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Fumaric acid a reversible inhibitor of tyrosinase.
Synonyms: 2-Butenedioic acid; Trans-Butenedioic acid; Tumaric acid
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CAS No. : | 110-17-8 |
Formula : | C4H4O4 |
M.W : | 116.07 |
SMILES Code : | O=C(O)/C=C/C(O)=O |
Synonyms : |
2-Butenedioic acid; Trans-Butenedioic acid; Tumaric acid
|
MDL No. : | MFCD00002700 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H319 |
Precautionary Statements: | P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; dichloromethane; ethyl acetate; for 0.166667h;Heating / reflux; | E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin- 6-YL}-ALLYL)-ACETAMIDE (2 grams), prepared according to the method of Example 1,2 or 3 was dissolved in a refluxing 16: 1 (V/V) mixture of ethyl acetate (160 mL)/dichloromethane (10 mL). A solution of fumaric acid was prepared by dissolving 2 equivalents (1 gram) of fumaric acid in hot ethanol (12 mL). This acid solution was added hot to the refluxing free base solution. The resulting mixture was stirred and refluxed for approximately ten minutes, and then cooled to room temperature. Hexane (-100 mL) was added until the reaction mixture turned cloudy. The mixture was then ultrasonicated until crystals were noted. The reaction mixture was heated to approximately 70C and stirred overnight to produce a slurry. The solids were then collected via cold filtration to give the product. The fumarate was a monofumarate HEMIPENTAHYDRATE (2.5 H2O) as determined by elemental analysis. |
Yield | Reaction Conditions | Operation in experiment |
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Pd-C; In methanol; methanolic ammonia; ethanol; 2-methyl-propan-1-ol; chloroform; | Example 15 (5R),(8S)-2-(5,6,7,8-Tetrahydro-8-isopropyl-5-methyl-quinolin-3-yl)amino-2-imidazoline (5R), (8S)-3-Amino-5,6,7,8-tetrahydro-8-isopropyl-5-methylquinoline. (-)-Menthone (390 mg, 2.53 mm(1) was mixed with 1-methyl-3,5-dinitro-2-pyridone (500 mg, 2.51 mmol) in 1M methanolic ammonia (50 mL, 50 mmol) and heated at reflux overnight. The solvent was evaporated off and the residue was dissolved in CHCl3 and flash chromatographed over silica gel (37 g) eluding with EtOAc/hexane (1:20) to afford a colorless oil (248 mg, 1.06 mmol). It was dissolved in MeOH (5 mL), treated with 10% Pd-C (27 mg) and hydrogenated at 1 atm for 2 h. Filtration through Celite gave a pale yellow solid (207 mg). It was partitioned between CH2 Cl2 and 2N HCl. The organic layer was further extracted with 2N HCl before the aqueous layer was basined with Na2 CO3 solution and extracted with CH2 Cl2 to afford a white solid (123 mg, 24% yield). (5R), (8S)-2-(5,6,7,8-Tetrahydro-8-isopropy-5-methyl-quinolin-3-yl)amino-2-imidazoline. The above amine (119 mg, 0.58 mmol) was mixed with 2-imidazolinesulfonic acid (180 mg, 1.20 mmol) in isobutyl alcohol (5 mL) aid heated at reflux for 2 days. The solvent was evaporated off to give a residue which was dissolved in CHCl3 and flash chromatographed over silica gel (17 g) eluding with EtOAc/MeOH/Et3 N (20:3:1) to afford a white solid (129 mg, 81% yield). It was dissolved in EtOH and reated with fumaric acid (110 mg) in EtOH. Upon addition of ether and refrigeration, the solution gave white crystals (43 mg): mp 151-154 C. Anal. Calcd. for C16 H24 N4.1.6C4 H4 O4: C, 58.73; H, 6.69; N, 12.23. Found: C, 58.41; H, 7.04; N, 12.24. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid; triethylamine; In ethanol; | EXAMPLE 14 1-(2,3-dihydro[1,4]benzoxathiin-5-yl)-4-(indan-2-ylamino)piperidine and its hemifumarate 0.17 g (1 mmol) of <strong>[2338-18-3]indan-2-ylamine hydrochloride</strong> is introduced into 7 ml of 1,2-dichloroethane and then, in order, 0.14 ml (1.5 mmol) of triethylamine, 0.25 g of 1-(2,3-dihydro[1,4]benzoxathiin-5-yl)piperid-4-one (Preparation 4), 0.32 g (1.5 mmol) of sodium triacetoxyborohydride and 58 mul (1 mmol) of acetic acid are added. The whole is stirred for 20 hours at room temperature and then poured into 10 ml of 1N sodium hydroxide solution and extracted twice with 25 ml of ether each time. The combined organic phases are washed and dried. Evaporation yields 0.36 g of the title product, which is converted into the hemifumarate by the action of a 2% solution of fumaric acid in ethanol. In that manner, 0.27 g of hemifumarate is obtained. M.p. (MK)=220-223 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethanol; hexane; ethyl acetate; | EXAMPLE 22 3-[[4-(2-Phenylethyl)amino]-1-cyclohexen-1-yl]-<strong>[23690-49-5]1H-indole-5-acetonitrile</strong> <strong>[23690-49-5]1H-indole-5-acetonitrile</strong>1 (0.25 g, 0.0016 