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[ CAS No. 162401-32-3 ] {[proInfo.proName]}

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Product Details of [ 162401-32-3 ]

CAS No. :162401-32-3 MDL No. :
Formula : C17H14Cl2F2N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :MNDBXUUTURYVHR-UHFFFAOYSA-N
M.W : 403.21 Pubchem ID :449193
Synonyms :
APTA-2217;BYK 20869;Daliresp;Daxas;BY 217;B9302-107
Chemical Name :3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide

Calculated chemistry of [ 162401-32-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 26
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.29
Num. rotatable bonds : 8
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 93.86
TPSA : 60.45 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.51 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.14
Log Po/w (XLOGP3) : 4.58
Log Po/w (WLOGP) : 5.62
Log Po/w (MLOGP) : 2.84
Log Po/w (SILICOS-IT) : 4.67
Consensus Log Po/w : 4.17

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.04
Solubility : 0.00369 mg/ml ; 0.00000914 mol/l
Class : Moderately soluble
Log S (Ali) : -5.57
Solubility : 0.00108 mg/ml ; 0.00000267 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.79
Solubility : 0.000066 mg/ml ; 0.000000164 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 2.55

Safety of [ 162401-32-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 162401-32-3 ]

* 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.

  • Downstream synthetic route of [ 162401-32-3 ]

[ 162401-32-3 ] Synthesis Path-Downstream   1~50

  • 1
  • Potassium salt of 4-amino-3, 5-dichloropyridine [ No CAS ]
  • [ 672883-68-0 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
In DMF (N,N-dimethyl-formamide); at 15 - 40℃; The potassium salt suspension of the anion of 4-AMINO-3, 5-dichloropyridine in DMF (2-2.5 equivalents) is introduced into a reaction vessel. A solution of 3CYCLOPROPYLMETHOXY-4-DIFLUOROMETHOXYBENZOYL chloride (1 equivalent) in DMF is slowly added to this suspension while stirring vigorously at a tempera- ture of 15 to 40C, preferably 20 to 30OC. After the reaction is complete, water is slowly added while stirring at 15-25C, and the pH is adjusted to 2-3 with hydrochloric acid. The solid is centrifuged or filtered, washed with water, resuspended in a sodium hydroxide solution (pH = 9-10), centrifuged or filtered again and washed with water. This moist crude material is, if desired, subjected to a recrystallization from an ISOPROPANOL/WATER mixture (ratio between 85: 15 and 100: 0, preferably 95: 5% by volume). The resulting product is centrifuged or filtered and dried in vacuo at a temperature not exceeding 60C.
In tetrahydrofuran; at 0 - 10℃; for 2.5h; Take intermediate 1 dissolved in 350mL tetrahydrofuran, add 500mL constant pressure dropping funnel, then, the tetrahydrofuran solution of the intermediate 1 was dropped into the tetrahydrofuran reaction solution of the intermediate 2, At the same time, the temperature of the reaction solution was controlled at 0 ~ 10 C, and the drop was completed in lh. After the intermediate 1 tetrahydrofuran solution was added dropwise, the reaction was incubated at 0-10 C for 1.5 h. Then add 350 mL of 1N hydrochloric acid at 0-15 C. After adding water, phase rhoEta=2~3, Separate the organic phase, The aqueous phase was washed with ethyl acetate (500 mL X 2) and the organic phases were combined and washed with saturated aqueous NaHCO 3 solution (600 mL X 2). After washing with water (600 mL X 3), the organic phase was evaporated to dryness under reduced pressure. The wet crude product was obtained, and the wet crude product was placed in a drying oven and dried at 60-65C for 2 hours. I have Roflumilast Crude 50g, The yield ranges from 85 to 95%.
  • 2
  • [ 22889-78-7 ]
  • [ 672883-68-0 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
With sodium hydride; In tetrahydrofuran; at 0℃; for 0.5h; The product obtained from Example 2 (LOG) was heated with thionyl chloride (5.8g) and catalytic amount of dimethylformamide (0. 5ml) at 80 to 85C for 1 hour. The solution was evaporated in vacuo and the oily residue was dissolved in dry tetrahydrofuran (50 ml). This was added dropwise at 0C to a suspension prepared from sodium hydride (3.75 g, 60% suspension) and 4-amino-3, 5-dichloro pyridine (9. 5G) in dry tetrahydrofuran (50 ml) with stirring. The reaction mixture was stirred for 30 minutes and then acidified to pH 2 with hydrochloric acid (1 N). The reaction mixture was extracted with ethyl acetate. The extracted solvent was washed with sodium bicarbonate solution (5%) and water followed by evaporation in vacuum. The residue was dissolved in methanol (45 ml) at 60C and 5 ml of water was added to get precipitate. The mixture was then cooled to 10C and filtered to obtain roflumilast. Yield: 9.2 g Purity: 99% m. p.: 157-158C
In a clean reaction vessel, tetrahydrofuran (5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was taken and to this 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid (1 eq) was added under stirring to get a clear solution. To this thionyl chloride (1.5 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was added drop wise at 20-25 C. and stirred for 30 min at 40-45 C. Thionyl chloride was distilled out at 40-45 C. to get an oil. This was swapped with tetrahydrofuran. In another flask sodium hydride (2.4 eq with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was taken in THF (5 vol. with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid). To this 4-amino 3,5 Dichloropyridine (1.2 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) was added and stirred for 30 minutes. The above obtained acid chloride was dissolved in tetrahydrofuran (5 vol. with respect to to 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid) and added dropwise to the above prepared mixture of 4-amino 3,5 Dichloropyridine and sodium hydride at a temperature below 30 C. The above reaction mixture was stirred for 1 hr at 20-25 C. To this EtOAc was added followed by the addition of water. EtOAc layer was separated and the aqueous layer was extracted with EtOAc. Combined EtOAc layer was washed with 10% HCl and then with 10% aq. NaOH solution. This was washed with water and ethyl acetate and distilled out at 45 50 C. to get a light yellow colored solid. To this isopropanol was added and heated to reflux until a clear solution was obtained. The solution was cooled to 20-25 C. slowly and maintained at 20-25 C. for 1 hour. The solid was filtered and washed with isopropanol to get crude Roflumilast.
