triethylamine (1 eq).. After stirring at ambient temperature overnight, the mixture was concentrated and purified by flash column chromatography and eluted with gradient of EtOAc in hexanes to provide the desired amide in 50- 90 % yield. ; Intermediate 3a: N- (4, 6-DIMETHYL-PYRIDIN-2-YL)-2- (4-METHOXY-PHENYL)-ACETAMIDE was prepared from 4-METHOXYPHENYLACETYL chloride and 2-amino-4, 6-dimethylpyridine following Method B. H NMR (300 MHz, CDCl3) No. 7.86 (s, 1 H), 7.73 (s, 1 H), 7.24 (d, 2H, J = 8.34 Hz), 6.91 (d, 2H, J = 8.59 Hz), 6.70 (s, 1H), 3.81 (s, 3H), 3.66 (s, 2H), 2.35 (s, 3H), 2.29 (s, 3H). LCMS (ESI+) [M+H] /z CALC D 271, found 271.
With triethylamine In dichloromethane at 0 - 25℃; for 12h;
3-Hydroxy-2- [2- (4-methoxy-phenyl)-acetylamino]-propionic acid methyl ester: to a suspensionofDL-serineHCl (2.0 g, 12.8 mmol) in dichloromethane (10 mL) at0 C were added dropwise triethylamine (3.58 mL, 25.7 mmol) and (4-methoxyphenyl) -acetyl chloride (1.96 mL, 12.8 mmol). The mixture was stirred at25 C for 12 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, separated, and evaporated to dryness and purified by column chromatography (hexanes: ethyl acetate from 25 to 100%). 3-Hydroxy-2-[2- (4-methoxy-phenyl)-acetylamino]-propionic acid methyl ester was isolated as a white solid (2g, 58 %). ESI-MSm/z calc. 267.3, found 268.2(M+1) +. Retention time of 1.83 minutes NMR (400 MHz,CDC13) 8 3.64 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 3.93 (qd, J = 14.6 and 4.0 Hz,2H), 4.66 (m, 1H), 6.40 (m, 1H), 7.01 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H).
With sodium carbonate; In water; benzene; at 0 - 20℃; for 12h;
The N-alcoxyamines 2a-c were purchased from Aldrich and Fluka Companies, and used without further purification. The N-alcoxyamine 2d was prepared following the procedure described in Brown, D. S.; Gallagher, P. T.; Lightfoot, A. P.; Moody, C. J.; Slawin, A. M. Z.; Swann, E. Tetrahedron 1995, 51, 11473-11488. To a vigorously stirred solution of N-alcoxyamine hydrochloride 2a-d (17.87 mmol) and sodium carbonate (32.50 mmol) in a mixture of benzene (23 ml) and H2O (23 ml) with ice-water bath cooling, was added 4-methoxyphenylacetyl chloride (1). The mixture was stirred at room temperature for 12 h under an argon atmosphere and the progress of the reaction was monitored by TLC (hexane-AcOEt, 1:2). Then, AcOEt (50 ml) was added and the organic layer separated. This process was repeated three times. The combined extracts were washed with brine (2 x 50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give the corresponding N-alcoxyamide 3a-d, which was used in the next reaction without further purification.
With aluminum (III) chloride In dichloromethane at -20 - -10℃; for 0.5h;
46.Ex-46A
Example 46: l-(5-Benzo[Λ]thien-2-yl-2,4-dimethoxy-phenyl)-2-(4-methoxy-phenyl)- propenone [0417] Ex-46A: l-Bromo-2,4-dimethoxybenzene (1.58 g, 7.27 mmol), 4-methoxyphenyl acetyl chloride (1.11 mL, 7.26 mmol) and CH2Cl2 (20 mL) were sequentially charged into a clean reaction vessel and the resulting solution was cooled to -20 0C. AlCl3 (1.1 g, 8.25 mmol) was then added over 20 min and aged at -15 0C. After an additional 10 min, the reaction was poured into 75 mL cold H2O and extracted with CH2Cl2. The organic cut was dried with MgSO4, filtered and concentrated to dryness. The crude product was dissolved in hot EtOAc (5 mL) and crystallized upon heptane (15 mL) addition. The product was filtered and then dried under vacuum affording 1.9 g (71% yield) of desired l-(5-bromo-2,4-dimethoxy-phenyl)-2-(4-methoxy-phenyl)-ethanone. 1H-NMR (300 MHz, CDCl3): δ 7.99 (s, IH), 7.12 (d, J= 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.43 (s, IH), 4.19* (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.78 (s, 3H).
21 Synthesis of 11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)-undecanoic Acid
Example 21 Synthesis of 11-[(3RS,4RS)-3-Ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)-undecanoic Acid A suspension of 2-hydroxy-4-methoxybenzaldehyde (6.10 g), 4-methoxyphenylacetylchloride (11.1 g) and potassium carbonate (20 g) in acetone (400 ml) was heated under reflux for 2 hours. The reaction mixture was evaporated to remove the solvent, followed by addition of water. The resulting precipitates were collected by filtration and dried under reduced pressure to give 7-methoxy-3-(4-methoxyphenyl)-chromen-2-one (10.1 g, Yield 89%). 1H-NMR (270 MHz, CDCl3): d 7.71 (s, 1H, Ar-H), 7.65 (d, 2H, J=8.9 Hz, Ar-H), 7.42 (d, 1H, J=8.9 Hz, Ar-H), 6.97 (d, 2H, J=8.9 Hz, Ar-H), 6.8-6.9 (m, 2H, Ar-H), 3.88 (s, 3H, MeO), 3.85 (s, 3H, MeO).
61%
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate In dichloromethane; water at 20℃;
Synthesis of 2-amino-4-(4-methoxyphenylmethyl)-6-[1-(3,4-methylenedioxybenzoyl)-3-piperidinyl]pyrimidine STR82 By a procedure similar to that described in Example 303, the titled compound (2.85 g, total yield of 44%) was prepared using <strong>[498-95-3]nipecotic acid</strong> and 4-methoxyphenylacetyl chloride instead of iso<strong>[498-95-3]nipecotic acid</strong> and 4-bromophenylacetyl chloride respectively. Melting Point:199-201 C. 1 H-NMR (CDCl3): delta 1.4-1.8 (3H, m), 1.97 (1H, m), 2.61 (1H, m), 2.97 (2H, m), 3.74 (1H, m), 3.80 (3H, s), 3.81 (2H, s), 4.6 (1H, m), 4.96 (2H, s), 5.99 (2H, s), 6.26 (1H, s), 6.85 (5H, m), 7.15 (2H, d, J=8.9).
16.A A.
A. 2-(4-Methoxyphenyl)-1-(2-thienyl)-ethanone (17) p-Methoxyphenylacetyl chloride (36.9 g, 0.2 mol) and thiopene (16.8 g, 0.2 mol) in CH2 Cl2 (400 ml) was cooled to 0° C. Stannic chloride (52.1 g, 0.2 mol) in CH2 Cl2 (100 ml) was added dropwise. The resulting green solution was quenched after 3 hours by pouring the mixture over a 10% HCl/ice slurry. The organic layer was washed with water and brine, dried over MgSO4, and the solvent was removed under reduced pressure. The solid residue was recrystallized from ether to afford 17 (32.0 g, 68.9%), m.p. 77°-78.4° C.
2-(4-methoxybenzyl)-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidin-1-ylpropyl)amino]benzamide; 4-methoxyphenyl-acetic chloride With acetic acid at 100℃; for 18h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Stage #3: With hydrogenchloride In diethyl ether
A2 2-(4-methoxybenzyl)-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamide hydrochloride
EXAMPLE A2 2-(4-methoxybenzyl)-N,N-bis(3-methylbutyl)-1-(3-piperidin-1-ylpropyl)-1H-benzimidazole-6-carboxamide hydrochloride 4-methoxyphenylacetylchloride (32 mg, 1.1 eq) is added to a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidin-1-ylpropyl)amino]benzamide (66 mg) in acid acetic (2 ml). The mixture is heated at 100° C. for 18 hours then cooled down and concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate is added to the residue obtained dissolved in dichloromethane. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue obtained by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of the free base. The corresponding hydrochloride salt is formed by the addition of a 1N solution of hydrochloric acid in diethyl ether. The precipitate obtained is filtered and dried in order to produce the expected monohydrochloride compound (51 mg, 59% yield). MS/LC: Calculated MM=546.8; m/z=547.5 (MH+) NMR 1H (400 MHz, DMSO-d6): δ0.63 (d, 6H), 0.94 (d, 6H), 1.24-1.92 (m, 12H), 2.11 (m, 2H), 2.73 (m, 2H), 3.03-3.29 (m, 6H), 3.40 (m, 2H), 3.74 (s, 3H), 4.56 (t, 2H), 4.62 (s, 2H), 6.96 (AB, 2H), 7.43 (m, 3H), 7.79 (AB, 1H), 8.03 (s, 1H), 11.02 (s, 1H).