mol), 4-[(2-phenylethyl)amino]cyclohexanone (0.522 g, 0.0024 mol) and pyrrolidine (0.5 mL) were dissolved in EtOH (80 mL) and refluxed for 24 h. A TLC (silica gel, 50% EtOAc in Hexane) showed that the reaction was not occurring, thus, the solvent volume was reduced in vacuo to a final volume of 5 mL. An additional equivalent of 4-[(2-phenylethyl)amino]cyclohexanone (0.0024 mol) and pyrrolidine (2 mL) was added. The reaction was heated at reflux for 4 h. The solvent was removed in vacuo. Silica gel chromatography (95:5:0.5 CH2 Cl2 -MeOHNH4 OH) of the residue yielded the product (0.275 g, 35%). The viscous yellow oil was dissolved in EtOAc and treated with fumaric acid in MeOH to afford the fumarate salt (0.132 g, 40%): mp 238-242 C. Anal. Calcd for C24 H25 N3.0.6 C 4 H4 O4: C 74.59; H 6.50; N 9.88. Found: C 74.66; H 6.61; N 9.80. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium cyanoborohydride; In methanol; water; acetic acid; acetonitrile; | EXAMPLE 12 5-Phenyl-3-(N-pyrrolidinomethyl)pyridine <strong>[113118-84-6]5-Phenyl-3-pyridinecarboxaldehyde</strong> (400 mg, 2.18 mmol) and pyrrolidine (300 mg, 4.39 mmol) were dissolved in acetonitrile (20 mL) with stirring. The reaction mixture was chilled (0 C.), sodium cyanoborohydride (30 mg, 4.4 mmol) was added and the mixture stirred at 0 C. for 30 minutes. Glacial acetic acid (0.25 mL) was added dropwise and the mixture stirred at 25 C. for 18 h. 1M HCl (10 mL) and methanol (10 mL) were added and the mixture concentrated in vacuo. Water (20 mL) was added and the solution basified with solid sodium hydroxide. This was extracted with methylene chloride (3*30 mL) and the combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel with ethyl acetate-hexane (2:3) as eluant to afford the title compound as an oil, 360 mg, 70%. This was converted to the fumarate derivative of the title compound by the addition of one equivalent of fumaric acid to a methanol (10 mL) solution of the free amine at 25 C. After 30 minutes, the solvent was removed in vacuo and the residue pumped under high vacuum. Trituration with diethyl ether, followed by recrystallization from ethyl acetate afforded 5-phenyl-3-(N-pyrrolidinomethyl)pyridine fumarate; M.p. 126-127 C. (EtOAc); 1 H NMR (DMSO-d6, 300 MHz): delta8.82 (s, 1H), 8.62 (s, 1H), 8.20 (s, 1H), 7.72 (bs, 2H), 7.50 (bs, 3H), 6.58 (s, 2H), 4.15 (s, 2H), 2.97 (s, 4H), 1.85 (s, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; tetrabutylammomium bromide; In dichloromethane; ammonia; ethylene dibromide; | d) A solution of 130 mg of <strong>[169674-02-6]4-chloro-5-fluoroindole</strong> in 3.7 ml of 1,2-dibromoethane was treated with 3.7 ml of 28% NaOH and 7.7 mg of tetrabutylammonium bromide. The mixture was stirred at 50 for 5 hours. The phases were separated and the aqueous phase was s extracted with toluene. The combined organic phases were washed with water and dried over sodium sulfate. The solvent was distilled off and the residue was chromatographed over 15 g of silica gel with hexane-ethyl acetate (5:1). There was obtained a yellow oil which was suspended in 30 ml of liquid ammonia and stirred in an autoclave at 80 for 16 hours. After evaporation of the ammonia the residue was taken up in dichloromethane and washed with water and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and the solvent was distilled off. The residue was chromatographed over 15 g of silica gel with ethyl acetate-methanol (5:1). There were obtained 110 mg of a yellow oil which was dissolved in 16 ml of ether, treated with 60 mg (0.5 mmol) of fumaric acid and stirred for 2 days. The crystals were filtered off and dried. There were obtained 150 mg (59%) of 2-(4-chloro-5-fluoro-indol-1-yl)-ethylamine fumarate (1:1) with m.p. 200-201 (dec.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; hydrogenchloride; sodium cyanoborohydride; In methanol; dichloromethane; ethyl acetate; | (v) (R)-Methyl 4-[(3,4-dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxylate fumarate (1:1) A solution of oxalyl chloride (0.1 ml) in dry dichloromethane (3 ml) at -70 was treated with a solution of dry dimethylsulphoxide (0.21 ml) in dry dichloromethane (2 ml) over a 5 min period. The mixture was stirred at -70 for 10 min and a solution of the product of stage (iv) (0.18 g) in dry dichloromethane (3 ml) was added. The reaction mixture was stirred at -70 for 140 min and a solution of N-methylmorpholine (0.25 ml) in dry dichloromethane (2 ml) was added. The mixture was stirred at -20 to -15 for 35 min and hydrochloric acid (0.01M; 20 ml) was added. The product was extracted with dichloromethane (2*10 ml), the combined extracts were washed