* 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 water; potassium hydroxide In ethanol for 18 h; Reflux
Potassium hydroxide (10.7g, 192mmol) was added to a solution of /V-(2-Chloro-3,5- dimethoxy-phenyl)-acetamide (intermediate 33) (8.8g, 38.3mmol) in EtOH (500ml_) and water (50ml_) and the reaction mixture heated to reflux for 18 hours. Upon cooling, water was added (ca 30ml_) and the EtOH removed in vacuum. The residue was then partitioned between water and diethyl ether. The organic layer was separated, dried (MgS04), filtered and concentrated to afford 7g (97percent) of intermediate 34 ( white solid).
82%
With potassium hydroxide In ethanol; water for 12 h; Reflux
c. 2-chloro~3f5-dimethoxy aniline Potassium hydroxide (2.19g} 39.18 mmol) was added to a solution of N-(2-chloro-3}5- dimethoxyphenyl)acetamide (1.8g, 7.837 mmol) in EtOH (lOOmL) and water (lOmL) and the reaction mixture heated to reflux for 12h. Excess EtOH was removed under reduced pressure to obtain a residue. The residue was then partitioned between water and diethyl ether. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.2g, 82percent of yield) as a white solid. 1HNMR (CDC13, 300MHz): δ 5.97 (s, 2H)S 4.08 (brs, 2H), 3,84 (s, 3H), 3.75 (s, 3H); MS (ESI): 188.1 [M+H .
1.00 g
With potassium hydroxide In ethanol; water at 95℃; for 16 h;
Step 3: Intermediate 4[00521j To a 125 mL sealed flask was added Intermediate 3 (1.90 g, 8.27 mmol) in EtOH(50 mL, 856 mmol) followed by potassium hydroxide (2.32 g, 41.4 mmol) in 10 mL of water.The reaction was allowed to stir at 95 °C for 16 h after which it was cooled and concentrated.The resultant oil was partitioned between water and EtOAc, the organic layer was dried overMg504, filtered and concentrated to provide 1.00 g of the title compound MS mlz: 188.1(M+H).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7066 - 7083
[2] Patent: WO2011/135376, 2011, A1, . Location in patent: Page/Page column 212
[3] Patent: WO2015/57938, 2015, A1, . Location in patent: Page/Page column 89-90
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2777 - 2779
[5] Patent: WO2014/144737, 2014, A1, . Location in patent: Paragraph 00521
Step 3 33.0 g of N-Acetoxy-2-chloro-3,5-dimethoxyaniline were dissolved in 2 l of ethanol and refluxed with 400 ml of potassium hydroxide. After 2 h 500 ml water were added and the ethanol was evaporated under reduced pressure. The aqueous phase was then extracted with 2*250 ml of ether. The ethereal phase was dried over magnesium sulfate and concentrated. 28 g of 2-chloro-3,5-dimethoxy-aniline were obtained
With potassium hydroxide; In of ethanol; water;
Step 3 33,0 g of N-Acetoxy-2-chloro-3,5-dimethoxyaniline were dissolved in 2 I of ethanol and refluxed with 400 ml of potassium hydroxide. After 2 h 500 ml water were added and the ethanol was evaporated under reduced pressure. The aqueous phase was then extracted with 2x250 ml of ether. The ethereal phase was dried over magnesium sulfate and concentrated. 28 g of 2-chloro-3,5-dimethoxy-aniline were obtained
(2-chloro-3,5-dimethoxy-phenyl)-thiourea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; ammonium chloride; In ethanol; water; acetone;
Step 4 14.4 g of potassium isocyanate were dissolved at 10 C. in 450 ml of acetone. 14.2 ml of benzoylchloride were added dropwise carefully. The white suspension was refluxed 10 minutes and then cooled again to 10 C. A solution of 28 g of <strong>[120758-03-4]2-chloro-3,5-dimethoxyaniline</strong> in 300 ml of acetone was then added and the obtained mixture refluxed over 3 h. 700 ml of water with ice were added and the aqueous phase was extracted with 3*600 ml of ethyl acetate. The organic phase was then dried over magnesium sulfate and concentrated. The brown residue was dissolved in 100 ml ethanol and refluxed together with 35 ml of an aqueous solution of potassium hydroxide. After 1 hour, 500 ml of water were added. Ethanol was distilled under reduced pressure. The brown solution was neutralized with 300 ml of an ammonium chloride solution and the solid which precipitated was filtered, washed with water and dried. 35 g of (2-chloro-3,5-dimethoxy-phenyl)-thiourea were obtained as a brown powder, m.p. 159-162 C.