aluminium trichloride; Zinc chloride; In 1,1-dichloroethane; 1,2-dichloro-ethane;
Synthesis of 1-(2-fluoro-6-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone To 1,2-dichloroethane (40 mL) were added anhydrous aluminum chloride (4.27 g) and zinc chloride (436 mg), followed by stirring 15 min. Under ice-cooling, a solution of <strong>[52189-63-6]1,3-dimethoxy-5-fluorobenzene</strong> (5 g) in 1,2-dichloroethane (15 mL) was added. The mixture was cooled to -10 C. and 4-methoxyphenylacetyl chloride (4.9 mL) in dichloroethane (10 mL) was added drop-wise. The mixture was stirred 30 min at -10 C., and 1 h at room temperature and then heated to reflux for 2 h. The mixture was cooled at 0 C., poured carefully into ice-water and extracted twice with dichloromethane. The dichloromethane layer was dried over MgSO4 and evaporated in vacuo to give the title compound (9.1 g); 1H NMR (CDCl3): 13.23 (s, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.88 (d, 2H, J=8.4 Hz), 6.24 (d, 1H, J=2.1 Hz), 6.18 (dd, 1H, J=13.8 Hz, J'=2.1 Hz), 4.20 (d, 2H, J=3.9 Hz), 3.82 (s, 3H), 3.80 (s, 3H); MS: 291 (MH+); containing 1-(4-fluoro-2-hydroxy-6-methoxyphenyl)-2-(4-methoxyphenyl)ethanone as a by-product. 1H NMR (CDCl3): 13.62 (s, 1H), 7.2-6.0 (6H), 4.29 (s, 2H), 3.90 (s, 3H), 3.81 (s, 3H).
(1S,4R,6S,14S,18R)-4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 4-cyclopropanesulfonylaminocarbonyl-14-[2-(4-methoxy-phenyl)-acetylamino]-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-18-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The starting material (AR00334191, Example 3-55,10 mg, 13.7 pmol) was dissolved in 1 mL of 50 % TFA (DCM) and stirred at RT for 1 h. The reaction mixture was then concentrated to dryness, taken up in acetonitrile and concentrated again. Repeat the above process once more to remove any excess TFA. The resulting solid residue was then dissolved in DCE (137 L), followed by addition of the acid chloride, (4-Methoxy-phenyl)-acetyl chloride (2 drps) and DIEA (4 drps). The mixture was stirred ar RT for overnight. After completion, the reaction was directly loaded onto a C-18 column and purified with reverse- phase column chromatography. The compound was further purified on normal phase silica gel chromatography (eluent = 40 % EtOAc/hexanes with 1 % formic acid) to give the target compound as a white solid. 1H NMR (500 MHz, CD30D) 8 7.33 (p, 1H), 7.15 (d, 1H), 7.05- 6.92 (m, 3H), 6.65 (dd, 2H), 5.68 (q, 1H), 5.40 (br s, 1H), 5.09 (t, 1H), 4.78-4. 46 (m, 7H), 4.43-4. 24 (m, 2H), 3. 89-3. 80 (m, 1H), 3.68 (d, 3H), 3.21 (d, 1H), 2.69-2. 57 (m, 1H), 2.52 - 2. 30 (m, 5H), 2.06-0. 80 (m, 15H); MS (APCI-): m/z 778.3 (M-1).
With triethylamine In acetonitrile at 20℃; for 2h;
B30
4-Methoxybenzeneacetyl chloride (0.135 g; 0.730 mmol) was added to a mixture of intermediate 63 (prepared according to A21.g) (0.272 g; 0.608 mmol) and TEA (0.130 ml; 0.912 mmol) dissolved in CH3CN (5 ml). The reaction mixture was stirred for 2 hours at room temperature. The formed crystalline product was filtered off, washed with water, z-PrOH, and hexane and dried on the air. Yield: 0.242 g of compound 351 (67 %).
45%
With triethylamine In dichloromethane at 20℃; for 0.5h;
B4.b
4-Methoxybenzeneacetyl chloride (0.135 g; 0.730 mmol) was added to a solution of intermediate 63 (prepared according to A21.g) (0.272 g; 0.608 mmol) and TEA (0.130 ml; 0.912 mmol) dissolved in DCM (5 ml). The reaction mixture was stirred for 0.5 hours at room temperature. The reaction mixture was concentrated in vacuum. The residue was treated with /-PrOH /hexane (3/1). A formed crystalline product was fltered, washed with small amount of z-PrOH, hexane and dried on air. Yield: 0.098 g of compound 351 (45 %).
With ammonium hydroxide; In ethyl acetate;Inert atmosphere;
In a round bottomed flask equipped with a magnetic stirringbar and argon gas inlet, 2-(4-methoxyphenyl)acetic acid (1a, 5.0 mmol) was dissolved in thionylchloride (10.0 mL). The mixture was allowed to heat to reflux for 3 h, which was concentrated toremove the additional thionyl chloride under reduced pressure to give the 2-(4-methoxyphenyl)acetylchloride (1b). Then ammonia solution (5.0 mmol ammonia gas in 5.0 mL water) was added into theacyl chloride in ethyl acetate (5.0 mL), and the 2-(4-methoxyphenyl)acetamide (1c) was crystallizeform the mixture in 95percent yield as white solids; Its spectral data were identical with those reportedwith the melting point of 169?170 °C (lit. [31] 163?165 °C). The 2-(4-methoxyphenyl)ethanethioamide(1d, 0.45 g) was synthesized and isolated by using Lawesson's reagent (5.0 mmol) in toluene (20.0 mL)under 50 °C for 2 h, and the residue was purified by flash column chromatography on silica gel(EtOAc/hexane, 1:1) to afford yellow solids with the yield of 85percent. 1H-NMR (400 MHz, DMSO-d6, delta ppm): 7.66 (s, 1H), 7.26?7.17 (m, 2H), 6.92?6.71 (m, 2H), 6.70 (s, 1H), 4.05 (s, 2H), 3.81 (s, 3H).
methyl {1-(2-chlorophenyl)-5-hydroxy-4-[(4-methoxyphenyl)acetyl]-1H-pyrazol-3-yl}acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With calcium hydroxide In 1,4-dioxane at 120℃; for 1h;
2.b
b) methyl {1-(2-chlorophenyl)-5-hydroxy-4-[(4-methoxyphenyl)acetyl]-1H-pyrazol-3-yl}acetate (Compound of Formula (X), Scheme 2). The mixture of the above obtained methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 1 g, 3.76 mmol, 1 eq.), was suspended in dioxane (10 mL) and Ca(OH)2 (0.557 g, 2 equiv.) and (4-methoxyphenyl)acetyl chloride (0.694 g) under nitrogen, was heated at 120 °C for 45-60 minutes. The resulting red solution was concentrated in vacuo to afford a red syrup that was partitioned between ethylacetate and cold 0.1M HCl. Organic phases were washed with brine and dried over Na2SO4. Evaporation of solvent gave methyl {1-(2-chlorophenyl)-5-hydroxy-4-[(4-methoxyphenyl)acetyl]-1H-pyrazol-3-yl}acetate as a pink solid (1.09 g, 70% yield, 89% HPLC purity). MS(ESI+): 415.9; MS(ESI-): 413.8.
aluminum (III) chloride; In dichloromethane; at 20℃;Reflux;
Example 3; Procedure for the preparation of 1-(2-fluoro-4-methoxyphenyl)-2-(4-methoxy-phenyl)ethanone (compound 1c); General Procedure C (See Scheme 1, Bottom Panel); 1-Fluoro-3-methoxybenzene (2.243 ml, 19.63 mmol) and 4-methoxyphenylacetyl-chloride (3.00 ml, 19.63 mmol) were dissolved in dichloromethane (50 ml) to obtain a brown solution. Aluminium chloride (3.14 g, 23.56 mmol) was added portion wise and the reaction mixture started refluxing. The mixture was stirred for 2 h at room temperature, poured into ice water (200 ml) and extracted with ethyl acetate (2×250 ml). The combined organic phases were dried with sodium sulfate and concentrated. The crude product was purified by column chromatography (heptane/ethyl acetate 85:15) to give compound 1c as a yellow oil (3.52 g, 65% yield). 1H NMR (CDCl3): delta 3.77 (s, 3H), 3.84 (s, 3H), 4.17 (d, J=3 Hz, 2H), 6.60 (dd, J1=13 Hz, J2=2 Hz, 1H), 6.73 (dd, J1=10 Hz, J2=2 Hz, 1H), 7.00 (AB, J1=115 Hz, J2=10 Hz, 4H), 7.87 (dd, J1/J2=10 Hz, 1H).