with hydrochloric acid (0.01M; 10 ml), dried and evaporated to give an oily residue (0.1 g). A solution of <strong>[25150-61-2]pyrrolidine hydrochloride</strong> (0.1 g) in methanol (3 ml) at 0 was treated with 3Å molecular sieves (0.1 g) followed by a solution of the above residue in methanol (2 ml). The mixture was stirred for 5 min and sodium cyanoborohydride (60 mg) was added. The mixture was stirred at ambient temperature for 2 days and then filtered through cotton wool. The filtrate was evaporated in vacuo and the residue was dissolved in dichloromethane (50 ml). The solution was washed with aqueous sodium carbonate (1M; 20 ml) dried and evaporated to give an oily residue which was purified by flash column chromatography eluding with dichloromethane/methanol/ammonia (200:8:1). A solution of the residue in ethyl acetate (2 ml) was treated with a solution of fumaric acid (8 mg) in a mixture of ethyl acetate and methanol (2 ml). The resulting solid was crystallized from a mixture of ethyl acetate and methanol to give the title compound as a solid (0.020 g), m.p. 184-185. Analysis. Found: C, 51.70; H, 5.75; N, 7.72. C19 H25 Cl2 N3 O3.C4 H4 O4 requires C, 52.08; H, 5.51; N, 7.92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; ethanol; ethyl acetate; | EXAMPLE 1 In 10 ml of dimethylformamide is suspended 0.82 g of 60% sodium hydride, and a solution of 3.4 g of 4-[2-(dimethylamino)ethyl]phenol in 10 ml of dimethylformamide is added dropwise to the suspension. The mixture is stirred at 60 C. for 2 hours. Thereto, a solution of 3.8 g of 2-chloro-3-(2-thenoyl)pyridine in 10 ml of dimethylformamide is added dropwise under ice-cooling. The mixture is stirred at 70 C. for 2 hours, and then is poured into ice-water, whereto ethyl acetate is added. The ethyl acetate layer is extracted with a dilute hydrochloric acid and the extract is rendered alkaline with potassium carbonate. The isolated oily substance is extracted with ethyl acetate. After the extract is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off. The obtained residue is converted into its salt with fumaric acid in ethanol, and the salt is recrystallized from ethanol to give 2-[4-(2-dimethylaminoethyl)phenoxy]-3-(2-thenoyl)pyridine 1/2 fumarate, m.p. 147-150 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; mineral oil; | Preparation 12 3-[(1-Methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrile fumarate [1:2] A solution of 55 g (0.55 mole) of <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong> in 55 ml of dry dimethylformamide was added dropwise to a suspension of 22 g (0.58 mole) of 60percent sodium hydride/40percent mineral oil in 300 ml of dimethylformamide. The mixture was stirred at room temperature for one hour and 73 g (0.53 mole) of 3-chloro-4-cyanopyridine in 200 ml of dimethylformamide was added dropwise with mild cooling to maintain a temperature of 30°-40° C. The solution was stirred 3 hours and an equal volume of water added. The solution was made acidic with dilute hydrochloric acid and extracted with isopropyl ether. The aqueous layer was made basic with sodium hydroxide and extracted 5 times with chloroform. The extracts were combined, dried over sodium sulfate and concentrated. The residue was treated with 50 g of fumaric acid in 400 ml of isopropyl alcohol and 40 ml of water. The resulting crystals (51 g; 21 percent) were collected. A 2 g sample was recrystallized from methyl isobutyl ketone. Yield of product was 1.5 g, m.p. 172°-174° C. Analysis: Calculated for C18 H21 N3 O9: C, 52.42; H, 4.86; N, 9.65. Found: C, 52.40; H, 4.90; N, 9.68. | |
In N-methyl-acetamide; water; mineral oil; | PREPARATION 12 3-[(1-Methyl-3-pyrrolidinyl)oxy]-4-pyridinecarbonitrile fumarate [1:2] A solution of 55 g (0.55 mole) of <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong> in 55 ml of dry dimethylformamide was added dropwise to a suspension of 22 g (0.58 mole) of 60percent sodium hydride/40percent mineral oil in 300 ml of dimethylformamide. The mixture was stirred at room temperature for one hour and 73 g (0.53 mole) of 3-chloro-4-cyanopyridine in 200 ml of dimethylformamide was added dropwise with mild cooling to maintain a temperature of 30°-40° C. The solution was stirred 3 hours and an equal volume of water added. The solution was made acidic with dilute hydrochloric acid and extracted with isopropyl ether. The aqueous layer was made basic with sodium hydroxide and extracted 5 times with chloroform. The extracts were combined, dried over sodium sulfate and concentrated. The residue was treated with 50 g of fumaric acid in 400 ml of isopropyl alcohol and 40 ml of water. The resulting crystals (51 g; 21percent) were collected. A 2 g sample was recrystallized from methyl isobutyl ketone. Yield of product was 1.5 g, m.p. 172°-174° C. Analysis: Calculated for C19 H21 N3 O9: C, 52.42; H, 4.86; N, 9.65. Found: C, 52.40; H, 4.90; N, 9.68. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; methanol; water; toluene; | EXAMPLE 1 4-(5-Chloropyridin-2-yl)-3-methyl-5-[(4-methylpiperazin-1-yl)carbonyl]oxy-1,2,4-triazole 50 g (0.24 mol) of 4-(5-chloropyridin-2-yl)-5-hydroxy-3-methyl-1,2,4-triazole are dissolved or suspended in 1 litre of absolute tetrahydrofuran. The sodium hydride, degreased with toluene, is added thereto from 10.8 g of a 55% sodium hydride dispersion and the mixture is stirred for 1 hour at ambient temperature. Then 39 g (0.24 mol) of freshly distilled 1-chlorocarbonyl-4-methyl-piperazine (Bp17: 120-124 C.) are added dropwise thereto and the mixture is stirred for a further 5 hours whilst moisture is excluded. The resulting suspension is concentrated by evaporation in vacuo and the residue is carefully mixed with water and neutralised. The solution containing the carbamate is extracted several times with methylene chloride and the organic phase is washed with water, dried and concentrated. The residue is triturated with ether and 55 g (68% of theory) of the title compound are obtained in the form of crystals, m.p. 121-122 C. 12.5 g of this base are dissolved in 100 ml of methanol and 4.3 g of fumaric acid are added hot. On cooling, the hemifumarate crystallises out, m.p. 173-175 C. (yield: 17 g). The compound is highly water-soluble; pH of the solution 3.5. The starting compound, 4-(5-chloropyridin-2-yl)-5-hydroxy-3-methyl-1,2,4-triazole, is obtained as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.15 g (15%) | With NaH; sodium acetate; In N,N-dimethyl-formamide; butan-1-ol; | EXAMPLE 107 1-(2-Methoxyphenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole fumarate A mixture of 4-(2-fluorobenzoyl)-1-methylpiperidine (14.6 g. 0.066 moles) of Example 1, <strong>[6971-45-5]2-methoxyphenylhydrazine hydrochloride</strong> (14.5 g, 0.083 moles) and sodium acetate (16.0 g, 0.195 moles) in n-butanol (280 ml) was refluxed for 7 hours. The mixture was cooled, filtered, and then concentrated to yield 22 g (100%) of an oil. To a solution of the oil (21.6 g, 0.063 moles) in DMF (220 ml) was added NaH (6.7 g, 0.139 moles, 50% oil dispersion). The mixture was stirred at 80 C. for 3 hours and then cooled and poured into H2 O. The aqueous mixture was extracted with ethyl acetate, dried (MgSO4) and concentrated to yield 22 g of an oil. A portion of the oil (9.5 g) was purified using HPLC (silica gel, 100% methanol) to yield 4.5 g of an oil. The oil was dissolved in ether and a solution of fumaric acid in ether was added to form a salt. The salt was recrystallized three times from ethanol-ether to yield 2.15 g (15%) of 1-(2-methoxyphenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole fumarate, m.p. 177-178 C. ANALYSIS: Calculated for C20 H23 N3 O.C4 H4 O4: 65.94%C, 6.21H, 9.59%N. Found: 65.87%C, 6.34%H, 9.57%N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; water; mineral oil; | EXAMPLE 11 11-[3-(4-Morpholinyl)propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine fumarate [1:1] To a stirred suspension of 1.10 g (0.046 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen pressure was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 15 min, warmed at 65-70 C. for 10 min and allowed to cool to room temperature. To the mixture was added, portionwise, 4.1 g (0.02 mole) of <strong>[57616-74-7]4-<strong>[57616-74-7](3-chloropropyl)morpholine hydrochloride</strong></strong>. The reaction mixture was stirred at room temperature for 16 hr and then poured into 800 ml of water. This mixture was extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 ml and 75 ml portions of 3 N hydrochloric acid and the combined aqueous extracts were basified with 3 N sodium hydroxide. The resulting suspension was extracted with two 150 ml portions of methylene chloride and these latter two extracts combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue, the free base of the title compound, was reacted with an equal molar amount of fumaric acid in warm isopropyl alcohol and the mixture treated with isopropyl ether. The fumarate salt was collected by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g, m.p. 154-7 C. Drying conditions prior to analyses were: 4 hr at 97-98 C./0.1 mm Hg; overnight at room temperature/0.1 mm Hg. Analysis: Calculated for C29 H30 N4 O5: C,67.69; H,5.88; N,10.88. Found: C,67.52; H,5.84; N,10.90. | |
