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CAS No. : | 100643-71-8 | MDL No. : | MFCD00871949 |
Formula : | C19H19ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JAUOIFJMECXRGI-UHFFFAOYSA-N |
M.W : | 310.82 | Pubchem ID : | 124087 |
Synonyms : |
Sch34117;Descarboethoxyloratadine;Aerius;Neoclarityn;Clarinex;NSC 675447
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.32 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 95.47 |
TPSA : | 24.92 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.0 cm/s |
Log Po/w (iLOGP) : | 3.04 |
Log Po/w (XLOGP3) : | 4.5 |
Log Po/w (WLOGP) : | 3.64 |
Log Po/w (MLOGP) : | 3.66 |
Log Po/w (SILICOS-IT) : | 5.17 |
Consensus Log Po/w : | 4.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.01 |
Solubility : | 0.00307 mg/ml ; 0.00000987 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.74 |
Solubility : | 0.0056 mg/ml ; 0.000018 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.38 |
Solubility : | 0.0000129 mg/ml ; 0.0000000416 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.21 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | Reflux; Inert atmosphere; Alkaline conditions | 40g of loratadine, 40g of sodium hydroxide, 500ml of absolute ethanol and 125ml of purified water were added to the reaction flask, The reaction solution was concentrated to a large amount of solid precipitated, filtered, washed and dried to obtain desloratadine 32 g, the yield was 98.5percent. The reaction was carried out under nitrogen atmosphere. (Molar ratio of loratadine to alkali is 1: 20; the ratio of purified water to anhydrous ethanol is 1: 4) |
98.5% | With C22H40N4(2+)*2BF4(1-) In toluene at 80℃; for 0.666667 h; | 0.1 mol of loratadine was dissolved in 20 g of [DBU- (CH2) 4-DBU2 +] 2BF4-,Water bath heated to 80 degrees Celsius,Stirring reaction 30min (no reflux and other devices);Then add 20 mL of toluene to continue stirring for 10 min,Static cooling stratification,Collect the organic layer, recover the ionic liquid, ammonia water after washing,The solvent is removed under reduced pressure to give desloratadine,The yield was 98.5percent and the HPLC purity was 99.98percent. |
96% | at 80℃; for 0.5 h; Green chemistry | 0.1 mol loratadine raw material was dissolved in 20g of [DBU-(CH2)4-DBU2 +] 2Br-. The water bath is heated to 80 degrees Celsius. Stir the reaction for 30min (without reflux and other devices); then add 20 ml toluene to continue stirring 10min, layered cooling at a standstill, the collection of the organic layer, after ammonia washing, the solvent is removed under reduced pressure, to obtain desloratadine, calculating yield 96percent, HPLC purity test 99.98percent. |
96% | at 80℃; for 0.5 h; | A solution of 0.1 mol of loratadine was dissolved20 g of [DBU- (CH2) 4-DBU2 +] · SO42-,Water bath heated to 80 degrees Celsius,Stirring reaction 30min (no reflux and other devices);Then add 20 mL of toluene to continue stirring for 10 min,Static cooling stratification,Collecting organic layer,Recovery of ionic liquid, ammonia washing, the solvent removed under reduced pressure, you can get desloratadine,The calculated yield was 96percentThe HPLC purity was 99.98percent. |
93.3% | With water; sodium hydroxide In ethanolReflux | To a solution of ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate (383 mg, 1 mmol) in ethanol, a 30percent sodium hydroxide aqueous solution was added. The mixture was refluxed overnight. The solvent was distilled off, and the resulting residue was dissolved in water and neutralized with concentrated hydrochloric acid. The extraction with ethyl acetate was performed 3 times, and the combined organic layer was dried over magnesium sulfate. The solvent was distilled off, and thus the title compound (290 mg, 93.3percent) was obtainedasayellowish white solid. 1H-NMR (CDCl3, δ): 2.3-2.4 (4H,m), 2.6-2.9 (4H,m) 3.0-3.1 (2H,m), 3.2-3.5 (2H,m), 7.1-7.2 (4H,m), 7.43 (1H,dd,J=1.4 Hz, 7.6 Hz), 8.40 (1H,dd,J=1.6 Hz, 4.9 Hz) |
91.5% | With sodium hydroxide In 2-methoxy-ethanol; water for 2 - 3 h; Heating / reflux | 100 ml of 2-methoxyethanol (methylcellosolve), 10 ml of an aqueous 40percent sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of loratadine are weighed in a vessel equipped with an intensive stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC. Preparation:90 ml 2-methoxyethanol are distilled off from the reaction mixture, whereupon 100 ml of icecold water and 100 ml of ethyl acetate are added to the residue. After the separation the organic layer is dried, the solvent is evaporated and the residue is crystallised from a mixture of hexane : ethyl acetate in a ratio of 10:1.Yield: 9.28 g (91.5percent) almost white crystalsMp.: 149-151 °C.Elementary analysis:C19Hi9ClN2 (310.8)Calculated: C:73.42 H:6.16 Cl:11.41 N:9.01Found: C:73.38 H:6.22 01:11.44 N:9.04HPLC purity: 99.1percent.; Example 3; Preparation of pseudopolymorph of desloratadine with half moles of carbon dioxide; 100 ml of 2-methoxyethanol (methylcellosolve), 12 ml of an aqueous 50percent sodium hydroxide solution and 12.5 g of loratadine are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for two hours. The end of the reaction is monitored with TLC. Preparation:90 ml 2-methoxyethanol are distilled off from the reactionmixture, whereupon 100 ml of icecold water and 100 ml ofethyl acetate are added to the residue. After the separation, ofthe layers the organic layer is clarified, dried, and 5.0 g dry iceare added to the pale yellow solution in small parts during halfhours. The crystals precipitate and the cold solution is filtered,the crystals obtained washed with ethyl acetate.Yield: 9.61 g (88.4 percent) almost white crystals.Analysis: C19H19C1N2X 1/2C02 (332.87)Mp.: 144-148 °C (slowly dec. above 100 °C)Calculated: C:70.71 H:5.79 Cl:10.62 N:8.41Found: C:70.01 H:5.86 Cl:10.51 N:8.38HPLC purity: 99.7 percent .; Example 5; Preparation of desloratadine hydrobromide (1:1); A mixture of 100 ml of 2-methoxyethanol (methylcellosolve) 10 ml of an aqueous 40percent sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of loratadine are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC.Preparation:90 ml 2-methoxyethanol is distilled off from the reactionmixture under reduced pressure, whereupon 100 ml of theicecold water and 100 ml of ethyl acetate are added to theresidue. After the separation of layers the product is extractedfrom the organic layer with a mixture of 5 ml of concentratedhydrochloric acid and 100 ml of icecold water. The aqueouslayer is clarified with activated carbon then filtered.Desloratadine base is set free with 5 ml of a 40percent sodiumhydroxide solution, extracted with 120 ml of ethyl acetate anddried. The base content of the pale yellow solution isdetermined, whereupon a solution of an equimolecular amountof hydrogen bromide in ethyl acetate is added. The whitecrystalline product is filtered at 0 °C, washed with ethanol.Yield: 7.33 g (93.6 percent) white crystals.Mp.: 268-272 °C (transformed at 198-200 °C )Analysis for the formula C19H19C1N2 * HBr (391.74)Calculated: C:58.26 H:5.15 Br:20.40 Cl:9.05 N:7.15Found: 58.08 H:5.17 Br:20.45 Cl:9.05 N:7.14HPLC purity >99.7percent |
87.5% | With sodium hydroxide In methanol at 82 - 95℃; for 2 - 12 h; Heating / reflux | mixture of 8-chloro-6, 11-dihydro-11- (1-ethoxycarbonyl-4-piperidilydene)-5H-benzo [5, 6] cyclohepta [1,2-b] pyridine (100 [GM,] 0.2612 mole), sodium hydroxide (110 gm, 2.75 mole) in methanol (400 [ML,] 9.89 mole) was refluxed for 2 hrs at 82o to [95OC.] After completion of reaction, 1000 ml of water is added to obtain crystals of 8-chloro-6,11- [DIHYDRO-LL- (4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta [1,2-b] pyridine, which was filtered at 25o-30oC, washed with plenty of water to remove salts, dried at [50-55OC.] The isolated yield was 76 gm. , with a purity of 99.8percent (OAB, HPLC) and an absorbance of 0.043 at 430 [NM.] giving a yield of 93.6percent The structure of the compound was confirmed by comparison of its [I. R., NMR] and Mass Spectra of reference standards. The quality results are shown in Table-3. The reaction is carried out as described in Example 1, but the amount of methanol used was [600ML] (14.83 mole) instead of [400ML.] The reaction was completed in 12 hrs. The isolated yield of [8-CHLORO-6,] [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.6percent (OAB, HPLC) and an absorbance of [0. 083] at 430 nm. giving a yield of 88.7percent The reaction was carried out as described in Example 1, but the amount of sodium hydroxide used was 92 gm (2.3 mole) instead of [110 GM.] The reaction is completed in 8 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-LL- (4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 71 gm with a purity of 99.7percent (OAB, HPLC) and an absorbance of 0.09 at 430 nm. giving a yield of 87.5percent |
82.5% | With potassium hydroxide In butan-1-ol for 1 h; | The reaction was carried out as described in Example 1, but the n-butanol [(400ML,] 4.37 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol [(400ML)] and sodium hydroxide [(11 OGM).] The reaction is completed in one hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 74 gm which is further purified in methanol-isopropyl to get product with a purity of 99.7percent (OAB, HPLC) and an absorbance of 0.08 (430 [NM)] giving a yield of 82. 5percent. |