YieldReaction ConditionsOperation in experiment
5. N-(3,5-Dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (m.p.: 158 C.)
  • 4
  • [ 162401-62-9 ]
  • [ 22889-78-7 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
95% 2, 4, 6-trinitrochlorobenzene (294 g) was dissolved in 2 L of dioxane, <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid</strong> (258 g) was added to the above solution, stirred and cooled to 20~35C. Pyridine (160 g) was added dropwise to the above system, and stirred for 3 h. The starting material <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid</strong> was essentially disappeared by TLC analysis. 3,5-Dichloro-4-aminopyridine (164 g) was added dropwise to the reaction solution, and mixed for 2h. The completion of the reaction was analysed by TLC, filtered and the filtrate was washed with saturated NaHCO3 solution and saturated NaCl solution,dried, filtered and decompressed at 45 C to obtain the final product of roflumilast 270 g. The yield was 95% and the purity was 99.5%.
91% 22. 8g (130mmol) 2- chloro-4,6-dimethoxy-1,3,5-triazine was dissolved into 250mL of methylene chloride 15.2 g (150mml) N- methyl morpholine, the reaction mixture was stirred mixture of 3-cyclopropylmethoxy-4-difluoromethoxy-benzoic acid25. 8g (lOOmmol) was added to the methylene chloride solution, and incubated with stirring at 0~10 C, the addition was completed, stirring was continued at room temperature for 3h, TLC analysis of <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxy benzoic acid</strong> disappeared 3,5-dichloro-4-aminopyridine 17.1g (105mmol) was dissolved in 100L of dichloromethane was added dropwise to the reaction mixture was added dropwise, stirring was continued for 2h, TLC analysis of the disappearance of the intermediate active ester, filtration, The filtrate was washed with saturated NaHCO3Solution, washed with saturated NaCl solution, dried over anhydrous Na2SO4Drying, filtration, pressure was lower than 45 final product roflumilast 38.8g, 96.3% yield, 98.9% purity The 10g (24.8mmol) Roflumilast crude added 50mL of acetonitrile was stirred and heated to 60-70 dissolved, 0.5g medical activated carbon, stirring, hot filtered and the filtrate was heated to slight reflux at the same temperature was added to the solution 20mL water, cooled to 50 and maintained at this temperature for 2 hours, at room temperature, and stirring was continued for 6-8 hours, the resulting crystals were collected by filtration, and the cake was washed with pure water, and dried under reduced pressure to give 9.1 roflumilast g, yield 91%, mp 157.7-158.6 , purity of 99.87% [HPLC normalization method: column HederaODS-2 (4.6mm * 150mm, 5um); mobile phase of acetonitrile - water (100: 50) detection wavelength: 215nm; column temperature was 25 ; flow rate of 1.0ml / min].
64% At 25 C, 250ml three bottles, The compound (II) (0.1 mol, 25.8 g) was dissolved in THF (100 ml)in, Then, pivaloyl chloride (0.11 mol, 13.3 g) and Na2CO3 (0.12 mol, 12.7 g) were added, After stirring for 2 hours, A solution of 3,5-dichloro-4-aminopyridine (0.1 mol, 16.3 g) in THF (50 ml) was slowly added dropwise. After dripping, Heated to 50 C, Stirring was continued for 4 hours until the starting material 3,5-dichloro-4-aminopyridine disappeared (HPLC monitoring) Add ethyl acetate diluted after washing, The aqueous phase was extracted twice with ethyl acetate. Combine organic phase, After drying anhydrous sodium sulfate, Filtration, concentration and recrystallization gave the off-white solid flufflustast (25.6 g, 64% yield, HPLC purity: 99.5%)
58.6% Following the disclosure provided in U. S. Patent No. 5,712, 298, 6.0 g of <strong>[162401-62-9]3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid</strong> are heated at reflux in 40 ml of toluene with 19.6 g of thionyl chloride until the evolution of gas is complete. The solution is evaporated to dryness under vacuum and the residue is dissolved in about 60 ml of dry tetrahydrofuran. This solution is added dropwise at 15-20 C. to a suspension prepared from 4.9 g of 4-amino-3, 5-dichloropyridine and 2. 0 g of sodium hydride (80% strength in mineral oil) in 60 mi of dry tetrahydrofuran, with stirring and cooling. After stirring for one hour, the reaction mixture is acidified to a pH of 2.0 with 1 N hydrochloric acid. The toluene/tetrahydrofuran phase is separated off and the aqueous phase is extracted two additional times with ethyl acetate. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and water, dried over sodium sulphate, and evaporated under vacuum. The residue is crystallized from isopropanol. The yield is 5.8 g (58.6% of theory) of the 3- cyclo-propylmethoxy-4-difluoromethoxy-N- [3, 5-di-chloropyrid-4-yl]- benzamid compound having a melting point of 158C.