In N-methyl-acetamide; water; mineral oil; | EXAMPLE 11 11-[3-(4-Morpholinyl)propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine fumarate [1:1] To a stirred suspension of 1.10 g (0.046 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen pressure was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 15 min, warmed at 65-70 C. for 10 min and allowed to cool to room temperature. To the mixture was added, portionwise, 4.1 g (0.02 mole) of <strong>[57616-74-7]4-<strong>[57616-74-7](3-chloropropyl)morpholine hydrochloride</strong></strong>. The reaction mixture was stirred at room temperature for 16 hr and then poured into 800 ml of water. This mixture was extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 ml and 75 ml portions of 3N hydrochloric acid and the combined aqueous extracts were basified with 3N sodium hydroxide. The resulting suspension was extracted with two 150 ml portions of methylene chloride and these latter two extracts combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue, the free base of the title compound, was reacted with an equal molar amount of fumaric acid in warm isopropyl alcohol and the mixture treated with isopropyl ether. The fumarate salt was collected by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g, m.p. 154-7 C. Drying conditions prior to analyses were: 4 hr at 97-98 C./0.1 mm Hg; overnight at room temperature/0.1 mm Hg. Analysis: Calculated for C29 H30 N4 O5: C, 67.69; H,5.88; N,10.88. Found: C,67.52; H,5.84; N,10.90. | |
In N-methyl-acetamide; water; mineral oil; | EXAMPLE 11 11-[3-(4-Morpholinyl)propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine fumarate [1:1] To a stirred suspension of 1.10 g (0.046 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen presssure was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 15 min, warmed at 65-70 C., for 10 min and allowed to cool to room temperature. To the mixture was added, portionwise, 4.1 g (0.02 mole) of <strong>[57616-74-7]4-<strong>[57616-74-7](3-chloropropyl)morpholine hydrochloride</strong></strong>. The reaction mixture was stirred at room temperature for 16 hr and then poured into 800 ml of water. This mixture was extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 ml and 75 ml portions of 3N hydrochloric acid and the combined aqueous extracts were basified with 3N sodium hydroxide. The resulting suspension was extracted with two 150 ml portions of methylene chloride and these latter two extracts combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue, the free base of the title compound, was reacted with an equal molar amount of fumaric acid in warm isopropyl alcohol and the mixture treated with isopropyl ether. The fumarate salt was collected by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g, m.p. 154-7 C. Drying conditions prior to analyses were: 4 hr at 97-98 C./0.1 mm Hg; overnight at room temperature/0.1 mm Hg. Analysis: Calculated for C29 H30 N4 O5: C,67.69; H,5.88; N,10.88. Found: C,67.52; H,5.84; N,10.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In chloroform; 1-bromo-hexane; water; Petroleum ether; | (ii) Preparation of Hexyl/Octyl Maleate/Fumarate Monooctyl maleic/fumaric acid (88 g, 0.39 mole) was dissolved in chloroform (200 ml) and was stirred in a 1 L Erlenmeyer (Quick Fit) flask, fitted with condenser, with a solution of potassium hydroxide (21 g, 0.38 mole) and tetrabutyl ammonium iodide (15 g, 0.04 mole) in 200 mls of water. To the stirred mixture was added hexyl bromide 64 g, 0.39 mole) and the two phase mixture was stirred rapidly under reflux for 5 hours. The chloroform layer was separated off, washed with sodium carbonate solution, then with water, and then dried over sodium sulphate. After filtering and evaporating the resulting oil was treated with 30/40 petroleum ether which precipitated the catalyst which could be reused. Filtration/evaporation yielded the crude product as an oil (77 g). Distillation in vacuo removed 13.1 g hexyl bromide. The yield of undistilled material was 59.3 g (62percent based on hexyl bromide). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; | EXAMPLE 18 To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 34 ml of a 10% aqueous potassium hydroxide solution and 5 ml of tetrahydrofuran is added at room temperature with stirring 5.2 g of 1-chloro-3-morpholinopropane hydrochloride and the resulting mixture is then stirred at 50 C for 2.5 hours. The reaction mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure. Resulting oily product is converted into the fumarate with 2.38 g of fumaric acid. Recrystallization from isopropyl alcohol gives 6.8 g of 2-(3-morpholinopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 169-171 C. Elementary analysis: for C22 H23 N3 OSCl2.C4 H4 O4 = 564.51: Calculated: C: 55.32, H: 4.82, N: 7.45; Found: C: 55.08, H: 4.79, N: 7.28. |