82.5% | With potassium hydroxide In isopropyl alcohol for 1 - 50 h; | The reaction was carried out as described in Example [1,] but the isopropanol [(400ML,] 5.23 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol [(400ML)] and sodium hydroxide [(LLOGM).] The reaction is completed in 4 hrs. The isolated yield of 8-chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 75 gm with a purity of 99.6percent (OAB, HPLC) and an absorbance of 0.27 at 430 [NM.] giving a yield of 92.4percent further purification as in example 4 results in the compound with absorbance of 0.07. The yield has increased to 83.8percent The reaction was carried out as described in Example 5, but the amount of isopropanol and potassium hydroxide used was one litre (21.23 mole) and [100GM] (1.786 mole) respectively instead of [400ML] and 160 gm. The reaction is completed in 50 hrs. The isolated yield of 8- chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 76 gm with a purity of 99.7percent (OAB, HPLC) and an absorbance of 0.2 at 430 nm. giving a yield of 93.62percent On purification yield was 82.5 and colour absorbance was 0.06. |
81.3% | With potassium hydroxide In benzyl alcohol for 1.5 h; | The reaction was carried out as described in Example 1, but the benzyl alcohol [(400ML,] 3.87 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol [(400ML)] and sodium hydroxide [(110GM).] The reaction is completed in 1.5 hrs. The isolated yield of 8-chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 74 gm as base. This was crystallized in methanol-isopropyl ether to get a purity of 99.6percent (OAB, HPLC) and an absorbance of 0.09 (430 [NM)] giving a yield of 66gm (81.3percent). |
81.3% | With potassium hydroxide In propan-1-ol for 1 h; | The reaction was carried out as described in Example [1,] but the n-propanol [(400ML,] 5.36 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol (400ml) and sodium hydroxide (110gm). The reaction is completed in one hrs. The isolated yield of 8-chloro-6, 11-dihydro- 11 -(4-piperidilydene) - 5H-benzo [5,6] cyclohepta (1,2-b) pyridine was 74 gm with a purity of 99.47percent giving a yield of 91.2percent. Further purification in methanol-isopropyl ether was achieved to get a yield of 66gm (81.3percent) with an absorbance of 0.08 (430 [NM).] |
80.1% | With sodium hydroxide In butan-1-ol for 3 h; | The reaction was carried out as described in Example 1, but the n-butanol [(400ML,] 4.37 mole) was used instead of methanol [(400ML)] The reaction is completed in 3 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.6percent (OAB, HPLC) giving a yield of 88.7percent. This was further purified to get an absorbance of 0.08 and yield of 65 gm (80. [1percent).] |
80.1% | With sodium hydroxide In benzyl alcohol for 3 h; | The reaction was carried out as described in Example 1, but the benzyl alcohol [(400ML,] 3.87 mole) was used instead of methanol (400ml). The reaction is completed in 3 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 73 gm which was further purified in methanol-isopropyl ether to get purity 99.76percent (OAB, HPLC) and an absorbance of 0.08 (430 nm) giving a yield of 80. [1percent.] |
78.8% | With sodium hydroxide In propan-1-ol for 4 h; | The reaction was carried out as described in Example 1, but the n-propanol [(400ML,] 5.36 mole) was used instead of methanol [(400ML).] The reaction is completed in 4 hrs. The isolated yield of 8-chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.5percent (OAB, HPLC) giving a yield of 88. [7percent.] Further purification in methanol-isopropyl ether provides the yield of 64 gm (78.8 percent) with an absorbance of 0.09 (430 nm). |
77.6% | With sodium hydroxide In ethanol for 5 h; | The reaction was carried out as described in Example 1, but the ethanol (400 [ML,] 6.83 mole) was used instead of methanol (400ml). The reaction is completed in 5 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5, [6]] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.5percent (OAB, HPLC) and an absorbance of 0.6 at 430 nm. giving a yield of 88.7percent Further purification with methanol-isopropyl ether results in 92percent yield, and 0.1 absorbance. |
48% | With sodium hydroxide; polyethylene glycol 400 In toluene for 2 h; Heating / reflux | EXAMPLE 1 Step-i-Preparation of 8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (Desloratadine) To a solution of loratadine (50 gms) in toluene (200 ml), polyethylene glycol 400 (100 ml) was added and stirred. Sodium hydroxide (50 gms) was added to the above reaction mixture and refluxed for 2 hours. The course of the reaction was monitored by HPLC and after completion of the reaction, water (750 ml) and toluene (100 ml) was added and stirred well. The organic layer was separated out; the aqueous layer was extracted with toluene (2.x.100 ml). The combined organic layer was washed with water (2.x.250 ml) followed by brine (1.x.250 ml) and evaporated the solvent under vacuum. Recrystallization The obtained solid was dissolved in the mixture of toluene: methylisobutyl ketone (1:1 v/v) at 85° C., followed by the addition of IPE at 60° C. and cooled to 5° C. to 10° C. The obtained solid was filtered off. This recrystallization may be repeated to obtain the desired quality and purity of Desloratadine. Yield: 19.0 gms (48.0percent). |