65%
aluminum (III) chloride; In dichloromethane; at 20℃;Reflux;
Example 3; Procedure for the preparation of 1-(2-fluoro-4-methoxyphenyl)-2-(4-methoxy- phenyl)ethanone (compound Ic); General Procedure C (see Scheme 1 , bottom panel); 1 -Fluoro-3-methoxybenzene (2.243 ml, 19.63 mmol) and 4-methoxyphenylacetyl- chloride (3.00 ml, 19.63 mmol) were dissolved in dichloromethane (50 ml) to obtain a brown solution. Aluminium chloride (3.14 g, 23.56 mmol) was added portion wise and the reaction mixture started refluxing. The mixture was stirred for 2h at room temperature, poured into ice water (200 ml) and extracted with ethyl15 acetate (2x 250 ml). The combined organic phases were dried with sodium sulfate and concentrated. The crude product was purified by column chromatography (heptane/ethyl acetate 85:15) to give compound Ic as a yellow oil (3.52 g, 65% yield). 1H NMR (CDCI3): delta 3.77 (s, 3H), 3.84 (s, 3H), 4.17 (d, J=3 Hz, 2H), 6.60 (dd, J1 =13 Hz, J2=2 Hz, 1 H), 6.73 (dd, J1 =10 Hz, J2=2 Hz, 1 H), 7.00 (AB, J1 =11520 Hz, J2=10 Hz, 4H), 7.87 (dd, J1/J2=10 Hz, 1 H).
With triethylamine In tetrahydrofuran at 20℃; for 0.5h;
105
Example 105N-(2-Cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-yl)-2-(4-methoxyphenyl)acetamideTo the solution of 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-amine (50 mg, 0.24 mmol) in THF ( 5 mL) was added triethylamine (48 micro L, 0.36 mmol) and 2-(4-methoxyphenyl)acetyl chloride (44 mg, 0.24 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with 5% aq NaHCO3 (50 mL) and brine (50 mL). The layers were separated and the organic layer was dried over Na2SO4, concentrated, and the residue was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA) to afford the desired product (60 mg, 71% yield) as dark purple-blue solid: ESI MS m/z 352 [C20H2,N3O3 + H]+.
With triethylamine In dichloromethane at 20℃; for 2h;
42.a
a) Synthesis of 1-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-2-(4-methoxy-phenyl)-ethanone In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and (4-methoxy-phenyl)-acetyl chloride (163 mg, 0.88 mmol) were dissolved in dichloromethane. Triethylamine (0.21 ml, 1.46 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water, the reaction mixture was extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound, i.e., 1-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-2-(4-methoxy-phenyl)-ethanone, as yellow liquid (198 mg, 95%). 1H-NMR (CDCl3, 300 MHz); δ=8.51 (br s, 1H), 8.22 (d, J=5.3 Hz, 1H), 7.23 (d, 2H, J=8.4 Hz), 6.85 (d, J=8.4 Hz, 2H), 6.81 (d, J=5.3 Hz, 1H), 4.21 (br s, 2H), 3.94 (br s, 2H), 3.91 (s, 2H), 3.79 (s, 3H). MS (ESI); 285.1 (M++1).
With triethylamine; In dichloromethane; at 0 - 20℃;
N-Methylaniline derivative (1 equiv) was mixed with Et3N (2 equiv) in dichloromethane. The solution was cooled at 0 C. The acyl chloride (1.2 equiv) was slowly added and the mixture stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The product was purified by column chromatography.
With aluminum (III) chloride In 1,1,2,2-tetrachloroethane at 0 - 20℃; Inert atmosphere;
XI
KY-5771 -Chemical pathway KY-577; [216] Synthesis of 2-[4-Biphenyl-4-yl-5-(4-methoxy-phenyl)-thiazol-2-yl]-hydrazono}-3-(2- nitro-phenyl)-propionic acid (KY-577); [217] Synthesis of l-BiphenyI-4-yl-2-(4-methoxy-phenyl)-ethanone: KY-560: In a round bottom flask equipped with gas inlet and magnetic stirrer were placed Biphenyl (2.1 gr,13.65 mmol), Aluminum trichloride (1.5 gr, 11.25 mmol), and 150 ml of tetrachloroethane (TCM). While the TCM solution was stirring, a solution of 25 ml of tetrachloroethane and 0.830 ml of (4-Methoxy-phenyl)-acetyl chloride (5.5 mmol) was dropwise over five minutes by syringe. The reaction mixture was stirred 3-4 h. 150 ml of water and 5 ml of HC1 were slowly added. The layers were separated. The aqueous layer was extracted with DCM. The combined DCM and TCE solution was washed with a saturated solution of NaCl in water. The organic solution was dried over Na2S04. filtration followed by rotary evaporation produced a dark yellow solid. Chromatography on flash chromatographic(CycloHexane: DCM). Yield 1.2 gr (71%) as a white solid.
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;
General procedure: To a solution of methyl piperidinecarboxylate hydrochloride 2 (0.02 mol) in methylene chloride (20 ml) was added in a dried round-bottom flask, to which triethylamine (0.05 mol) and solution of phenylacetyl chloride in methylene chloride (0.024 mol) was added dropwise separately in an ice bath for over 20 min, next the cold bath was removed. The reaction was stirred at room temperature for 12 h, and TLC traced the reaction to completion. After the completion of the reaction, the solution was dissolved in water (20 ml), and the aqueous solution was extracted with methylene chloride (30 ml × 2) twice. The combined organic phases were washed with 5% Na2CO3 solution (30 ml × 2) and water to neutrality and dried over anhydrous Na2SO4. After filtration and concentration, the corresponding compound 5 were received through the above methods.
With triethylamine In dichloromethane at 0℃; for 2h;
13
PREPARATION x13: 1-(2-(1-(tert-butyldimethylsilyl)-1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-(4-methoxyphenyl)ethanone 2-(1-(tert-Butyldimethylsilyl)-1H-indol-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x12, 42 mg, 0.100 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. 2-(4-Methoxyphenyl)acetyl chloride (0.018 mL, 0.120 mmol) was added, followed by triethylamine (0.028 mL, 0.199 mmol) to give a yellow solution. The reaction mixture was stirred for 2 hours at 0° C. The solvent was subsequently removed in vacuo and the resulting concentrate was loaded onto an ISCO silica gel cartridge (4 g) and eluted using an ethyl acetate/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow oil (42 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 0.64 (s, 6H), 0.89 (s, 9H), 3.02-3.22 (m, 4H), 3.42-3.61 (m, 2H), 3.66-3.78 (m, 3H), 3.87-3.92 (m, 2H), 3.91-3.98 (m, 1H), 4.30-4.47 (m, 1H), 4.64-4.75 (m, 1H), 6.79-6.93 (m, 2H), 7.00-7.30 (m, 3H), 7.42-7.51 (m, 2H), 7.61-7.68 (m, 1H), 8.02-8.07 (m, 1H), 8.32-9.02 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C32H39N5O3Si, 570.28. found 570.6.
Stage #1: C15H21NO3 With aluminum (III) chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.25h; Inert atmosphere;
Stage #2: 4-methoxyphenyl-acetic chloride In dichloromethane at 20℃; for 24h; stereoselective reaction;
General Procedure and selected data for the syntheses of amides 3: To a stirred suspension of AlCl3 or TiCl4·2THF (1.0 mmol) in CH2Cl2 (5 mL) under an atmosphere of nitrogen, a solution of allylic morpholine 1 (1 mmol) in CH2Cl2 (5 mL) was added dropwise, followed by DIPEA (1.5 mmol) dropwise. The resulting mixture was stirred at room temperature for 15 min, then a solution of acid chloride 2 (1.2 mmol) in CH2Cl2 (5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Aqueous NaOH solution (2 M, 10 mL) was added, the layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography to give amides 3.
Stage #1: 1-morpholyl-2-butene With aluminum (III) chloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.25h; Inert atmosphere;
Stage #2: 4-methoxyphenyl-acetic chloride In dichloromethane at 20℃; for 24h; stereoselective reaction;
General Procedure and selected data for the syntheses of amides 3: To a stirred suspension of AlCl3 or TiCl4·2THF (1.0 mmol) in CH2Cl2 (5 mL) under an atmosphere of nitrogen, a solution of allylic morpholine 1 (1 mmol) in CH2Cl2 (5 mL) was added dropwise, followed by DIPEA (1.5 mmol) dropwise. The resulting mixture was stirred at room temperature for 15 min, then a solution of acid chloride 2 (1.2 mmol) in CH2Cl2 (5 mL) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Aqueous NaOH solution (2 M, 10 mL) was added, the layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography to give amides 3.