  • 5
  • [ 162401-32-3 ]
  • roflumilast N-oxide [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 20℃; for 44h;Product distribution / selectivity; <strong>[162401-32-3]Roflumilast</strong> was dissolved in chloroform. The oxidizing agent3-chloroperoxy-benzoic acid was added and the mixture was stirred for 44 h at ambient temperature. The solvent was then partially evaporated under vacuum. The resulting oily residue was triturated with diethyl ether and stirred for 1 h. The solid was filtered off, washed with diethyl ether and dried in vacuum at 40 C to yield <strong>[162401-32-3]Roflumilast</strong> N-oxide. The yield of <strong>[162401-32-3]Roflumilast</strong>-N-oxide was 93.0 %.
82.7% With dihydrogen peroxide; acetic acid; at 70℃; for 6h; The three-port into reaction by adding <strong>[162401-32-3]Roflumilast</strong> (5g, 12.4mmol), acetic acid (24 ml), 30% hydrogen peroxide (6.3 ml, 62mmol), heating up to 70 C stirring 6 hours. The end of the reaction, cooling to room temperature, the reaction solution is poured into 150 ml ice water, adding sodium carbonate to adjust the pH value to 7 - 8, the aqueous phase is extracted with ethyl acetate (150 ml × 3). The combined organic phase, dried with anhydrous sodium sulfate, filtered, concentrated, get <strong>[162401-32-3]Roflumilast</strong> N - oxide (HPLC purity 96.9%). Recrystallization:The obtained product <strong>[162401-32-3]roflumilast</strong> N - oxide by adding isopropanol (50 ml) in, stirring under heating to 80 C, about 20 minutes is completely dissolved, continuously stirred for 30 minutes. The solution of the natural cooling to room temperature, precipitated white solid, filtered, the filter cake is washed with cold isopropanol (10 ml × 3), after the purification of the obtained white solid <strong>[162401-32-3]roflumilast</strong> N - oxide (4.3g, yield 82.7%, HPLC purity 97.5%).
  • 10
  • 3-cyclopropylmethoxy-4-hydroxybenzoic acid methyl ester [ No CAS ]
  • [ 162401-32-3 ]
  • 11
  • 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester [ No CAS ]
  • [ 162401-32-3 ]
  • 12
  • [ 162401-62-9 ]
  • [ 162401-32-3 ]
  • 15
  • [ 1454574-39-0 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
92.4% With sodium chlorite; 2-methyl-but-2-ene; acetic acid; In water; acetonitrile; at 20 - 30℃; for 3h;Cooling with ice; Vb (24 g, 62.0 mmol, 1.0 eq.) was dissolved in a mixture of CH3CN (96 mL) and 2-methyl-2-butene (17.5 g, 248.2 mmol, 4.0 eq.). Then 25% aqueous NaClO2 [28.0 g (80% solid, 249 mmol) in 84 mL H2O (4.0 eq)] was added in one portion. The mixture was placed into an ice-water bath. A solution of aqueous CH3COOH [CH3COOH (11.2 g, 186 mmol) diluted in H2O (48 mL, 3.0 eq).] was added and the temperature was maintained below 25 C. The reaction mixture was vigorously stirred at 20-30 C. while product precipitated slowly as the reaction progressed. The reaction was stirred for 2 hours, 96 mL of H2O was added and stirring was continued for 1 hour. The resulting slurry was filtered and the filter cake was washed with H2O (36 mL). The product was dried under reduced pressure at 40 C. for 3 hours to obtain crude VIb, roflumilast (22.4 g, 92.4% yield with 98.0% purity). Recrystallization of Roflumilast.