48% | With sodium hydroxide In decaethylene glycol; toluene for 2 h; Heating / reflux | Example 1; Step-i-Preparation of 8-chloro-6,l 1-dihydro-l l-(4-piperidinyIidene)-5H- benzof5,61cycloheptafl,2-b1pyridine (Desloratadine); To a solution of loratadine (50 gms) in toluene (200 ml), polyethylene glycol 400 (100 ml) was added and stirred. Sodium hydroxide (50 gms) was added to the above reaction mixture and refluxed for 2 hours. The course of the reaction was <n="6"/>monitored by HPLC and after completion of the reaction, water (750 ml) and toluene (100 ml) was added and stirred well. The organic layer was separated out; the aqueous layer was extracted with toluene (2 X 100 ml). The combined organic layer was washed with water (2 X 250 ml) followed by brine (1 X 250 ml) and evaporated the solvent under vacuum.Recrvstallization :The obtained solid was dissolved in the mixture of toluene : methylisobutyl ketone (1:1 v/v) at 85°C, followed by the addition of IPE at 60°C and cooled to 5° C to 10° C. The obtained solid was filtered off. This recrystallization may be repeated to obtain the derived quality of Desloratadine.Yield: 19.0 gms (- 48.0 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | In ethanol; water;Reflux; Inert atmosphere; Alkaline conditions; | 40g of <strong>[79794-75-5]loratadine</strong>, 40g of sodium hydroxide, 500ml of absolute ethanol and 125ml of purified water were added to the reaction flask, The reaction solution was concentrated to a large amount of solid precipitated, filtered, washed and dried to obtain des<strong>[79794-75-5]loratadine</strong> 32 g, the yield was 98.5%. The reaction was carried out under nitrogen atmosphere. (Molar ratio of <strong>[79794-75-5]loratadine</strong> to alkali is 1: 20; the ratio of purified water to anhydrous ethanol is 1: 4) |
98.5% | With C22H40N4(2+)*2BF4(1-); In toluene; at 80℃; for 0.666667h; | 0.1 mol of <strong>[79794-75-5]loratadine</strong> was dissolved in 20 g of [DBU- (CH2) 4-DBU2 +] 2BF4-,Water bath heated to 80 degrees Celsius,Stirring reaction 30min (no reflux and other devices);Then add 20 mL of toluene to continue stirring for 10 min,Static cooling stratification,Collect the organic layer, recover the ionic liquid, ammonia water after washing,The solvent is removed under reduced pressure to give des<strong>[79794-75-5]loratadine</strong>,The yield was 98.5% and the HPLC purity was 99.98%. |
96% | With [1,1'-(butane-1,4-diyl)bis(1,8-diazabicyclo[5.4.0]undec-7-ene)] dibromide; at 80℃; for 0.5h;Green chemistry; | 0.1 mol <strong>[79794-75-5]loratadine</strong> raw material was dissolved in 20g of [DBU-(CH2)4-DBU2 +] 2Br-. The water bath is heated to 80 degrees Celsius. Stir the reaction for 30min (without reflux and other devices); then add 20 ml toluene to continue stirring 10min, layered cooling at a standstill, the collection of the organic layer, after ammonia washing, the solvent is removed under reduced pressure, to obtain des<strong>[79794-75-5]loratadine</strong>, calculating yield 96%, HPLC purity test 99.98%. |
96% | With C22H40N4(2+)*O4S(2-); at 80℃; for 0.5h; | A solution of 0.1 mol of <strong>[79794-75-5]loratadine</strong> was dissolved20 g of [DBU- (CH2) 4-DBU2 +] · SO42-,Water bath heated to 80 degrees Celsius,Stirring reaction 30min (no reflux and other devices);Then add 20 mL of toluene to continue stirring for 10 min,Static cooling stratification,Collecting organic layer,Recovery of ionic liquid, ammonia washing, the solvent removed under reduced pressure, you can get des<strong>[79794-75-5]loratadine</strong>,The calculated yield was 96%The HPLC purity was 99.98%. |
93.3% | With water; sodium hydroxide; In ethanol;Reflux; | To a solution of ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate (383 mg, 1 mmol) in ethanol, a 30% sodium hydroxide aqueous solution was added. The mixture was refluxed overnight. The solvent was distilled off, and the resulting residue was dissolved in water and neutralized with concentrated hydrochloric acid. The extraction with ethyl acetate was performed 3 times, and the combined organic layer was dried over magnesium sulfate. The solvent was distilled off, and thus the title compound (290 mg, 93.3%) was obtainedasayellowish white solid. 1H-NMR (CDCl3, delta): 2.3-2.4 (4H,m), 2.6-2.9 (4H,m) 3.0-3.1 (2H,m), 3.2-3.5 (2H,m), 7.1-7.2 (4H,m), 7.43 (1H,dd,J=1.4 Hz, 7.6 Hz), 8.40 (1H,dd,J=1.6 Hz, 4.9 Hz) |