2-(4-methoxy-phenyl)-N-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With triethylamine In tetrahydrofuran at 20℃; for 2h;
20 Preparation of 2-(4-methoxy-phenyl)-N-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-acetamide (Compound 20)
Example 20 Preparation of 2-(4-methoxy-phenyl)-N-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-acetamide (Compound 20) 100 mg (0.28 mmol) of the compound obtained in Preparation Example <1-3> was dissolved in 8 mL of tetrahydrofuran, and then 116 μl (0.84 mmol) of triethylamine and 77 mg (0.42 mmol) of 4-methoxy acetyl chloride were added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was dissolved again in 50 mL of ethyl acetate, and then the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica column chromatography (acetone:methylene chloride=1:4) to give 100 mg of a yellow foam solid compound (yield: 71%). 1H-NMR (300 MHz, CDCl3) δ 1.67-1.73 (m, 1H), 2.08-2.17 (m, 1H), 2.32-2.51 (m, 2H), 3.57 (s, 2H), 3.66 (s, 3H), 3.80 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H), 4.56-4.63 (m, 1H), 6.13-6.15 (d, 1H, J=6 Hz), 6.49 (s, 1H), 6.78-6.82 (d, 1H, J=12 Hz), 6.87-6.90 (d, 2H, J=8.7 Hz), 7.16-7.19 (d, 2H, J=8.4 Hz), 7.26-7.30 (d, 1H, J=12 Hz)
71%
With triethylamine In tetrahydrofuran at 20℃; for 2h;
20 Example 20: Preparation of 2-(4-methoxy-phenyl)-N-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benxo[a]heptalen-7-yl)-acetamide (Compound 20)
Example 20 Preparation of 2-(4-methoxy-phenyl)-N-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydro-benxo[a]heptalen-7-yl)-acetamide (Compound 20) 100 mg (0.28 mmol) of the compound obtained in Preparation Example <1-3> was dissolved in 8 mL of tetrahydrofuran, and then 116 μl (0.84 mmol) of triethylamine and 77 mg (0.42 mmol) of 4-methoxy acetyl chloride were added and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was dissolved again in 50 mL of ethyl acetate, and then the organic layer was washed with distilled water three times. The organic layer was dried with anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica column chromatography (acetone: methylene chloride=1:4) to give 100 mg of a yellow foam solid compound (yield: 71 %). 1H-NMR(300 MHz, CDCl3) δ 1.67-1.73(m, 1H), 2.08-2.17(m, 1H), 2.32-2.51(m, 2H), 3.57(s, 2H), 3.66(s, 3H), 3.80(s, 3H), 3.88(s, 3H), 3.93(s, 3H), 3.98(s, 3H), 4.56-4.63(m, 1H), 6.13-6.15(d, 1 H, J = 6 Hz), 6.49(s, 1 H), 6.78-6.82(d, 1H, J = 12 Hz), 6.87-6.90(d, 2H, J = 8.7 Hz), 7.18-7.19(d, 2H, J = 8.4 Hz), 7.26-7.30(d, 1H, J = 12 Hz)MS (m/e, M+): 505
2-bromo-1-(bromomethyl)ethyl 2-(4-methoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With dmap; dicyclohexyl-carbodiimide In dichloromethane Inert atmosphere;
Esters 2b-f, 2h, and 2i; General Procedure
General procedure: The appropriate carboxylic acid (0.75 mmol), DMAP (0.05 mmol), and DCC (0.75 mmol) were added to a soln of the dibromo alcohol (0.5 mmol) in anhyd CH2Cl2 (5 mL) under N2, and the mixture was stirred overnight. The precipitate was filtered off and the organic phase was washed with 1 M aq HCl (10 mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the organic layers were combined, washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The crude mixture was purified by chromatography [silica gel, pentane-CH2Cl2 (8:2 to 0:1)].
2-chloro-4-hydroxy-3-indan-5-yl-5-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-indan-5-yl-ethanone; ethyl 2-cyanoacetate With ammonium acetate; acetic acid In toluene for 10h; Reflux;
Stage #2: With morpholine; sulfur In ethanol for 20h; Reflux;
Stage #3: 4-methoxyphenyl-acetic chloride Further stages;
1 2-chloro-4-hydroxy-3-indan-5-yl-5-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridin-6-one
Step : 1 -(indan-5-yl)ethanone (10 g, 62.4 mmol) was dissolved in toluene (200ml) followed by acetic acid (3.57 mL, 62.4 mmol), ammonium acetate (12.03 g, 156 mmol) and ethyl 2-cyanoacetate (160 mL, 1503 mmol). The reaction mixture was boiled for 10h. Upon cooling, water was added and ethyl acetate extraction was performed (3X200mL). Organic phases were combined and washed with brine, dried over sodium sulfate. After removal of the solvent, the crude product was purified over silica (heptane/ethyl acetate 60/40) affording 13g (44%) of an oil. LC/MS: purity 54%, M-1 = 254 Step 2: step 1 compound (10.4 g , 22 mmol) was dissolved in ethanol (100mL). Morpholine (2.3 mL, 26.4 mmol) and sulphur (1 .7 g, 6.6 mmol) were added to the reaction mixture and the whole was refluxed for 20h. Upon cooling, the reaction mixture was filtered and the solids rinsed with water. The aqueous layer was extracted with ether, washed with brine and dried over sodium sulfate. Removal of the solvent afforded 4.3 g (68%) of a brown oil. NMR H (DMSO-d6): 0,95 (t, 3H); 2,03 (m, 2H); 2,86 (m, 4H); 2,97 (q, 2H); 6,12 (s, 1 H); 6,99 (d, 1 H); 7,10 (s, 1 H); 7,15 (dd, 1 H); 7,36 (bs, 2H) Step 3: step 2 compound (8.98 g, 31 .2 mmol) was dissolved in CH2CI2 (200 mL).N-chlorosuccinimide (4.17 g, 31 .2 mmol) was slowly added and the reaction was stirred at 20 °C for 1 hour. Water was added. The aqueous layer was extracted with ethyl acetate (3x100ml) and the combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent, the crude product was purified over silica (heptane/ AcOEt 95/5) affording 5.9 g (47%) of expected product. LC/MS: purity 80%, M+1 = 322 Step 4: To step 3 compound (1 .6 g, 4.3 mmol) and potassium carbonate (893 mg, 6,5 mmol) in tetrahydrofuran (20ml_) was added 4-methoxyphenyl acetyl chloride (0.66 ml, 4.3 mmol). The reaction mixture was stirred 18h at 20 °G Water was added and ether extraction (3x100ml_) was performed. The combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent, the crude product was purified over silica (heptane/ether 80/20) affording 886 mg (43.9%) of the expected product. LC/MS: purity 98.1 %, M-1 = 468.0 Step 5: To potassium bis(trimethylsilyl)amide (1 .50 g, 7.5 mmol in THF (20 ml_)) was added step 4 compound (884 mg, 1 .9 mmol) and the reaction mixture was stirred 30 minutes at 10 °C The reaction mixture was poured in a mixture of HCI 1 N / ice, and extracted with ethylacetate (3 x 100 ml_). The combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent, the crude solid was poured into a mixture of heptane/ether. After filtration, 77 mg (6%) of the expected compound was obtained. LC: RT 5.49 min, purity 93.1 % MS: M-1 = 422 NMR H (DMSO-d6): 2,02 (m, 2H); 2,87 (m, 4H); 3,74 (s, 3H); 6,88 (dd, 2H); 7,09 (dd, 1 H); 7,12 (dd, 2H); 7,19-7,24 (m, 3H); 9,28 (bs, 1 H)
General procedure: Amide formation: (0088) The acid chloride (1 eq) formed on the corresponding 2-aminobenzothiazole (1 eq) is added introduced in a microwave vial. The vial is introduced in the microwave reactor and heated to the temperature for the time indicated in each case. Dichloromethane (50 mL) is added and extracted with a 0.1 M HCl (50 mL) solution. Next, the organic phase is washed with saturated NaHC03 solution (50 mL) and then with saturated NaCl (50 mL) solution. The organic phase is dried over anhydrous MgS04 and the solvent removed under reduced pressure. The residue obtained was purified by flash column chromatography using Isolera One equipment. In all cases a mixture of hexane and ethyl acetate was used as eluent. All the acid chlorides required for the synthesis of the amide derivatives were synthesised in situ except: 2-(4-chlorophenyl)acetyl chloride, 2-(2,5-dimethoxyphenyl)acetyl chloride and 2-phenylbutanoyl chloride, which were purchased directly from the company Sigma AldrichN-(6-trifluoromethylbenzothiazole-2-yl)-2-(4-methoxyphenyl)acetamide (3): (0090) Reagents: 2-(4-methoxyphenyl)acetyl chloride (21 1.7 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol) and THF (1 mL). Reaction conditions: 10 min under microwave irradiation at 110°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a yellow solid. Yield: 184.8 mg, 44percent. Mp: 133°C-134°C 1H NMR (300 MHz, DMSO-d6) delta: 12.79 (s, 1 H), 8.47 (s, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.26 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.77 (s, 2H), 3.72 (s, 3H). 13C NMR (75 MHz, DMSO-d6) delta: 171.0, 161.1, 158.3, 151.3, 132.0, 130.4, 126.3, 124.5 (d, J = 272.2 Hz), 123.7 (d, J = 31.9 Hz), 122.9 (d, J = 3.7 Hz), 120.9, 119.8 (d, J = 4.3 Hz), 113.9, 55.0, 40.9. HPLC purity: >99percent. MS (ES) m/z: 367 [M+H]+. Elemental analysis (C17H13F3N2O2S): Theoretical percentC 55.73, percentH 3,58, percentN 7,65, percentS 8.75; Found percentC 55.48, percentH 3.31, percentN 7.44, percentS 8,97.