82% With sodium chlorite; 2-methyl-but-2-ene; acetic acid; In water; acetonitrile; at 20 - 30℃; for 2h;Cooling with ice; Vb (24 g, 62.0 mmol, 1.0 eq.) was dissolved in a mixture of CH3CN (96 mL) and 2- methyl-2-butene (17.5 g, 248.2 mmol, 4.0 eq.). Then 25% aqueous NaClO2 [28.0 g (80% solid, 249 mmol) in 84 mL H2O (4.0 eq)] was added in one portion. The mixture was placed into an ice-water bath. A solution of aqueous CH3COOH [CH3COOH (11.2 g, 186 mmol) diluted in H2O (48 mL, 3.0 eq).] was added and the temperature was maintained below 25 C. The reaction mixture was vigorously stirred at 20-30 C while product precipitated slowly as the reaction progressed. The reaction was stirred for 2 hours, 96 mL of H2O was added and stirring was continued for 1 hour. The resulting slurry was filtered and the filter cake was washed with H2O (36 mL). The product was dried under reduced pressure at 40 C for 3 hours to obtain crude VIb, roflumilast (22.4 g, 92.4% yield with 98.0% purity). Recrystallization of roflumilast. Crude roflumilast (10 g, 24.8 mmol) and CH3CN (45 mL) were placed in a 250-mL reactor. The mixture was stirred and heated 65 C to dissolve material. Insoluble material was removed by hot filtration. The mixture was heated to 70 C then H20 (22.3 mL) was added to the solution at the same temperature, then cooled down to 68 ± 2C and held at that temperature for 2 hours. The mixture was cooled to 25 ± 3 C and continuously stirred at this temperature for 12 hours. The resulting crystals were collected by filtration, and the filter cake washed with H2O (10 mL), dried at 40 ± 2 C under reduced pressure for 4 hours to get roflumilast (8.2 g, 82% yield with 99.7% purity). MS m/z (M+1): 403.0 IR (KBr): 3445, 3262, 1651, 1503, 1156 -1 cm; 1H NMR (300 MHz, CDC13) delta 8.58 (s, 2H), 7.66 (s, 1H), 7.59 (d, 1H, J= 2.1 Hz), 7.49 (dd, 1H, J= 2.1, 8.4 Hz), 7.31 (d, 1H, J= 8.4 Hz), 7.00-6.50 (t, 1H, J= 74.7 Hz), 3.98 (d, 2H, J= 6.9), 1.4-1.2 (m, 1H), 0.70-0.67 (m, 2H), 0.39-0.37 (m, 2H). 12C NMR (125 MHz, CDCl3) delta 163.70, 150.99, 148.38, 143.94, 139.70, 130.88, 128.91, 122.36, 119.93, 117.76 (CF2, JCF = 261 Hz), 115.68 (CF2), 114.32, 113.66 (CF2), 74.26, 10.02, 3.29. 19F NMR (282 MHz, CDCl3) delta -82.35, -82.62.
57% With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene; In tetrahydrofuran; water; 3-(cyclopropylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-(difluoromethoxy) benzamide (VIb). Vb (387 mg, 1.0 mmol, 1.0 eq) was dissolved in a mixture of THF (5 mL) and 2-methylbut-2-ene (1.1 mL, 10.0 mmol, 10.0 eq), and then NaClO2 (452 mg, 5.0 mmol, 5.0 eq) was added to the solution. The reaction mixture was vigorously stirred while an aqueous solution of NaH2PO4 (3.3 M, 1.5 mL, 5.0 mmol, 5.0 eq) was added dropwise. Upon reaction completion as assessed by TLC, the reaction mixture was diluted with EtOAc (30 mL) and washed with water, 10% aqueous Na2S2O3, and brine (10 mL each). The organic layer was dried over MgSO4 and solvents were evaporated to afford crude roflumilast VIb (400 mg). Recrystallization of roflumilast. Crude roflumilast, IPA (6 mL), and purified water (2.1 mL) were added to a 25 mL flask. The mixture was stirred and heated to 75 ± 5C to dissolve all material, and then the clear solution was cooled to the cloud point (55C). The mixture was then held at the same temperature for 30 minutes. The mixture was cooled to 25 ± 5C and continuously stirred at this temperature for 2 hours. The crystals were collected by filtration. The filter cake was washed with purified water and dried at 50 ± 5C under reduced pressure to yield 230 mg (57% yield) of roflumilast as a colorless solid. 1H NMR (300 MHz, CDCl3) delta 8.58 (s, 2H), 7.66 (s, 1H), 7.59 (d, 1H, J= 2.1 Hz), 7.49 (dd, 1H, J= 2.1, 8.4 Hz), 7.31 (d, lH, J= 8.4 Hz), 7.00-6.50 (t, 1H, J= 74.7 Hz), 3.98 (d, 2H, J= 6.9), 1.4-1.2 (m, 1H), 0.70-0.67 (m, 2H), 0.39-0.37 (m, 2H). 13C NMR (125 MHz, CDCl3) delta 163.70, 150.99, 148.38, 143.94, 139.70, 130.88, 128.91, 122.36, 119.93, 117.76 (CF2, JCF = 261 Hz), 115.68 (CF2), 114.32, 113.66 (CF2), 74.26, 10.02, 3.29. 19F NMR (282 MHz, CDCl3) delta - 82.35, - 82.62.
  • 16
  • [ 22889-78-7 ]
  • [ 151103-09-2 ]
  • [ 162401-32-3 ]
  • 17
  • [ 1454798-33-4 ]
  • [ 162401-32-3 ]
  • 18
  • [ 22889-78-7 ]
  • [ 1590361-85-5 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
88% 50 mL of DMSO were added to 7.58 g of 3,5-dicloropyridin-4-amine (III) (1 .2 eq) and 16.47 g of CsF (2.8 eq). The mixture was stirred at a temperature of 90C for 3 h. A suspension was obtained. A solution in DMSO of (3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)(1 H- imidazol-1 -yl)-methanone (IVa) was slowly loaded over the previous suspension for 30 min at a temperature of 90-95C. The reaction was allowed to react at this temperature for 6 h. Once the reaction was completed, 100 mL of water were added and the pH was adjusted to pH=5.0 with 1 N HCI. Product precipitation was seen and isolated by filtration. The filtered solid was washed with 100 mL of H20. The washed solid was dried in a vacuum oven for 14 h at 50C. 15.3 g of raw product were obtained and recrystallised with a mixture of isopropanol-water at 90%. The recrystallised solid was dried in a vacuum oven at 50C. 13.90 g of roflumilast were obtained (yield 88%). The X-ray diffraction diagram is consistent with that of Example 3.