91.5% | With sodium hydroxide; In 2-methoxy-ethanol; water; for 2 - 3h;Heating / reflux;Product distribution / selectivity; | 100 ml of 2-methoxyethanol (methylcellosolve), 10 ml of an aqueous 40% sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of <strong>[79794-75-5]loratadine</strong> are weighed in a vessel equipped with an intensive stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC. Preparation:90 ml 2-methoxyethanol are distilled off from the reaction mixture, whereupon 100 ml of icecold water and 100 ml of ethyl acetate are added to the residue. After the separation the organic layer is dried, the solvent is evaporated and the residue is crystallised from a mixture of hexane : ethyl acetate in a ratio of 10:1.Yield: 9.28 g (91.5%) almost white crystalsMp.: 149-151 C.Elementary analysis:C19Hi9ClN2 (310.8)Calculated: C:73.42 H:6.16 Cl:11.41 N:9.01Found: C:73.38 H:6.22 01:11.44 N:9.04HPLC purity: 99.1%.; Example 3; Preparation of pseudopolymorph of des<strong>[79794-75-5]loratadine</strong> with half moles of carbon dioxide; 100 ml of 2-methoxyethanol (methylcellosolve), 12 ml of an aqueous 50% sodium hydroxide solution and 12.5 g of <strong>[79794-75-5]loratadine</strong> are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for two hours. The end of the reaction is monitored with TLC. Preparation:90 ml 2-methoxyethanol are distilled off from the reactionmixture, whereupon 100 ml of icecold water and 100 ml ofethyl acetate are added to the residue. After the separation, ofthe layers the organic layer is clarified, dried, and 5.0 g dry iceare added to the pale yellow solution in small parts during halfhours. The crystals precipitate and the cold solution is filtered,the crystals obtained washed with ethyl acetate.Yield: 9.61 g (88.4 %) almost white crystals.Analysis: C19H19C1N2X 1/2C02 (332.87)Mp.: 144-148 C (slowly dec. above 100 C)Calculated: C:70.71 H:5.79 Cl:10.62 N:8.41Found: C:70.01 H:5.86 Cl:10.51 N:8.38HPLC purity: 99.7 % .; Example 5; Preparation of des<strong>[79794-75-5]loratadine</strong> hydrobromide (1:1); A mixture of 100 ml of 2-methoxyethanol (methylcellosolve) 10 ml of an aqueous 40% sodium hydroxide solution, 2.5 g of sodium hydroxide and 12.5 g (32.65 moles) of <strong>[79794-75-5]loratadine</strong> are weighed in a vessel equipped with vigorous stirrer. The mixture is boiled for three hours. The end of the reaction is monitored with TLC.Preparation:90 ml 2-methoxyethanol is distilled off from the reactionmixture under reduced pressure, whereupon 100 ml of theicecold water and 100 ml of ethyl acetate are added to theresidue. After the separation of layers the product is extractedfrom the organic layer with a mixture of 5 ml of concentratedhydrochloric acid and 100 ml of icecold water. The aqueouslayer is clarified with activated carbon then filtered.Des<strong>[79794-75-5]loratadine</strong> base is set free with 5 ml of a 40% sodiumhydroxide solution, extracted with 120 ml of ethyl acetate anddried. The base content of the pale yellow solution isdetermined, whereupon a solution of an equimolecular amountof hydrogen bromide in ethyl acetate is added. The whitecrystalline product is filtered at 0 C, washed with ethanol.Yield: 7.33 g (93.6 %) white crystals.Mp.: 268-272 C (transformed at 198-200 C )Analysis for the formula C19H19C1N2 * HBr (391.74)Calculated: C:58.26 H:5.15 Br:20.40 Cl:9.05 N:7.15Found: 58.08 H:5.17 Br:20.45 Cl:9.05 N:7.14HPLC purity >99.7% |
87.5 - 93.6% | With sodium hydroxide; In methanol; at 82 - 95℃; for 2 - 12h;Heating / reflux; | mixture of 8-chloro-6, 11-dihydro-11- (1-ethoxycarbonyl-4-piperidilydene)-5H-benzo [5, 6] cyclohepta [1,2-b] pyridine (100 [GM,] 0.2612 mole), sodium hydroxide (110 gm, 2.75 mole) in methanol (400 [ML,] 9.89 mole) was refluxed for 2 hrs at 82o to [95OC.] After completion of reaction, 1000 ml of water is added to obtain crystals of 8-chloro-6,11- [DIHYDRO-LL- (4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta [1,2-b] pyridine, which was filtered at 25o-30oC, washed with plenty of water to remove salts, dried at [50-55OC.] The isolated yield was 76 gm. , with a purity of 99.8% (OAB, HPLC) and an absorbance of 0.043 at 430 [NM.] giving a yield of 93.6% The structure of the compound was confirmed by comparison of its [I. R., NMR] and Mass Spectra of reference standards. The quality results are shown in Table-3. The reaction is carried out as described in Example 1, but the amount of methanol used was [600ML] (14.83 mole) instead of [400ML.] The reaction was completed in 12 hrs. The isolated yield of [8-CHLORO-6,] [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.6% (OAB, HPLC) and an absorbance of [0. 083] at 430 nm. giving a yield of 88.7% The reaction was carried out as described in Example 1, but the amount of sodium hydroxide used was 92 gm (2.3 mole) instead of [110 GM.] The reaction is completed in 8 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-LL- (4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 71 gm with a purity of 99.7% (OAB, HPLC) and an absorbance of 0.09 at 430 nm. giving a yield of 87.5% |