Yield | Reaction Conditions | Operation in experiment |
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4Og of SPP100 base is dissolved in 51 g of ethanol ALI. A solution of fumaric acid in ethanol ALI (2g/46g) at 35C, is dropped at room temperature to the base in 20 min. The solution is heated and a part of ethanol is distilled until the ratio SPP/EtOH 1/0.9 is reached. Then 30 g of acetonitrile is added at 500C with 1.7 g of ethanol to adjust the ratio EtOH/CH3CN to 40/60. Additional 98g of acetonitrile is added at T>37C to reach the ratio CH3CN/EtOH 87/13.The solution is seeded at 37C with 0.5 ml of SPP100 modification A in suspension (obtained e.g. from equilibration experiments as in Example 10 f) (iv)) and is cooled down from 37C to 17C in 200 min. The suspension is stirred 20 min and then heated up from 17C to 37C in 40 min. and stirred for 10 min. The suspension is cooled down from 37C to 17C for 200 <n="38"/>min., stirred for 20 min and heated up from 17 to 37C in 40min. After 10 minutes under stirring the suspension is cooled down to 22C in 200 min and stirred for 20 min. The suspension is distilled off and 115 g of CH3CN is added at 200C. The suspension is cooled down at 3C in 180 min and filtrated. The solid is washed with a portion of the mother liquor to obtain Crystal Modification A of aliskiren hemifumarate.Characterisation:The form is a dried product of solvated form SA obtained in acetonitrile/ethanol mixtures (Example 2). a) Differential Scanning Calorimetry (DSC) Studies:Influence of heating rateTable 2:Modification A Instrument: Mettler Toledo DSC822e (Nr. 17-1), heating rate: 10 K/minMelting (0C) Enthalpy (J/g)Mean value: X = 6 96.6 29According to the heating rate applied, the presence of an additional thermal event can be observed at about 600C corresponding to the glass transition. The presence of amorphous part in modification A is also observed by X Ray powder diffraction (XRPD) (calculated to be approximately 50%). b) X Ray powder diffraction (XRPD)A batch of Modification A shows an X-Ray pattern with the following peaks (under the conditions given in the description to Fig. 1): Peaks (2Theta): 6.0, 7.3, 8.6, 9.2, 9.9, 15.0, 17.2 and 17.9, e.g. in more detail 6.0, 7.3, 8.6, 9.2, 9.9, 15.0, 17.2, 17.9, 19.2, 19.7, 20.1. For example, a batch shows the X-Ray diffraction pattern given in Fig. 1.c) X-ray powder diffraction study of modification A at various Relative Humidities (RH)The aim is to evaluate the influence of the storage condition on the crystalline form of SPP100 hemifumarate For this purpose, two different experiments have been performed. The first one consists to submit SPP100 hemifumarate modification A to a nitrogen flow and to record at various time the corresponding XRPD pattern. During the second experiment the <n="39"/>influence of relative humidity on the crystalline modification A is determined by XRPD measurement. The corresponding results have been summarized in the following tables.(i) Table 3 Storage under nitrogen flowTime 0.00 2.25 4.53 7.80 13.10 14.75 (hour)XRPD Mod A Mod A Mod A Mod A Mod A Mod AChange none none none none none noneComment: No change of the modification is observed during storage under nitrogen flow.(ii) Table 4: Influence of relative humidity Modification ATime 0 2.55 5.01 7.4 9.8 24.23 26.86 32.51 47.6 143.9 (h)RH (%) 0%* 10% 25% 35% 45% 45% 60% 70% 70% 70%XRPD Mod Mod Mod Mod Mod Mod Mod Mod Mod Mod A A A A A A A A A AComment: No significant variation is observed. | ||
3.8 g | In methanol; at 40 - 45℃; | A solution of compound of Formula X-N-130C (5.0g, 0.0077 mol) in dichloromethane (50 mE) was cooled to 0-5 C. Concentrated hydrochloric acid (6.6 mE, 0.0770 mol) was slowly added at 0-5 C. and stirred reaction mass at 0-5 C. for 3 h. Afier completion of reaction (TEC), 20% aqueous sodium carbonate (42 mE) was added at 0-5 C. and warmed to room temperature. The aqueous layer was extracted with dichioromethane (50 mE) and combined dichloromethane was washed with DM water (50 mE). The solvent were distilled off under reduced pressure at 40-45 C. to afford <strong>[173334-57-1]Aliskiren</strong> free base as colorless as oil. To oily residue methanol (25 mE) and fumaric acid (0.42 g, 0.0036) were added and dissolved at 40-45 C. Solvent were removed at 40-45 C. under reduced pressure to afford title compound as foaming solid. The foaming solid were dissolved in 5% ethanol/acetonitrile (125 mE) and heated to 50-55C. for 15 minute. The reaction mixture was allowed to cool slowly to room temperature and stirred for further 12 h. The reaction mass was filtered under nitrogen and solid was suck dried for 10 minute. under nitrogen and dried for 12 h under vacuum at 40-50 C. to afford white solid (3.8 g, 85.6%). |