  • 19
  • [ 22889-78-7 ]
  • [ 1601300-21-3 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
79% 25 mL of DMSO were added to 3.79 g of 3,5-dicloropyridin-4-amine (III) (1 .2 eq) and 8.23 g of CsF (2.8 eq). The mixture was stirred at a temperature of 90C for 3 h. A suspension was obtained. A solution of (3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)(1 H-1 ,2,4-triazol-1 - yl)-methanone (IVb) in DMSO was slowly loaded over the previous suspension in DMSO at a temperature of 90-95C. The reaction was allowed to react at this temperature for 3 h. Once the reaction was completed, 50 mL of water were added and the pH was adjusted to pH=4.5 with 1 N HCI. Product precipitation was seen and isolated by filtration. The filtered solid was washed with 100 mL of H20. The washed solid was dried in a vacuum oven for 14 h at 50C. 6.55 g of raw product were obtained and recrystallised with a mixture of isopropanol-water at 90%. The recrystallised solid was dried in a vacuum oven at 50C. 6.15 g of Roflumilast were obtained (yield 79%). The X-ray diffraction diagram is consistent with that of Example 3.
  • 21
  • [ 96-32-2 ]
  • [ 162401-32-3 ]
  • N-(3,5-dichloropyrid-4-yl)-N-methoxycarbonylmethyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
649 mg To a solution of 0.5 g (1.24 mmol) of <strong>[162401-32-3]roflumilast</strong> in dry DMF (5 mL) was added 56.5 mg of sodium hydride (60% dispersion in oil, 1.41 mmol) under nitrogen stream and the resulting mixture was stirred at room temperature for about 15 minutes. Then, 0.25 mL (2.73 mmol) of methyl bromoacetate was added thereto and the resulting mixture was stirred at room temperature for 2.5 hours followed by stirring at 60 C. for 4.5 hours. The reaction mixture was left to cool to room temperature and 3 mL of water was added thereto. The mixture was extracted with 9 mL of chloroform three times. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 649 mg (1.37 mmol) of the title compound as an orange oil.
  • 22
  • [ 74-88-4 ]
  • [ 162401-32-3 ]
  • [ 1616666-83-1 ]
YieldReaction ConditionsOperation in experiment
0.16 g With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 12h;Inert atmosphere; To a solution of 0.25 g (0.60 mmol) of <strong>[162401-32-3]roflumilast</strong> in dry DMF (5 mL) were added 72 mg of sodium hydride (60% dispersion in oil, 3.0 mmol) and 0.19 mL (3.0 mmol) of methyl iodide at 0 C. under nitrogen stream and the resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added 3 mL of water and the resulting mixture was extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified using ODS column (acetonitrile/water/THF) and further desalted (NH cartridge, dichloromethane/methanol). The solvent was evaporated to give 0.16 g (0.38 mmol) of the title compound as a dark brown oil. (0079) Melting point: 68 C. (0080) 1H-NMR (400 MHz, CDCl3) delta 0.32 (m, 2H), 0.63 (m, 2H), 1.20 (m, 1H), 3.31 (s, 3H), 3.76 (d, 2H), 6.57 (t, 1H), 6.90 (dd, 1H), 6.94 (d, 1H), 7.08 (d, 1H), 8.48 (s, 2H).