With potassium hydroxide; ammonium chloride; In of'acetone; ethanol; water; acetone;
Step 4 14.4 g of potassium isocyanate were dissolved at 10ØC in 450 ml of'acetone. 14.2 ml of benzoylchloride were added dropwise carefully. The white suspension was refluxed 10 minutes and then cooled again to 10ØC. A solution of 28 g of <strong>[120758-03-4]2-chloro-3,5-dimethoxyaniline</strong> in 300 m! of acetone was then added and the obtained mixture refluxed over 3 h. 700 ml of water with ice were added and the aqueous phase was extracted with 3x600 ml of ethyl acetate. The organic phase was then dried over magnesium sulfate and concentrated. The brown residue was dissolved in 100 ml ethanol and refluxed together with 35 ml of an aqueous solution of potassium hydroxide. After 1 hour, 500 ml of water were added. Ethanol was distilled under reduced pressure. The brown solution was neutralized with 300 ml of an ammonium chloride solution and the solid which precipitated was filtered, washed with water and dried. 35 g of (2-chloro-3,5-dimethoxy-phenyl)-thiourea were obtained as a brown powder, m.p. 159-162ØC
2,6-dimethyl-1-phenyl-1,3,5-octanetrione[ No CAS ]
[ 120758-03-4 ]
1-(2-chloro-3,5-dimethoxyphenyl)-6-sec-butyl-3-methyl-2-phenyl-4(1H)-pyridinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; toluene-4-sulfonic acid; sodium sulfate; In 5,5-dimethyl-1,3-cyclohexadiene; chloroform;
Example 10 Synthesis of 1-(2-chloro-3,5-dimethoxyphenyl)-6-sec-butyl-3-methyl-2-phenyl-4(1H)-pyridinone (Compound 131) To 500 ml of xylene were added 5.2 g of 2,6-dimethyl-1-phenyl-1,3,5-octanetrione, 5.2 g of <strong>[120758-03-4]2-chloro-3,5-dimethoxyaniline</strong> and 5.7 g of p-toluenesulfonic acid, followed by reflux the reaction mixture with a Dean-Stark trap for 1 hour. After cooling, the reaction mixture was poured into water, followed by addition of 200 ml of chloroform. After extraction with chloroform, the organic layer was washed first with a 10% aqueous solution of sodium sulfate and then with 10% hydrochloric acid. After washing the solution in chloroform further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel (eluent: 1:1 mixed solvent of n-hexane and chloroform). The resulting crystals were recrystallized from acetone, thereby affording 2.3 g of 1-(2-chloro-3,5-dimethoxyphenyl)-6-sec-butyl-3-methyl-2-phenyl-4(1H)-pyridinone having a melting point of 220-221 C.
1-cyclohexyl-5-cyclopentyl-2-methyl-1,3,5-pentanetrione[ No CAS ]
[ 120758-03-4 ]
1-(2-chloro-3,5-dimethoxyphenyl)-2-cyclohexyl-6-cyclopentyl-3-methyl-4(1H)-pyridinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide;titanium tetrachloride; In chlorobenzene;
Example 14 Synthesis of 1-(2-chloro-3,5-dimethoxyphenyl)-2-cyclohexyl-6-cyclopentyl-3-methyl-4(1H)-pyridinone (Compound 81) In 150 ml of chlorobenzene were dissolved 4.5 g of 1-cyclohexyl-5-cyclopentyl-2-methyl-1,3,5-pentanetrione and 6.0 g of <strong>[120758-03-4]2-chloro-3,5-dimethoxyaniline</strong>. To the mixture was added 2.0 g of titanium tetrachloride, followed by refluxing for 4 hours. The chlorobenzene of the reaction mixture was distilled off and the residue was extracted with 150 ml of chloroform. The organic layer was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. After washing the organic layer with water, it was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography on silica gel (eluent: chloroform). The resulting crystals were recrystallized from ethyl acetate, affording 0.6 g of 1-(2-chloro-3,5-dimethoxyphenyl)-2-cyclohexyl-6-cyclopentyl-3-methyl-4(1H)-pyridinone having a melting point of 230-231 C.
{5-[(2-Chloro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7.36 g (93%)
With concentrated sulfuric acid; In toluene;
EXAMPLE 61 {5-[(2-Chloro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-ethyl-amine Into a solution of 3.78 g (20.2 mmol) of <strong>[120758-03-4]2-chloro-3,5-dimethoxy-phenylamine</strong> in 110 mL of toluene was added 3.97 g (20.15 mmol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde. The reaction vessel was equipped with a Dean-Stark trap, and the reaction was warmed to reflux. After 3 hours, two drops of concentrated sulfuric acid were added to the reaction. The reaction was refluxed overnight then concentrated in vacuo to give 7.36 g (93%) of the title compound, which was used as is in the following example: mp 196.5-198.5 C. MS (APCI) (m+1)/z 367.0.