3-(4-methoxyphenyl)-4H-pyrimido[1,2-c]quinazolin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine In dichloromethane at 20℃; for 2h;
General procedure for the preparation of phenylpyrido[1,2-a]pyrimidinones, phenylpyrimido-[1,2-c]quinazolinones and phenylpyrazino[1,2-a]pyrimidinones 5 - 11.
General procedure: A suspension of formamidine derivative of various heterocyclic amines (4 mmol) and 3 (4.8 mmol) in thepresence of a catalytic amount of triethylamine in CH2Cl2 (10 mL) was stirred at rt for 2 h. The solidproduct was filtered, washed with EtOAc and dried. The crude product was recrystallized from EtOH togive 5 - 11.
(E)-N,N-dimethyl-N-(thieno[2,3-d]pyrimidin-4-yl)formimidamide[ No CAS ]
[ 4693-91-8 ]
3-(4-methoxyphenyl)-4H-pyrimido[1,2-c]thieno[3,2-e]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With triethylamine In dichloromethane at 20℃; for 2h;
General procedure for the preparation of phenylpyrimido[1,2-c]thieno[3,2-e]pyrimidinone (4Aa-t)and phenylpyrimido[1,2-c]thieno[2,3-e]pyrimidinone (4Ba-g).
General procedure: A suspension of 2A or 2B (4 mmol) and 3 (4.8 mmol) in the presence of a catalytic amount oftriethylamine in CH2Cl2 (10 mL) was stirred at rt for 2 h. The solid product was filtered, washed withEtOAc and dried. The crude product was recrystallized from EtOH to give 4A or 4B.
(E)-N,N-dimethyl-N-(thieno[3,2-d]pyrimidin-4-yl)formimidamide[ No CAS ]
[ 4693-91-8 ]
8-(4-methoxyphenyl)-7H-pyrimido[1,2-c]thieno[2,3-e]pyrimidin-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With triethylamine In dichloromethane at 20℃; for 2h;
General procedure for the preparation of phenylpyrimido[1,2-c]thieno[3,2-e]pyrimidinone (4Aa-t)and phenylpyrimido[1,2-c]thieno[2,3-e]pyrimidinone (4Ba-g).
General procedure: A suspension of 2A or 2B (4 mmol) and 3 (4.8 mmol) in the presence of a catalytic amount oftriethylamine in CH2Cl2 (10 mL) was stirred at rt for 2 h. The solid product was filtered, washed withEtOAc and dried. The crude product was recrystallized from EtOH to give 4A or 4B.
(E)-N,N-dimethyl-N’-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)formimidamide[ No CAS ]
[ 4693-91-8 ]
3-(4-methoxyphenyl)-9,10,11,12-tetrahydro-4H-benzo[4,5]thieno[3,2-e]pyrimido[1,2-c]pyrimidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With triethylamine In dichloromethane at 20℃; for 2h;
General procedure for the preparation of phenylpyrimido[1,2-c]thieno[3,2-e]pyrimidinone (4Aa-t)and phenylpyrimido[1,2-c]thieno[2,3-e]pyrimidinone (4Ba-g).
General procedure: A suspension of 2A or 2B (4 mmol) and 3 (4.8 mmol) in the presence of a catalytic amount oftriethylamine in CH2Cl2 (10 mL) was stirred at rt for 2 h. The solid product was filtered, washed withEtOAc and dried. The crude product was recrystallized from EtOH to give 4A or 4B.
(E)-N’-(6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide[ No CAS ]
[ 4693-91-8 ]
3-(4-methoxyphenyl)-10,11-dihydrocyclopenta[4,5]thieno[3,2-e]pyrimido[1,2-c]pyrimidin-4(9H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With triethylamine In dichloromethane at 20℃; for 2h;
General procedure for the preparation of phenylpyrimido[1,2-c]thieno[3,2-e]pyrimidinone (4Aa-t)and phenylpyrimido[1,2-c]thieno[2,3-e]pyrimidinone (4Ba-g).
General procedure: A suspension of 2A or 2B (4 mmol) and 3 (4.8 mmol) in the presence of a catalytic amount oftriethylamine in CH2Cl2 (10 mL) was stirred at rt for 2 h. The solid product was filtered, washed withEtOAc and dried. The crude product was recrystallized from EtOH to give 4A or 4B.
3-hydrazinyl-5-(2-(methylthio)pyrimidin-4-yl)pyridazine[ No CAS ]
[ 4693-91-8 ]
3-(4-methoxybenzyl)-7-(2-(methylthio)pyrimidin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With triethylamine In 1,4-dioxane at 20℃; for 2.5h; Reflux;
125.1
[00420] Step 1 : To a suspension of 3-hydrazinyl-5-(2-(methylthio)pyrimidin-4- yl)pyridazine (98 mg, 0.418 mmol) in 1,4-dioxane (8366 μ, 0.418 mmol) and triethylamine (58.3 μL, 0.418 mmol) was added dropwise 2-(4-methoxyphenyl)acetyl chloride (84.9 mg, 0.460 mmol). The mixture was stirred at room temperature for 30 minutes and then heated at reflux for 2 hours. The mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue obtained was partitioned between DCM (30 mL) and saturated aqueous NaHC03 (5 mL). The organic layer was dried (MgS04), filtered and concentrated in vacuo. The solid residue obtained was triturated with CH3CN to provide 3-(4- methoxybenzyl)-7-(2-(methylthio)pyrimidin-4-yl)-[l,2,4]triazolo[4,3-0]pyridazine (90 mg, 59% yield) as a solid. LCMS (APCI+) m/z 365.1 (M+l).
8-methyl-2-[1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl]-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine[ No CAS ]
[ 4693-91-8 ]
2-(4-methoxyphenyl)-N-{8-Methyl-2-[1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl]-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl}phenylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine In 1,4-dioxane for 18h; Inert atmosphere; Reflux;
General procedure for acylation of amino group at the 5 position (5-7)
General procedure: Amino compound3 (206 mg, 0.5 mmol) was dissolved in freshly distilled dioxane (15 ml) and the appropriateacyl chloride (1 mmol) and triethylamine (1 mmol, 140 μL) were added. The mixturewas refluxed under argon for 18 hours. Then the solvent was removed under reduced pressureand the residue was dissolved in EtOAc (30 ml) and washed twice with water (15 ml). Theorganic phase was dried on anhydrous Na2SO4 and concentrated under reduced pressure. Theresidue was purified by flash chromatography (EtOAc-light petroleum 8:2) to afford the desired compounds (5-7).
2-(4-methoxyphenyl)-N'-(2-(4-methoxyphenyl)acetyl)acetohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydrazine In ethyl acetate at 0℃; for 0.0833333h;
2-(4-Methoxyphenyl)-N1-(2-(4-methoxyphenyl)acetyl)acetohydrazide (4a).