  • 23
  • [ 13057-17-5 ]
  • [ 162401-32-3 ]
  • N-(3,5-dichloropyrid-4-yl)-N-methoxymethyl-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 2h;Inert atmosphere; To a solution of 505 mg (1.25 mmol) of <strong>[162401-32-3]roflumilast</strong> in dry DMF (5 mL) was added under nitrogen stream 69 mg (60% dispersion in oil, 1.73 mmol) of sodium hydride followed by addition of 0.3 mL (3.67 mmol) of bromomethyl methyl ether. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 5 mL of water and the resulting mixture was extracted with chloroform three times to give organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give a crude oil product. The crude product was purified by silica gel column chromatography (n-hexane/dichloromethane). The resulting light yellow solid was recrystallized from dichloromethane/n-hexane to give 188 mg (0.42 mmol, yield 34%) of the title compound as a white solid. (0095) 1H-NMR (500 MHz, CDCl3) delta 0.32 (m, 2H), 0.64 (m, 2H), 1.20 (m, 1H), 3.60 (s, 3H), 3.75 (d, 2H), 5.26 (s, 2H), 6.57 (t, 1H), 6.92 (dd, 1H), 6.95 (d, 1H), 7.10 (d, 1H), 8.50 (s, 2H)
  • 24
  • [ 79-07-2 ]
  • [ 162401-32-3 ]
  • N-carbamoylmethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
16% A solution of 0.5 g (1.24 mmol) of <strong>[162401-32-3]roflumilast</strong> in dry DMF (5 mL) was added 55.3 mg (60% dispersion in oil, 1.38 mmol) of sodium hydride under nitrogen stream and the resulting mixture was stirred at room temperature for about 15 minutes. To the reaction mixture were added 0.25 (1.63 mmol) of chloroacetamide and 0.41 g (2.74 mmol) of sodium iodide and the resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added 5 mL of water and the mixture was extracted with 5 mL of chloroform three times. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/dichloromethane) and further purified by gel filtration chromatography to give 94 mg (0.204 mmol, yield 16%) of the title compound as a light yellow solid. (0098) Melting point: 90.99 C. (0099) 1H-NMR (500 MHz, DMSO-d6) delta 0.38 (m, 2H), 0.56 (m, 2H), 1.23 (m, 1H), 3.91 (d, 2H), 4.35 (s, 2H), 7.15 (t, 1H), 7.19 (d, 1H), 7.48 (s, 1H), 7.49 (dd, 1H), 7.59 (d, 1H), 7.78 (s, 1H), 8.28 (s, 2H)
  • 25
  • [ 107-14-2 ]
  • [ 162401-32-3 ]
  • N-cyanomethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% To a solution of 0.5 g (1.24 mmol) of <strong>[162401-32-3]roflumilast</strong> in dry DMF (5 mL) was added 56.4 mg of sodium hydride (60% dispersion in oil, 1.41 mmol) under nitrogen stream and the resulting mixture was stirred at room temperature for about 15 minutes. To the reaction mixture were added 0.172 mL (2.73 mmol) of chloroacetonitrile and 0.4 g (0.269 mmol) of sodium iodide and the resulting mixture was kept at room temperature for 2 hours. After completion of the reaction, 5 mL of water was added to the mixture and the resultant was extracted with mL of chloroform three times. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and the resulting crude product was further purified by gel filtration chromatography to give 213 mg (0.481 mmol, yield 48%) of the title compound as a light yellow oil. (0069) Melting point: 196 C. (0070) 1H-NMR (500 MHz, CDCl3) delta 0.35 (m, 2H), 0.65 (m, 2H), 1.21 (m, 1H), 3.78 (d, 2H), 4.65 (s, 2H), 6.61 (t, 1H), 6.87 (dd, 1H), 6.96 (d, 1H), 7.15 (d, 1H), 8.57 (s, 2H).
  • 26
  • [ 23737-52-2 ]
  • [ 162401-32-3 ]
  • C23H24Cl2F2N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
14% With potassium hydroxide; In dimethyl sulfoxide; at 100℃; for 24h;Inert atmosphere; A solution of 0.32 g (0.8 mmol) of <strong>[162401-32-3]roflumilast</strong>, 0.29 g (1.21 mmol) of the compound obtained in the Preparatory Example 2-1, and 92 mg (1.64 mmol) of potassium hydroxide in dry DMSO (5 mL) was stirred at 100 C. for a day under nitrogen stream. After the reaction mixture was left to cool, chloroform was added to the reaction mixture and the resultant was further stirred. The deposited solid was filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 56.5 mg (0.11 mmol, yield 14%) of the title compound as an oil.
  • 27
  • [ 89031-84-5 ]
  • [ 162401-32-3 ]
  • N-(3,5-dichloropyrid-4-yl)-N-(3-tert-butyldimethylsilyloxypropan-1-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% With sodium hydride; In mineral oil; at 20 - 70℃; for 12h;Inert atmosphere; To a solution of 0.5 g (1.2 mmol) of <strong>[162401-32-3]roflumilast</strong> in DMI (5 mL) were added 139 mg (60% dispersion in oil, 3.5 mmol) of sodium hydride and 0.25 mL (2.9 mmol) of 3-tert-butyldimethylsilyloxypropyl bromide at room temperature under nitrogen stream. The mixture was heated to 70 C. and stirred for 12 hours. To the reaction mixture was added 3 mL of water. The reaction mixture was extracted with ethyl acetate three times. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate) to give 212 mg (0.368 mmol, yield 31%) of the title compound as a white solid.
  • 28
  • [ 162401-32-3 ]
  • N-(3,5-dichloropyrid-4-yl.)-N-(2-hydroxyethyl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
  • 29
  • [ 162401-32-3 ]
  • N-carboxymethyl-N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide [ No CAS ]
  • 30
  • [ 162401-32-3 ]
  • C17H14Cl2F2N2O3*1.5H2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
272.6 g With water; potassium nitrate; In cyclohexanone; acetonitrile; at 20 - 70℃; for 12h; In a 5000 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 300 g of <strong>[162401-32-3]roflumilast</strong> and 3300 ml of a mixture of cyclohexanone-acetonitrile-water (7: 9: 1) were added and the mixture was stirred and heated to 65 C. -70 C,To be all clear, add 1.8 grams of potassium nitrate, hot filtered.The filtrate was naturally cooled to room temperature, and then incubated for 12 hours,Precipitated crystals, filtered, and dried indoors to obtain a high purity of 272.6 g of the white crystals of the above <strong>[162401-32-3]roflumilast</strong> Sesquihydrate, with a content of 99.96% and a single impurity of less than 0.06%.As determined by Karl Fischer method, it contains 6.18% (weight percent) moisture.