82.5% | With potassium hydroxide; In butan-1-ol; for 1h; | The reaction was carried out as described in Example 1, but the n-butanol [(400ML,] 4.37 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol [(400ML)] and sodium hydroxide [(11 OGM).] The reaction is completed in one hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 74 gm which is further purified in methanol-isopropyl to get product with a purity of 99.7% (OAB, HPLC) and an absorbance of 0.08 (430 [NM)] giving a yield of 82. 5%. |
82.5 - 85.0% | With potassium hydroxide; In isopropyl alcohol; for 1 - 50h; | The reaction was carried out as described in Example [1,] but the isopropanol [(400ML,] 5.23 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol [(400ML)] and sodium hydroxide [(LLOGM).] The reaction is completed in 4 hrs. The isolated yield of 8-chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 75 gm with a purity of 99.6% (OAB, HPLC) and an absorbance of 0.27 at 430 [NM.] giving a yield of 92.4% further purification as in example 4 results in the compound with absorbance of 0.07. The yield has increased to 83.8% The reaction was carried out as described in Example 5, but the amount of isopropanol and potassium hydroxide used was one litre (21.23 mole) and [100GM] (1.786 mole) respectively instead of [400ML] and 160 gm. The reaction is completed in 50 hrs. The isolated yield of 8- chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 76 gm with a purity of 99.7% (OAB, HPLC) and an absorbance of 0.2 at 430 nm. giving a yield of 93.62% On purification yield was 82.5 and colour absorbance was 0.06. |
81.3% | With potassium hydroxide; In benzyl alcohol; for 1.5h; | The reaction was carried out as described in Example 1, but the benzyl alcohol [(400ML,] 3.87 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol [(400ML)] and sodium hydroxide [(110GM).] The reaction is completed in 1.5 hrs. The isolated yield of 8-chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 74 gm as base. This was crystallized in methanol-isopropyl ether to get a purity of 99.6% (OAB, HPLC) and an absorbance of 0.09 (430 [NM)] giving a yield of 66gm (81.3%). |
81.3% | With potassium hydroxide; In propan-1-ol; for 1h; | The reaction was carried out as described in Example [1,] but the n-propanol [(400ML,] 5.36 mole) and potassium hydroxide (160gm, 2.857 mole) were used instead of methanol (400ml) and sodium hydroxide (110gm). The reaction is completed in one hrs. The isolated yield of 8-chloro-6, 11-dihydro- 11 -(4-piperidilydene) - 5H-benzo [5,6] cyclohepta (1,2-b) pyridine was 74 gm with a purity of 99.47% giving a yield of 91.2%. Further purification in methanol-isopropyl ether was achieved to get a yield of 66gm (81.3%) with an absorbance of 0.08 (430 [NM).] |
80.1% | With sodium hydroxide; In butan-1-ol; for 3h; | The reaction was carried out as described in Example 1, but the n-butanol [(400ML,] 4.37 mole) was used instead of methanol [(400ML)] The reaction is completed in 3 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.6% (OAB, HPLC) giving a yield of 88.7%. This was further purified to get an absorbance of 0.08 and yield of 65 gm (80. [1%).] |
80.1% | With sodium hydroxide; In benzyl alcohol; for 3h; | The reaction was carried out as described in Example 1, but the benzyl alcohol [(400ML,] 3.87 mole) was used instead of methanol (400ml). The reaction is completed in 3 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 73 gm which was further purified in methanol-isopropyl ether to get purity 99.76% (OAB, HPLC) and an absorbance of 0.08 (430 nm) giving a yield of 80. [1%.] |
78.8% | With sodium hydroxide; In propan-1-ol; for 4h; | The reaction was carried out as described in Example 1, but the n-propanol [(400ML,] 5.36 mole) was used instead of methanol [(400ML).] The reaction is completed in 4 hrs. The isolated yield of 8-chloro-6, [11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5,6] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.5% (OAB, HPLC) giving a yield of 88. [7%.] Further purification in methanol-isopropyl ether provides the yield of 64 gm (78.8 %) with an absorbance of 0.09 (430 nm). |