2-(4-Methoxyphenyl)acetylchloride (1b, 5.0 mmol) was dissolved in anhydrous ethyl acetate (20.0 mL) under 0 °C, then 80%hydrazine was added. Then the bisacetohydrazide 4a was immediately precipitated within 5 min. Thewhite solids were collected by filtration, washed with ethyl acetate (2 x 10.0 mL) and dried undervacuum to afford analytically pure product in 90% yield, mp 108-109 °C. 1H-NMR (DMSO-d6, δ ppm):7.16 (br s, 2H), 7.19 (d, J = 8.4 Hz, 4H), 6.85 (d, J = 8.4 Hz, 4H), 3.71 (s, 6H), 3.37 (s, 4H). 13C-NMR(DMSO-d6, δ ppm): 169.22, 157.96, 130.00, 127.63, 113.62, 55.02, 39.21.
6-methoxy-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydroquinazolin-4(1H)-one[ No CAS ]
[ 4693-91-8 ]
6-methoxy-1-(2-(4-methoxyphenyl)acetyl)-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydroquinazolin-4(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.4%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 24h;
5.2.20 1-(2-(4-chlorophenyl)acetyl)-6-methoxy-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydroquinazolin-4(1H)-one(X254)
General procedure: To a solution of 2-(4-chlorophenyl) acetic acid (0.08g, 0.47mmol) and 5 (X=CH2, 0.15g, 0.43mmol) in 2mL DMF at 0°C was added EDCI (0.11g, 0.55mmol) in 0.5mL DMF. Then DMAP (5.1mg, 0.04mmol) was added to the reaction. The mixture was stirred for 24hat room temperature. The reaction was quenched by addition of 3mL cold water and extracted with DCM (3×3mL). The combined organic layers were washed with 5mL water 5mL brine, dried over anhydrous Na2SO4, and filtered, and then the filtrate was concentrated in vacuo. The resulted residue was chromatographed on silica gel eluting with CH2Cl2/MeOH (60/1-30/1) to give the desired compound X254 as white solid (112mg, 55.78%.).
4-(4-(6-methoxy-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)morpholin-3-one[ No CAS ]
[ 4693-91-8 ]
4-(4-(6-methoxy-1-(2-(4-methoxyphenyl)acetyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)morpholin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.5%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 24h;
5.2.20 1-(2-(4-chlorophenyl)acetyl)-6-methoxy-3-(4-(2-oxopiperidin-1-yl)phenyl)-2,3-dihydroquinazolin-4(1H)-one(X254)
General procedure: To a solution of 2-(4-chlorophenyl) acetic acid (0.08g, 0.47mmol) and 5 (X=CH2, 0.15g, 0.43mmol) in 2mL DMF at 0°C was added EDCI (0.11g, 0.55mmol) in 0.5mL DMF. Then DMAP (5.1mg, 0.04mmol) was added to the reaction. The mixture was stirred for 24hat room temperature. The reaction was quenched by addition of 3mL cold water and extracted with DCM (3×3mL). The combined organic layers were washed with 5mL water 5mL brine, dried over anhydrous Na2SO4, and filtered, and then the filtrate was concentrated in vacuo. The resulted residue was chromatographed on silica gel eluting with CH2Cl2/MeOH (60/1-30/1) to give the desired compound X254 as white solid (112mg, 55.78%.).
ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
Stage #1: ethyl (triphenylphosphoranylidene)acetate With triethylamine In dichloromethane for 0.166667h;
Stage #2: 4-methoxyphenyl-acetic chloride In dichloromethane at -20 - 0℃; for 0.166667h;
With TEA In dichloromethane at 0 - 20℃;
Stage #1: ethyl (triphenylphosphoranylidene)acetate With triethylamine In dichloromethane for 0.166667h;
Stage #2: 4-methoxyphenyl-acetic chloride In dichloromethane at 20℃; for 16.5h;
With triethylamine In dichloromethane at 20℃; for 1h;
2.5.2 Preparation of allenic esters
General procedure: Phosphorus ylide (1.0 equiv, 10 mmol) was dissolved in 100 mL CH2Cl2 in a 250 mL round-bottom flask with a stir bar, then Et3N (1.0 equiv, 10 mmol) was added, to the stirring mixture, a solution of acyl chloride (1.0 equiv, 10 mmol) in 20 mL CH2Cl2 was slowly added at room temperature. After the addition was finished, the reaction mixture was stirred for further 1 h at room temperature, then the solution was concentrated and treated with petroleum ether (80 mL) and EtOAc (20 mL), the solution was stirred for 0.5 h again. Finally, the mixture was filtered and the filtrate was evaporated, the crude residue was purified by column chromatography on silica gel (5% EtOAc/ petroleum ether) to afford the title allenic esters.
4-(4-methoxyphenyl)-N-methyl-N-phenylbuta-2,3-dienamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h;
2,3-Dienamides 1a-v; General Procedure
General procedure: 2,3-Dienamides 1a-v were synthesized by using the procedure re-ported by Himbert et al. 12 A solution of phenylacetyl chloride (371mg, 2.4 mmol) in CH 2 Cl 2 (40 mL) was transferred slowly by cannulainto a solution of the respective phosphonium ylide (2 mmol) and i-Pr 2 NEt (1.03 g, 8 mmol) in CH 2 Cl 2 (20 mL). The mixture was stirred atr.t. for 12 h and quenched with H 2 O (50 mL). The organic layer wasseparated and washed with H 2 O, brine, and dried (Na 2 SO 4 ). After re-moval of the solvent, the orange residue was purified by columnchromatography on silica gel to afford the desired amide 1.
methyl 3-amino-5-(2-(4-methoxyphenyl)acetamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
To a separate oven-dried sample vial equipped with Teflon coated stir bar, 3- amino-5-nitrobenzoate (49 mg, 0.25 mmol), triethylamine (33 mg, 0.33 mmol), CH2C12 (1 mL) were sequentially added. The resulting solution was cooled to 0 C and 2-(4- methoxyphenyl)acetyl chloride (46 mg, 0.25 mmol) was added dropwise to the reaction mixture, then slowly warmed to ft and stirred for 2 h. After the reaction, H20 (1 mL) was added, the organic phase was separated and the volatiles were removed under vacuum. To the residue was transferred iron nanomaterial (12 mg, 0.8%) and 2 wt % TPGS-750-M (1 mL), and stirred at ft for 1 mm. The septum was removed and NaBH4 (21 mg, 0.55 mmol) was slowly added to the reaction mixture. During addition of NaBH4, the reaction mixture turned black with evolution of hydrogen gas. The vial was covered and the contents stirred vigorously for 8 h. The mixture was then extracted with EtOAc (0.3 mL x 2), concentrated in vacuo, and purified by flash chromatography over silica gel with EtOAc/hexanes (15/85 to 30/70) to yield methyl 3-amino-5-(2-(4-methoxyphenyl)acetamido)benzoate 56 (63 mg, 0.2 mmol, 80%) as a colorless oil; Spectral data matched the literature. GC-MS, mlz: 314 [Mj.
With triethylamine In dichloromethane at 0 - 20℃; for 3h;
3.2.1. Synthesis of N-Prop-2-ynylamide (8a-8o)
General procedure: The compounds 8a-8o were all synthesized by the following general procedure. To a solutioncontaining 7a (5 g, 40.94 mmol) and DMF (0.05 mL, 0.65 mmol) dissolved in dichloromethane (100 mL)was added a solution of oxalyl chloride (3.8 mL, 45.03 mmol) dissolved in dichloromethane (10 mL)dropwise at 0 °C. After stirring the reaction mixture at r.t. for 3 h, the solution was concentrated underreduced pressure to give the corresponding acyl chloride. To a solution composed of propargylamine(3.1 mL, 45.03 mmol) and triethylamine (8.5 mL, 61.41 mmol) dissolved in dichloromethane (100 mL)was added dropwise at 0 ° C a solution of the corresponding acyl chloride previously dissolved indichloromethane (30 mL). After stirring at r.t. for 3 h, the mixture was washed with a solution ofdiluted hydrochloric acid (1 M, 100 mL) followed by an extraction with dichloromethane (3 100 mL).The combined organic layers were then dried over anhydrous sodium sulfate and then concentratedunder reduced pressure to afford the crude product 8a. The residue was then crystallized with amixture of ethyl acetate/petroleum ether to afford the pure product 8a. The spectral data for thecompounds 8a-8o are given in the Supporting-Information.