Yield | Reaction Conditions | Operation in experiment |
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19%; 10%; 35%; 20%; 8% | With dihydrogen peroxide;methyltrioxorhenium(VII); In dichloromethane; water; acetonitrile; at 20℃; | Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below. |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol; | Example 7: c/s-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1 -(2-phenyl-quinolin-7-yl)- imidazo[1 ,5-a]pyrazin-7-ium 3-carboxy-acrylateThis material was prepared by heating <strong>[867160-71-2]OSI-906</strong> with a slight excess of fumaric acid in ethanol/ water and then allowing the mixture to cool. The solid was collected by filtration and dried. The DSC, XRPD, and 1H NMR (300MHz, DMSO-d6) of the sample were recorded and are reproduced in Figs. 10, 1 1 , and 12, respectively |
Yield | Reaction Conditions | Operation in experiment |
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at 80.0℃; for 72h;Sonication; | Copper(II) meso-tetra(4-carboxyphenyl)porphine (8.8 mg, 0.01 mmol) and fumaric acid (9.9 mg, 0.06 mmol) were dissolved in DMF (5 mL) in a small capped vial, sonicated to ensure homogeneity and heated to 80 C for 72 h, followed by 72 h of evaporation in a crystallizing dish, yielding diffraction quality fibrous red crystals. numax/cm-1: 3403 (C(sp2)H), 2770 (OH), 1390-1280 (C=O). 1600-1450 (CC), 1320 (CO), 1380 (CN), 1006 (CuTCPP), 790-600 (CH). Found: C, 59.91; H, 5.17; N, 9.54; O, 18.40. Calc. for C66H68CuN10O14: C, 61.50; H, 5.32; N, 10.87; O, 17.38. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; In water; at 90℃; for 58.0h;Autoclave; High pressure; | General procedure: A mixture of Ag2O (11.6 mg, 0.05 mmol), bpz (19 mg, 0.1 mmol), maleic acid (11.6 mg, 0.1 mmol), 5 mL H2O, and 0.15 mL pyridine was heated to 90 C for 8 h in a 25 mL Teflon-lined reaction vessel, kept at 90 C for 50 h, then slowly cooled to 30 C in 10 h. The pH values of the system were 6.06 and 6.10 before and after the hydrothermal reaction, respectively. Colorless block crystals of 1 were isolated by filtration, washed with H2O, and dried in air. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; at 20 - 65℃; for 18.0h; | The hemi-fumarate salt of SRi can be prepared as follows:<strong>[1227633-49-9]4-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol</strong> free base (0.60 gram; 1.40 mmoles) aredissolved in 18 ml methanol at 65 C. Fumaric acid (0.164gram; 1.40 mmoles) and 6 ml methanol are added. The solution is allowed to cool over about 30 minutes to room temperature. Some seed crystals are added at 60 C. and crystallization takes place slowly. The suspension is stirred for 18hours at room temperature and filtered. The solid is washedwith 6 ml methanol in three portions and dried as describedherein for the other salts. The material has a melting point atabout 223 C. with a melting enthalpy of 83 g/J.In another embodiment, the hemi-fumarate salt of SRicomprises the following powder X-ray diffraction peaks(Angle 2-0): 7.2,8.7, 14.4, 15.8, 17.4, 19.0,23.7; and whichin an additional embodiment comprises the following powderX-ray diffraction peaks (Angle 2-0): 7.2, 8.7, 10.8, 14.4,15.8, 17.4, 17.8, 19.0, 20.1, 23.7, 27.5. |
Yield | Reaction Conditions | Operation in experiment |
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In water; acetonitrile; for 24h;Heating; | A solution of fumaric acid (1a) (0.22 g, 0.0019 mol) in hot distilledwater (5 mL) was added dropwise to a solution of acid 1 (0.5 g,0.0019 mol) in acetonitrile (5 mL) with continuous stirring. Thereaction mixture was allowed to stand for 1 days. 31P NMRspectrum of the reaction mixture (D2O, δ: 26.6 (3a), 28.8 (4)(both s). The second signal increased with time. Anhydrous diethyl ether was poured to the reaction mixture, a precipitateformed was filtered on a Shott funnel, washed with diethyl ether,and dried in vacuo. The product 4 is well soluble in water andethanol with heating, insoluble in acetonitrile, m.p. 236 C (fromethanol). The yield was 0.591 g (82.08%). IR (Nujol), ν/cm-1:1680 (COO-). 1H NMR (D2O)), δ: 2.38-2.45 (m, 4 H, CH2C(O));3.04-3.11 (m, 4 H, PCH2); 7.57-7.76 (m, 10 H, Ar). 13C NMR,δ: 16.73 (d, PCH2, 1JP,C = 53.0 Hz); 27.28 (d, PCH2CH2,2JP,C = 3.0 Hz); 116.51 (d, Cipso, 1JP,C = 85.0 Hz); 129.99 (d, Co,2JP,C = 13.0 Hz); 132.86 (d, Cm, 3JP,C = 10.0 Hz); 135.03 (d, Cp,4JP,C = 3.0 Hz); 175.87 (d, C(O)O, 3JP,C = 14.5 Hz). 31P NMR,δ: 28.8. Found (%): C, 66.27; H, 5.50; P, 9.09. C18H19O4P.Calculated (%): C, 65.45; H, 5.75; P, 9.39. |