77.6 - 88.7% | With sodium hydroxide; In ethanol; for 5h; | The reaction was carried out as described in Example 1, but the ethanol (400 [ML,] 6.83 mole) was used instead of methanol (400ml). The reaction is completed in 5 hrs. The isolated yield [OF 8-CHLORO-6, 11-DIHYDRO-11-(4-PIPERIDILYDENE)-5H-BENZO] [5, [6]] cyclohepta (1,2-b) pyridine was 72 gm with a purity of 99.5% (OAB, HPLC) and an absorbance of 0.6 at 430 nm. giving a yield of 88.7% Further purification with methanol-isopropyl ether results in 92% yield, and 0.1 absorbance. |
~ 48% | With sodium hydroxide; polyethylene glycol 400; In toluene; for 2h;Heating / reflux; | EXAMPLE 1 Step-i-Preparation of 8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (Des<strong>[79794-75-5]loratadine</strong>) To a solution of <strong>[79794-75-5]loratadine</strong> (50 gms) in toluene (200 ml), polyethylene glycol 400 (100 ml) was added and stirred. Sodium hydroxide (50 gms) was added to the above reaction mixture and refluxed for 2 hours. The course of the reaction was monitored by HPLC and after completion of the reaction, water (750 ml) and toluene (100 ml) was added and stirred well. The organic layer was separated out; the aqueous layer was extracted with toluene (2×100 ml). The combined organic layer was washed with water (2×250 ml) followed by brine (1×250 ml) and evaporated the solvent under vacuum. Recrystallization The obtained solid was dissolved in the mixture of toluene: methylisobutyl ketone (1:1 v/v) at 85 C., followed by the addition of IPE at 60 C. and cooled to 5 C. to 10 C. The obtained solid was filtered off. This recrystallization may be repeated to obtain the desired quality and purity of Des<strong>[79794-75-5]loratadine</strong>. Yield: 19.0 gms (48.0%). |
~ 48% | With sodium hydroxide; In decaethylene glycol; toluene; for 2h;Heating / reflux; | Example 1; Step-i-Preparation of 8-chloro-6,l 1-dihydro-l l-(4-piperidinyIidene)-5H- benzof5,61cycloheptafl,2-b1pyridine (Des<strong>[79794-75-5]loratadine</strong>); To a solution of <strong>[79794-75-5]loratadine</strong> (50 gms) in toluene (200 ml), polyethylene glycol 400 (100 ml) was added and stirred. Sodium hydroxide (50 gms) was added to the above reaction mixture and refluxed for 2 hours. The course of the reaction was <n="6"/>monitored by HPLC and after completion of the reaction, water (750 ml) and toluene (100 ml) was added and stirred well. The organic layer was separated out; the aqueous layer was extracted with toluene (2 X 100 ml). The combined organic layer was washed with water (2 X 250 ml) followed by brine (1 X 250 ml) and evaporated the solvent under vacuum.Recrvstallization :The obtained solid was dissolved in the mixture of toluene : methylisobutyl ketone (1:1 v/v) at 85C, followed by the addition of IPE at 60C and cooled to 5 C to 10 C. The obtained solid was filtered off. This recrystallization may be repeated to obtain the derived quality of Des<strong>[79794-75-5]loratadine</strong>.Yield: 19.0 gms (- 48.0 %). |
With potassium hydroxide; In ethanol; water; | G. 8-Chloro-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR68 Hydrolize the title compound of Preparative Example 1F, 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in EtOH (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the EtOH and dilute the residue with brine, and extract with EtOAc (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, melting point 154-155 C.). | |
With potassium hydroxide; In ethanol; water; | G. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR71 Hydrolize the title compound of Preparative Example 1F, 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in ethanol (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the ethanol and dilute the residue with brine, and extract with ethyl acetate (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, melting point 154-155 C.). | |
With potassium hydroxide; In ethanol; water; | G. 8-Chloro-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR69 Hydrolize the title compound of Preparative Example 1F, 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in ethanol (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the ethanol and dilute the residue with brine, and extract with ethyl acetate (3x). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, melting point 154-155 C.). | |
With potassium hydroxide; In ethanol; water; | G. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR99 Hydrolize the title compound of Preparative Example 1F, 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in EtOH (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the EtOH and dilute the residue with brine, and extract with EtOAc (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, melting point 154-155 C.). | |