  • 31
  • sodium 5-methyl-2-methoxyphenolate [ No CAS ]
  • [ 162401-32-3 ]
  • 32
  • Na(1+)*C8H7O4(1-) [ No CAS ]
  • [ 162401-32-3 ]
  • 33
  • Na(1+)*C8H6ClO3(1-) [ No CAS ]
  • [ 162401-32-3 ]
  • 34
  • C13H9Cl2N2O3(1-)*Na(1+) [ No CAS ]
  • [ 162401-32-3 ]
  • 35
  • [ 144036-24-8 ]
  • [ 162401-32-3 ]
  • 36
  • [ 159782-26-0 ]
  • [ 162401-32-3 ]
  • 37
  • [ 1426-06-8 ]
  • 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide [ No CAS ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
20.76 g With sulfuric acid; at 140℃; for 7h;Inert atmosphere; (2) 3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(methyloxy)benzamide 9 (18.39) produced in step (1) g, 3.62mol) in hydroiodic acid (100ml) in the presence of added promoter ethanol (50ml),Stir well, react for 2 hours, and a reduction reaction occurs.3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide 10 (15.1 g, 3.44 mol) was generated, The resulting 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-hydroxybenzamide 10 (15.1 g, 3.44 mol) in 98% concentrated sulfuric acid Heat to 140C in the presence of a solution (80 ml).Difluoromethoxy 11 (10.5 g, 2.82 mol) was added slowly under nitrogen protection.Incubation and stirring reaction for 7 hours,Intermolecular dehydration occurs and etherification reactions occur.3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide 12 (20.76 g, 3.8 mol) was produced.
  • 38
  • [ 22002-44-4 ]
  • [ 162401-32-3 ]
  • 39
  • [ 1520-31-6 ]
  • [ 162401-32-3 ]
  • C19H19Cl2F2N3O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With TEMPO; 3,6?di?tert?butyl?9?mesityl?10?phenylacridin?10?ium tetrafluoroborate; oxygen; In 1,2-dichloro-ethane; at 37℃; for 14h;Sealed tube; Irradiation; General procedure: To a microwave vial equipped with a stir bar was added the substrate(1.0 equiv, 0.4-1.0 mmol), sulfoximine (2.0 equiv), photocatalyst(0.05 equiv), and TEMPO (0.2 equiv), then the vial wasclosed with a septum cap. DCE or MeCN (0.1 M) was added, andthe mixture was sparged with oxygen. The reaction mixturewas subsequently irradiated in a Hepatochem PhotoRedOx Duophotoreactor and two Kessil LED lamps (each 40 W, A160WE) ora PennOC photoreactor m1 (450 nm). For the reaction workup,the mixture was either directly evaporated or half-saturatedaqueous NaHCO3 solution was added followed by extraction (5 ×EtOAc, Na2SO4). Purification was performed using an automatedIsolera Spektra System or preparative HPLC as described inthe Supporting Information.
  • 40
  • [ 92523-32-5 ]
  • [ 162401-32-3 ]
  • C21H23Cl2F2N3O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With TEMPO; 3,6?di?tert?butyl?9?mesityl?10?phenylacridin?10?ium tetrafluoroborate; oxygen; In 1,2-dichloro-ethane; at 37℃; for 14h;Sealed tube; Irradiation; General procedure: To a microwave vial equipped with a stir bar was added the substrate(1.0 equiv, 0.4-1.0 mmol), sulfoximine (2.0 equiv), photocatalyst(0.05 equiv), and TEMPO (0.2 equiv), then the vial wasclosed with a septum cap. DCE or MeCN (0.1 M) was added, andthe mixture was sparged with oxygen. The reaction mixturewas subsequently irradiated in a Hepatochem PhotoRedOx Duophotoreactor and two Kessil LED lamps (each 40 W, A160WE) ora PennOC photoreactor m1 (450 nm). For the reaction workup,the mixture was either directly evaporated or half-saturatedaqueous NaHCO3 solution was added followed by extraction (5 ×EtOAc, Na2SO4). Purification was performed using an automatedIsolera Spektra System or preparative HPLC as described inthe Supporting Information.
  • 41
  • [ 35188-35-3 ]
  • [ 162401-32-3 ]
  • C22H23Cl2F2N3O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With TEMPO; 3,6?di?tert?butyl?9?mesityl?10?phenylacridin?10?ium tetrafluoroborate; oxygen; In 1,2-dichloro-ethane; at 37℃; for 14h;Sealed tube; Irradiation; General procedure: To a microwave vial equipped with a stir bar was added the substrate(1.0 equiv, 0.4-1.0 mmol), sulfoximine (2.0 equiv), photocatalyst(0.05 equiv), and TEMPO (0.2 equiv), then the vial wasclosed with a septum cap. DCE or MeCN (0.1 M) was added, andthe mixture was sparged with oxygen. The reaction mixturewas subsequently irradiated in a Hepatochem PhotoRedOx Duophotoreactor and two Kessil LED lamps (each 40 W, A160WE) ora PennOC photoreactor m1 (450 nm). For the reaction workup,the mixture was either directly evaporated or half-saturatedaqueous NaHCO3 solution was added followed by extraction (5 ×EtOAc, Na2SO4). Purification was performed using an automatedIsolera Spektra System or preparative HPLC as described inthe Supporting Information.