Yield | Reaction Conditions | Operation in experiment |
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87.3% | 1) Preparation of the compound (I-III)The citrus lactone (2.0 g, 8.6 mmol) was dissolved in dichloromethane (10 mL)A solution of peroxybenzoic acid (2.1 g, 10.3 mmol) in dichloromethane (20 mL) was slowly added dropwise to the above system,Reaction at room temperature for 3 hours,Saturated sodium thiosulfate aqueous solution quenching reaction,The organic layer was washed with saturated aqueous sodium bicarbonate (20 mL x 3)Dried and concentrated,The crude compound (I-III) (white solid, 2.0 g, yield 94%) was purified by column chromatography (petroleum ether: ethyl acetate = 5: 2)2) Preparation of compound (III)The compound (I-III) (300.0 mg, 1.29 mmol) obtained in the above step was dissolved in dichloromethane (50 mL)To the above mixture was added dimethylamine hydrochloride (1.6 g, 19.4 mmol) and potassium carbonate (5.2 g, 37.4 mmol)Heated to reflux for 3 hours,The solid was removed by filtration,The filtrate was washed with water,Dried and concentrated, and the resulting crude product was dissolved in methanol (7 mL)To the above mixed system was added fumaric acid (130.1 mg, 1.11 mmol)The reaction was stirred for 0.5 hour,Remove the solvent,Add ethyl acetate to dissolve,The compound (III) was collected by filtration (white solid, 369.6 mg, yield: 87.3%)Determination of compound (II) by elemental analysis Molecular formula: C22H35NO7 |
Yield | Reaction Conditions | Operation in experiment |
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7.1g | Weighing 6.10g of <strong>[436-77-1]fangchinoline</strong>,2.50 g of 2,5-difluorobenzyl bromide dissolved in DMSO 100 mL in a 500 mL three-necked flask,Then add 0.20g of sodium ethoxide, stir to boiling, and stir to react for 8h.The whole reaction of the <strong>[436-77-1]fangchinoline</strong>base was detected by HPLC, the solvent was distilled off under reduced pressure, and the solvent was evaporated under reduced pressure.Cool down to room temperature, add 20% fumaric acid (to solution pH = 7.5) and stir to boiling for 8 h.Cool down to room temperature, add 100 mL of water and extract 3 times with acetone (200 mL × 3).HPLC separates the separation and purification process of the reaction and the product,The extract was dried overnight with anhydrous Na 2 SO 4 to recover dichloromethane.The solid was dried at 60 C for 4 h to give 7.10 g of product as pale yellow powder.The desired product has the melting point: 221.5-222.8 C, TOF-HRMS: M/e (1103.1052),The molecule is C62H56O10N2F6,That is, compound III168 in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
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6.25 g | Weigh 6.10g of <strong>[436-77-1]fangchinoline</strong>, 2.10g of 2,5-difluorobenzyl bromide, dissolved in DMSO 100mL in 500mL three-necked flaskIn addition, add 1.20g of sodium ethoxide, stir to boiling, and stir the reaction for 8h. TLC is used to detect the total reaction of anti-ninoline.The solvent was distilled off under reduced pressure, cooled to room temperature, and then neutralized to pH=7.1 with 20% fumaric acid, 50 mL of water and 3 times with dichloromethane.(50mL × 3), TLC tracking reaction and product separation and purification process, the extract was dried overnight with anhydrous Na2SO4 to recover dichloroMethane, the solid was dried at 60 C for 4 h to give the product as a pale yellow powder, 6.25 g. |
Yield | Reaction Conditions | Operation in experiment |
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5.55 g | Weighing 6.10g of <strong>[436-77-1]fangchinoline</strong>,2-fluoro-4-pyridylmethyl bromide 2.00g dissolved in 90%150mL of ethanol in a 500mL three-necked flask,Then add 10mL of diethylamine,Stir and mix together to heat to 80 C, and stir the reaction for 4 h.TLC detection All the nolin base is reacted, and the solvent is distilled off under reduced pressure.Cool down to room temperature, 30%Fumaric acidNeutralize to pH=7.1, distill off the solvent under reduced pressure.After solid matter was dissolved in 200 mL of water, it was treated with 500 g of D-101 macroporous adsorption resin, washed with water and then eluted with 95% ethanol.The TLC traces the reaction and the separation and purification process of the product, collects the ethanol fraction, and distills off the ethanol under reduced pressure to obtain a solid, solid matter.Drying at 60 C for 6 h gave a product of 5.55 g as a pale yellow powder. |