1-(3,4-bis(4-methoxyphenyl)-1H-pyrrol-1-yl)-2-(4-methoxyphenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: 3,4-bis (4-methoxyphenyl)-1H-pyrrole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 4-methoxyphenyl-acetic chloride In tetrahydrofuran at -78℃; for 1h;
3 (3,4-bis (4-methoxyphenyl) pyrrole-1) 2- (4-methoxyphenyl) ethanone
To a nitrogen-protected two-necked flask was added 0.28 g of 3,4-bis (4-methoxyphenyl) -1H-pyrrole (1 mmol)Absolute anhydrous THF (5 mL),A solution of 0.5 mL of n-butyllithium (1.2 mmol, 2 M) in n-hexane was slowly added at -78 ° C,After the drop reaction is completed for half an hour,A solution of the above-prepared methyl methoxyacetyl chloride (1.5 mmol) in THF (5 mL) was slowly added dropwise,After completion of the dropwise addition, the reaction was carried out at -78 ° C for one hour, and the temperature was gradually raised to room temperature,After TLC detection, the reaction was quenched by adding water to the reaction system, extracted three times with ethyl acetate,Organic phase and water washed 3 times, saturated sodium chloride solution washed once, anhydrous magnesium sulfate dry, filtered, evaporated solvent,The crude product was separated by column (petroleum ether: dichloromethane: ethyl acetate = 10: 10: 1)0.21 g of a white powdery solid, 50.0% yield
N-[4-fluoro-5-[1-[(4-methoxyphenyl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[rac-(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide[ No CAS ]
[ 4693-91-8 ]
N-[4-fluoro-5-[1-[2-(4-methoxyphenyl)acetyl]-3,6-dihydro-2H-pyridin-4-yl]-2-[rac-(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.333333h;
208 N-[4-fluoro-5-[l-[2-(4-methoxyphenyl)acetyl]-3, 6-dihydro-2H-pyridin-4-yl]-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH- pyridine-3-carboxamide
To N-(4-fluoro-5-(l,2,3,6-tetrahydropyridin-4-yl)-2-((3S,5R)-3,4,5- trimethylpiperazin- 1 -yl)phenyl)-6-oxo-4-(trifluoromethyl)- 1 ,6-dihydropyridine-3- carboxamide (30 mg, 0.059 mmol obtained from Example 148) and N,N- diisopropylethylamine (0.021 ml, 0.118 mmol) in DCM (3 ml) at RT was added 4- methoxy phenyl acetyl chloride (9.75 μ, 0.065 mmol). The milky reaction mixture became a clear solution. It was stirred at RT. Complete disappearance of the starting material and formation of the desired product was observed after 20 min at rt. The reaction was worked up at this point and purified using standard methods to give the title compound (31.5 mg, 77% yield). 11H NMR (500MHz, METHANOL-d4) δ = 7.89 - 7.77 (m, 1H), 7.66 - 7.55 (m, 1H), 7.15 - 7.01 (m, 2H), 6.88 - 6.75 (m, 4H), 5.96 - 5.75 (m, 1H), 4.19 - 4.09 (m, 2H), 3.72 - 3.59 (m, 7H), 2.97 - 2.85 (m, 2H), 2.54 - 2.39 (m, 5H), 2.30 - 2.23 (m, 4H), 1.09 - 1.03 (m, 6H); LCMS [M+H]+ 656.6.
4-(4-aminobenzyl)-5-(dibromomethylene)furan-2(5H)-one[ No CAS ]
[ 4693-91-8 ]
N-(4-((2-(dibromomethylene)-5-oxo-2,5-dihydrofuran-3-yl)methyl)phenyl)-2-(4-methoxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With pyridine In dichloromethane at 0 - 20℃;
General Procedures for Synthesis of 1a-1m and 2a-2m
General procedure: The acyl chloride (0.22mmol) was added dropwise to a mixture of 6 (or 7) (0.2mmol) and dry pyridine (0.24mmol) in DCM at 0°C. The solution was stirred at room temperature overnight, then saturated NH4Cl solution (10mL) was added to the final mixture, then extracted with EtOAc (3×15mL). Afer the combined organic phase was washed and dried, the solvent was removed. The crude product was chromatographed on a silica gel column using DCM/EtOAc (10:1).
(Z)-4-(4-aminobenzyl)-5-(bromomethylene)furan-2(5H)-one[ No CAS ]
[ 4693-91-8 ]
(Z)-N-(4-((2-(bromomethylene)-5-oxo-2,5-dihydrofuran-3-yl)methyl)phenyl)-2-(4-methoxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With pyridine In dichloromethane at 0 - 20℃;
General Procedures for Synthesis of 1a-1m and 2a-2m
General procedure: The acyl chloride (0.22mmol) was added dropwise to a mixture of 6 (or 7) (0.2mmol) and dry pyridine (0.24mmol) in DCM at 0°C. The solution was stirred at room temperature overnight, then saturated NH4Cl solution (10mL) was added to the final mixture, then extracted with EtOAc (3×15mL). Afer the combined organic phase was washed and dried, the solvent was removed. The crude product was chromatographed on a silica gel column using DCM/EtOAc (10:1).
N-(2-(9H-carbazol-1-yl)phenyl)-2-(4-methoxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With pyridine In dichloromethane at 20℃; for 16h; Inert atmosphere;
General Procedure A: Sulfonamide/carboxamide synthesis
General procedure: To a stirred solution of 2-(9H-carbazol-1-yl)aniline (1 eq) in CH2Cl2 (0.1 M, anhydrous) was added pyridine (1.3 eq) followed by sulfonyl chloride or acid chloride (1.1 eq) and the solution was allowed to stir at room temperature under a nitrogen atmsophere. Upon reaction completion the crude mixture was concentrated onto silica gel and purified by Isolera Biotage LPLC (CH/EA 8:2) to afford pure sulfonamide/amide.
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h;
General procedure: To a solution of methyl piperidinecarboxylate hydrochloride 2 (0.02 mol) in methylene chloride (20 ml) was added in a dried round-bottom flask, to which triethylamine (0.05 mol) and solution of phenylacetyl chloride in methylene chloride (0.024 mol) was added dropwise separately in an ice bath for over 20 min, next the cold bath was removed. The reaction was stirred at room temperature for 12 h, and TLC traced the reaction to completion. After the completion of the reaction, the solution was dissolved in water (20 ml), and the aqueous solution was extracted with methylene chloride (30 ml × 2) twice. The combined organic phases were washed with 5% Na2CO3 solution (30 ml × 2) and water to neutrality and dried over anhydrous Na2SO4. After filtration and concentration, the corresponding compound 5 were received through the above methods.
tert-butyl N-(5-aminopyrazine-2-carbonyl)-N-(4-(5-(4’-ethyl-[1,1’-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)benzyl)glycinate[ No CAS ]
[ 4693-91-8 ]
tert-butyl N-(4-(5-(4’-ethyl-[1,1‘-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)benzyl)-N-(5-(2-(4-methoxyphenyl)acetamido)pyrazine-2-carbonyl)glycinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
Stage #1: tert-butyl N-(5-aminopyrazine-2-carbonyl)-N-(4-(5-(4’-ethyl-[1,1’-bi(cyclohexan)]-3-en-4-yl)pyrimidin-2-yl)benzyl)glycinate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h;
Stage #2: 4-methoxyphenyl-acetic chloride In tetrahydrofuran; mineral oil at 0 - 20℃; for 18h;
Tert-butyl N-(4-(5-(( 1 ‘r,4’r)-4’-ethyl-[ 1.1 ‘-bi(cyclohexan)1-3 -en-4-yl)pyrimidin-2- yl)benzyl)-N-(5 -(2-(4-methoxyphenyl)acetamido)pyrazine-2-carbonyl)glycinate
To a solution of tert-butyl N-(5 -aminopyrazine-2-carbonyl)-N-(4-(5-((1 ‘r,4’r)-4’-ethyl-[ 1,1 ‘-bi(cyclohexan)] -3 -en-4-yl)pyrimidin-2-yl)benzyl)glycinate(600.0 mg, 0.98 mmol) in anhydrous THF (20 mL) was added sodium hydride (47.04mg, 1.96 mmol, 60% dispersion in mineral oil). The reaction mixture stirred at 0 °C for2 h and then at RT for 1 h. The 2-(4-methoxyphenyl)acetyl chloride (542.78 mg, 2.94mmol) was added to above solution at 0 °C and the reaction mixture was allowed to warm to RT. The mixture stirred was stirred for 18 h. After evaporated THF solvent, the reaction mixture was diluted with EA then washed with saturated aqueous NaHCO3 and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by chromatography (EA / hexanes from 0 to 70%) to provide 350 mg (47%) oftert-butyl N-(4-(5 -((1 ‘r,4’r)-4’-ethyl-[ 1,1 ‘-bi(cyclohexan)] -3 -en-4-yl)pyrimidin-2- yl)benzyl)-N-(5 -(2-(4-methoxy-phenyl)acetamido)pyrazine-2-carbonyl)glycinate.LCMS-ESI (m/z) calculated for C45H54N605: 758.9; found 759.3 [M+H], tR = 5.053 minutes (Method 2).