With sodium hydrogencarbonate; trifluoroacetic acid;
PREPARATION 13 2-Chloro-3,5-dimethoxy-phenylamine To 6.01 g (0.021 mmol) of (2-chloro-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester was added 15 mL of trifluoroacetic acid. The reaction was stirred for 3 hours at room temperature, then concentrated in vacuo. The residue was made basic with a saturated solution of sodium bicarbonate, then extracted three times with dichloromethane. The combined dichloromethane layers were dried with magnesium sulfate and concentrated in vacuo to give 3.98 g of the title compound, which was used as is in the following example. MS (APCI) (m+1)/z 188.
With water; potassium hydroxide; In ethanol; for 18h;Reflux;
Potassium hydroxide (10.7g, 192mmol) was added to a solution of /V-(2-Chloro-3,5- dimethoxy-phenyl)-acetamide (intermediate 33) (8.8g, 38.3mmol) in EtOH (500ml_) and water (50ml_) and the reaction mixture heated to reflux for 18 hours. Upon cooling, water was added (ca 30ml_) and the EtOH removed in vacuum. The residue was then partitioned between water and diethyl ether. The organic layer was separated, dried (MgS04), filtered and concentrated to afford 7g (97%) of intermediate 34 ( white solid).
82%
With potassium hydroxide; In ethanol; water; for 12h;Reflux;
c. 2-chloro~3f5-dimethoxy aniline Potassium hydroxide (2.19g} 39.18 mmol) was added to a solution of N-(2-chloro-3}5- dimethoxyphenyl)acetamide (1.8g, 7.837 mmol) in EtOH (lOOmL) and water (lOmL) and the reaction mixture heated to reflux for 12h. Excess EtOH was removed under reduced pressure to obtain a residue. The residue was then partitioned between water and diethyl ether. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.2g, 82% of yield) as a white solid. 1HNMR (CDC13, 300MHz): delta 5.97 (s, 2H)S 4.08 (brs, 2H), 3,84 (s, 3H), 3.75 (s, 3H); MS (ESI): 188.1 [M+H .
1.00 g
With potassium hydroxide; In ethanol; water; at 95℃; for 16h;
Step 3: Intermediate 4[00521j To a 125 mL sealed flask was added Intermediate 3 (1.90 g, 8.27 mmol) in EtOH(50 mL, 856 mmol) followed by potassium hydroxide (2.32 g, 41.4 mmol) in 10 mL of water.The reaction was allowed to stir at 95 C for 16 h after which it was cooled and concentrated.The resultant oil was partitioned between water and EtOAc, the organic layer was dried overMg504, filtered and concentrated to provide 1.00 g of the title compound MS mlz: 188.1(M+H).
A mixture of 1-(2,4,6-trifluorophenyl)-1-propanone (7.0 g, 37.2 mmol), <strong>[120758-03-4]2-chloro-3,5-dimethoxybenzenamine</strong> (see European Patent 1333028 for a method of preparation) (6.96 g, 37.1 mmol) and p-toluenesulfonic acid (1.41 g, 8.2 mmol) in toluene (80 mL) was heated at reflux with use of a Dean-Stark trap to remove water. After 20 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water, sulfuric acid (1 N), water and saturated aqueous sodium chloride solution. The organic layer was dried (Na2SO4), filtered and concentrated to provide the title compound (10 g) which was used without further purification in Step C below.
With N-chloro-succinimide; acetic acid; at 0 - 20℃; for 0.5h;
2-Chloro-5 -iodobenzene- 1,3 -dio 1 was synthesised in 3 steps from 3,5 -dimethoxyanilineaccording to WO 2011/027106 Al, with a modification to the first step to prepare 4- chloro-3,5-dimethoxyaniline in which the reagent Nchlorosuccinimide was added portion wise as a suspension in acetic acid (50 mL) to a solution of 3,5-dimethoxyaniline (10.01 g, 65.35 mmol) in acetic acid (50 mL) at 0C and warmed to room temperature after 30 mm.
Step 4: Synthesis of Intermediate 5 [00522j Into a sealed vessel was added Intermediate 4 (1.50 g, 8.00 mmol) in DMA (5 mL, 53.3 mmol), followed by DIPEA (820 tl, 8.80 mmol). The reaction mixture was allowed to stir for 10 mm. at ambient temperature, and 2,4-dichloro-5-(iodomethyl)pyrimidine from Example 1 (2.31 g, 8.00 mmol) was added. The reaction mixture was allowed to stir at 60 °C for 7.5 h, then 16 h at ambient temperature. The reaction mixture was concentrated and azeotroped several times with toluene. EtOAc was added and the organic layer washed with brine (3 x). The organic layers were dried with sodium sulfate, concentrated and purified by flash column chromatography (eluting with 5-25percent EtOAc in heptane) to give 1.75 g of the title compound MS mlz: 348.2 (M+H).
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