  • 42
  • [ 4381-25-3 ]
  • [ 162401-32-3 ]
  • C24H21Cl2F2N3O4S [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% With TEMPO; 3,6?di?tert?butyl?9?mesityl?10?phenylacridin?10?ium tetrafluoroborate; oxygen; In 1,2-dichloro-ethane; at 37℃; for 14h;Sealed tube; Irradiation; General procedure: To a microwave vial equipped with a stir bar was added the substrate(1.0 equiv, 0.4-1.0 mmol), sulfoximine (2.0 equiv), photocatalyst(0.05 equiv), and TEMPO (0.2 equiv), then the vial wasclosed with a septum cap. DCE or MeCN (0.1 M) was added, andthe mixture was sparged with oxygen. The reaction mixturewas subsequently irradiated in a Hepatochem PhotoRedOx Duophotoreactor and two Kessil LED lamps (each 40 W, A160WE) ora PennOC photoreactor m1 (450 nm). For the reaction workup,the mixture was either directly evaporated or half-saturatedaqueous NaHCO3 solution was added followed by extraction (5 ×EtOAc, Na2SO4). Purification was performed using an automatedIsolera Spektra System or preparative HPLC as described inthe Supporting Information.
  • 43
  • [ 1391052-76-8 ]
  • [ 7051-34-5 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
82.3% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; N,N-dimethylformamide, N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)-3-hydroxybenzoyl, potassium carbonate,Mix bromomethylcyclopropane,After stirring for 5 minutes,Slowly warm to 80 C, keep warm for 2 h, cool to room temperature, add ice water,The organic phase is extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated.Recrystallization from a mixed solvent of 95:5 by volume of isopropanol and water gives roflumilast.Wherein, N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)-3-hydroxybenzoyl,The molar ratio of potassium carbonate to bromomethylcyclopropane is 1:2:1.2, and the molar volume (mol/l) ratio of bromomethylcyclopropane and N,N-dimethylformamide is 0.52:3, N, N. The volume ratio of dimethylformamide to ice water is 0.3:2.
  • 44
  • [ 4837-20-1 ]
  • [ 162401-32-3 ]
  • 45
  • [ 57320-63-5 ]
  • [ 162401-32-3 ]
  • 46
  • N-(3,5-dichloro-4-pyridyl)-4-(difluoromethoxy)benzamide [ No CAS ]
  • [ 162401-32-3 ]
  • 47
  • [ 110-82-7 ]
  • [ 162401-32-3 ]
  • 3-(cyclopropylmethoxy)-N-(3,5-dichloro-2,6-dicyclohexylpyridin-4-yl)-4-(difluoromethoxy)benzamide [ No CAS ]
  • 48
  • [ 162401-32-3 ]
  • 3-(cyclopropylmethoxy)-N-(3,5-dichloro-2-(1,1,1-trifluoro-6-hydroxyhexan-3-yl)pyridin-4-yl)-4-(difluoromethoxy)benzamide [ No CAS ]
  • 49
  • [ 162401-32-3 ]
  • 3,5-dichloro-4-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzamido)-1-(pent-4-en-1-yloxy)pyridin-1-ium 4-methylbenzenesulfonate [ No CAS ]
  • 50
  • [ 22889-78-7 ]
  • [ 162401-69-6 ]
  • [ 162401-32-3 ]
YieldReaction ConditionsOperation in experiment
95% Stage #1: 3-(difluoromethoxy)-4-(cyclopropylmethoxy)-benzoic acid With thionyl chloride In toluene for 2h; Reflux; Stage #2: 3,5-dichloro-4-aminopyridine With sodium hydride In tetrahydrofuran at 15 - 20℃; Step 1) Acylation reaction: Add thionyl chloride (1075mL, 14.88mol) dropwise to 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (535g, 2.07mol) in toluene (4500mL) and the reaction mixture was heated to reflux for 2h, Then it was concentrated under reduced pressure to remove the solvent, and the residue after concentration was dissolved in about 5400 mL of tetrahydrofuran, and the solution was added dropwise to 15-20 under stirring. 4-amino-3,5-dichloropyridine (370g, 2.27mol) and sodium hydride (purity: 60%) (195g, 4.96mol) in 5400mL tetrahydrofuran solution; After stirring for 1 to 2 hours, the reaction solution was acidified with 1N hydrochloric acid to a pH of 2 to 3, the solution was separated into layers, and the aqueous layer was extracted twice with ethyl acetate, each with 4500 mL, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate solution (about 5L) and water (about 5L), and then dried with 5Kg anhydrous sodium sulfate for 23h. Filter, concentrate the filtrate under reduced pressure to remove the solvent, add about 2500 mL of isopropanol to the resulting residue and heat under reflux for 30 min. Then the temperature is naturally lowered to room temperature, a large amount of crystals are precipitated, filtered with suction, and the filter cake is dried to obtain an off-white solid, which is the crude roflumilast product. The yield range is 65% to 75%.
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