1.1-3.1
Another 500 ml reactor was charged with 25.1 g of p-hydroxyphenylglycine, and 135 g of water was added thereto, and the temperature was lowered to 0 ° C under stirring conditions, while sodium hydroxide (14.6 g, dissolved in 20 ml of water) solution and the above-obtained 31.2 g p-methoxyphenyl acetyl chloride 31.2g (purity 96%) were added dropwise, temperature was controlled to 0~ 5 ° C, the PH value was controlled to 9 ~ 11 during addition. After addition, the resulting mixture was reacted at 5 ° C for 2h, filtered, solid was added to excess alkali, the filtrate was combined, the temperature of the filtrate was lowered to 0 to 5 ° C, and hydrochloric acid was added dropwise to the filtrate under stirring. The temperature was controlled to be 0 to 5 ° C during the dropwise addition, and dropping of hydrochloric acid was was stopped when the pH of the system was 3 to 4. The mixture was stirred for 0.5 hour, and then filtered to obtain a step product of 37.1 g, a liquid phase purity of 94.9%, and a yield of 74.2%. The total yield in two steps was 62.6%.
(3,4-bis(4-methoxyphenyl)-1H-pyrrol-1-yl)(3-methoxyphenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: 3,4-bis (4-methoxyphenyl)-1H-pyrrole With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 4-methoxyphenyl-acetic chloride In tetrahydrofuran at -78 - 20℃; for 2h; Inert atmosphere;
Method B:
General procedure: Under a nitrogen atmosphere, n-butyllithium (1.6 M, 1.2 or 1.3equiv) was added dropwise at -78into a solution 3,4-diarylpyrrole8aor8b(1equiv) in anhydrous THF. After stirring for 30 min, the acid chloride materials (1.5 or 5equiv, dissolved in anhydrous THF) was added dropwise at -78°C, transferred to room temperature and reacted for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate or dichloromethane. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to give the desired products2d, 2e, 2g, 2i, 2j.
2,3,10-trimethoxy-9-p-methoxyphenylacetoxylprotopalmatine chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
Stage #1: Palmatrubine hydrochloride With triethylamine In acetonitrile for 0.166667h;
Stage #2: 4-methoxyphenyl-acetic chloride In acetonitrile at 65℃;
General procedure: Triethylamine (1.80 mmol) was added to a stirred solution of 3 (100 mg, 0.40 mmol) inanhydrous CH3CN (6 mL) first, 10 min. later, corresponding acyl chloride (1.2 mmol) or sulfonylchloride (1.2 mmol) were added in the reaction system. The reaction mixture was heated at 65 °Cfor 3-8 h. The system was cooled, filtered, and the resulting residue was purified by flashchromatography using CH2Cl2/CH3OH as the gradient eluent, to acquire desired compounds.
General procedure: Oxalyl chloride (1.65 equiv) was added to a solution of arylacetic acid (1.5 equiv), dimethylformamide (10 ml), anddichloromethane (2.0 M) at 0 C. After 10 min, the solution was warmed to 23 C and stirred for 1 h (bubbling stops). Thesolution was concentrated in vacuo. In a separate flask, n-butyllithium (1.1 equiv, 2.42 M in hexanes) was added to asolution of <strong>[168297-85-6](S)-4-benzyl-5,5-dimethyloxazolidin-2-one</strong> (1.0 equiv) in THF (0.3 M) at -78 C under argon. The solution wasstirred for 30 min at -78 C. A solution of the crude acyl chloride in THF was added dropwise at -78 C. After stirring at -78 C for 2 h, the reaction mixture was quenched with saturated ammonium chloride. The aqueous layer was extractedwith ethyl acetate (3 x 20 ml). The combined organic layers were washed with brine, dried with sodium sulfate andconcentrated in vacuo.
4-(3-phenylureido)phenyl 2-(4-methoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.73%
With triethylamine In tetrahydrofuran Reflux;
4.2.5 General procedures for the synthesis of the target compounds (13a-b), (14a-l) and (15a-b)
General procedure: To a stirred solution of compounds 8a-g and 10 (1mmol) and Et3N (1mmol, 0.1) in tetrahydrofuran (THF) (20ml) at reflux temperature, were added substituted acyl chlorides (1mmol) 5, 11a-f and 12. Then the reaction was continued at room temperature and monitored by TLC (n-Hex: EA=7:3) [42]. After completion of the reaction, the precipitates were filtered and recrystallized from ethanol to obtain the desired target compounds 13a-b, 14a-l and 15a-b respectively.
(4bR,8aS,9S)‐3,7‐dimethoxy‐11‐methyl‐6‐oxo‐1‐(piperidin‐1‐ylmethyl)‐6,8a,9,10‐tetrahydro‐5H‐9,4b‐(epiminoethano)phenanthren‐4‐yl 2‐(4‐methoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
3.1.1. General Procedure for the Synthesis of Compounds 5a-5k
General procedure: To a mixture of 1-(1-pyrrolidinylmethyl)-Sinomenine or 1-(1-piperidinylmethyl)-Sinomenine(1.0 mmol) and Et3N (2.5 mmol) in CH2Cl2 (5 mL) was added acyl chloride (2.5mmol) at 0 °C. The reaction mixture was then stirred at room temperature. After the completionof the reaction, sat. NaHCO3 was added and then extracted with CH2Cl2. The organiclayers were combined and dried with anhydrous Na2SO4 and evaporated under reducedpressure. The mixture was evaporated under vacuum, and the residue was purifiedby flash chromatography with dichloromethane and methanol as the eluents to producethe pure product.
(4bR,8aS,9S)‐3,7‐dimethoxy‐11‐methyl‐6‐oxo‐1‐(pyrrolidin‐1‐ylmethyl)‐6,8a,9,10‐tetrahydro‐5H‐9,4b‐(epiminoethano)phenanthren‐4‐yl 2‐(4‐methoxyphenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
3.1.2. General Procedure for the Synthesis of Compounds 6a-6l
General procedure: To a mixture of 1-(1-pyrrolidinylmethyl)-Sinomenine or 1-(1-piperidinylmethyl)-Sinomenine(1.0 mmol) and Et3N (2.5 mmol) in CH2Cl2 (5 mL) was added acyl chloride (2.5mmol) at 0 °C. The reaction mixture was then stirred at room temperature. After completionof the reaction, sat. NaHCO3 was added and then extracted with CH2Cl2. The organiclayers were combined and dried with anhydrous Na2SO4 and evaporated under reducedpressure. The mixture was evaporated under vacuum, and the residue was purified byflash chromatography with dichloromethane and methanol as the eluent to give the pureproduct.
With pyridine In acetone at 0 - 20℃; for 18h; Inert atmosphere;
N-formyl-2-(4-methoxyphenyl) acetamide (4):
To a Stirred solution of 2-(4-methoxyphenyl) acetic acid (1.5 g,9.036 mmol) in oxalyl chloride (10 vol) at reflux temperature for5 h. The reaction mixture was concentrated under vacuum in inertatmosphere to obtain crude compound of (4-methoxyphenyl)acetyl chloride (5) was used for the next step without purification.The crude compound was diluted in acetone (3 ml, 2 volumes)under argon atmosphere and added the mixture of pyridine(610.0 mg, 13.55 mmol) and formamide (1.07 g, 13.55 mmol) inacetone (3 ml) drop wise at 0 C. The reaction mixture was allowingto room temperature and stirred for 18 h. The reaction mixturewas concentrated under vacuum at room temperature. The mixturewas diluted in ethyl acetate and washed with 1 N aqueousHCl, sat NaHCO3, water, brine, dried over anhydrous Na2SO4 andconcentrated under vacuum, crude compound was obtained. Thecrude compound was titrated with diethyl ether the solid productwas filtered and dried under vacuum to obtain N-formyl-2-(4-methoxyphenyl) acetamide (4) (1.22 g, 70%) as Light-yellow solid.Purification crude product via titrated with diethyl ether thesolid product was filtered and dried under vacuum to obtain lightyellow solid, 70% yield. MP = 118-121 C; FT-IR (KBr): mmax = 3005,2954, 2836, 1726, 1512, 1387, 1271, 1254, 1177, 1030, 751.; 1HNMR (400 MHz, DMSO): d 11.26 (d, J = 9.4 Hz, 1H), 8.96 (d,J = 9.5 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H),3.71 (s, 3H), 3.57 (s, 2H).; 13C NMR (101 MHz, DMSO d6): d173.15, 163.84, 158.70, 130.91, 126.30, 114.26, 55.48, 41.73.;LCMS: m/z 194.2 [M + H]: 211.2 [M + H2O].
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