With potassium hydroxide; In ethanol; water; | G. 8-Chloro-11-(4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR82 Hydrolize the title compound of Preparative Example 1 F, 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in EtOH (305 mL) and water (270 mL) at reflux under an argon atmosphere 5 for 64 hours. Partially distill off the EtOH and dilute the residue with brine, and extract with EtOAc (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, melting point 154-155 C.). | |
With potassium hydroxide; In ethanol; water; | G. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR46 Hydrolize the title compound of Preparative Example 1F, 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in ethanol (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the ethanol and dilute the residue with brine, and extract with ethyl acetate (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77%, melting point 154-155 C.). | |
With methanol; sodium hydroxide; water; at 78 - 82℃; for 6 - 8h;Heating / reflux; | A mixture of <strong>[79794-75-5]loratadine</strong> (10 g) and sodium hydroxide (11 g) in water (10 ml) and methanol (40 ml) was refluxed for about 6 to about 8 hours at a temperature ranging from about 78 C. to about 82 C. After completion of reaction as determined by TLC, the methanol was distilled out at a temperature of about 50 C., and then cooled to a temperature ranging from about 25 C. to about 30 C. until a thick slurry was obtained. Water (30 ml) and dichloromethane (40 ml) were added. The mixture was stirred at a temperature ranging from about 25 C. to about 30 C. for about 5 to about 10 minutes and the layers were allowed to settle. The organic layer was separated and the aqueous layer was further extracted with 2 portions of dichloromethane (50 ml). The combined organic layers were washed with water until a pH of about 7 to about 9 was achieved. The combined layers were then dried over sodium sulfate and stirred at a temperature ranging from about 25 to about 30 C. for about 96 hours. The solid separated was filtered, washed with chilled (0 C.) dichloromethane (2-5 ml) and dried at a temperature ranging from about 50 C. to about 60 C. under vacuum until loss on drying (?LOD?) was less than about 0.5% to give des<strong>[79794-75-5]loratadine</strong> Form III (about 4.8 g; yield-about 48% w/w). The XRD of the final product is set forth in FIG. 1 and was recorded and identified as crystalline Form III of des<strong>[79794-75-5]loratadine</strong>.; EXAMPLE 2 Preparation of Polymorph Form V of Des<strong>[79794-75-5]loratadine</strong> A mixture of <strong>[79794-75-5]loratadine</strong> (10 g) and sodium hydroxide (11 g) in water (10 ml) and methanol (40 ml) was refluxed for about 6 to about 8 hours at a temperature ranging from about 78 to about 82 C. After completion of reaction as determined by TLC, water (40 ml) and dichloromethane (40 ml) were added. The mixture was stirred at temperature ranging from about 25 C. to about 30 C. for about 5 to about 10 minutes and the layers were allowed to settle. The organic layer was separated and the aqueous layer was further extracted with 2-3 portions of dichloromethane 50 ml. The combined organic layers were washed with water until a pH of about 8 was achieved. The solvent was distilled out until about 20 ml volume remained. The remaining mixture was stirred at a temperature ranging from about 15 C. to about 25 C. for about 2 to about 3 hours. The solid separated was filtered, washed with n-hexane (10 ml) and dried at a temperature ranging from about 50 C. to about 60 C. under vacuum until LOD was less than about 0.5% to give des<strong>[79794-75-5]loratadine</strong> Form V (about 3.0 g; yield-30% w/w). The XRD of the final product is set forth in FIG. 2 and was recorded and identified as crystalline Form V of des<strong>[79794-75-5]loratadine</strong>. | |
With potassium hydroxide; water; In ethanol; at 43 - 45℃; for 12 - 14h;Heating / reflux; | To a solution of potassium hydroxide (120 g) in ethanol (694 ml) and water (70 ml) was added <strong>[79794-75-5]loratadine</strong> (100 g) at 43-45 C. under an atmosphere of nitrogen. The contents were refluxed for 12-14 hours. The reaction mixture was monitored by HPLC and was continued till un-reacted <strong>[79794-75-5]loratadine</strong> was not more than 1%. The reaction mixture was cooled to 35-40 C. and de-ionized water (625 ml) was added. Ethanol was recovered under reduced pressure at a temperature of 50-55 C. The residue was extracted twice with ethyl acetate (500 ml+300 ml) at room temperature. The organic layer was washed with 10% sodium chloride solution, decolorized with activated carbon, dried with sodium sulphate and filtered through hyflo bed. The organic layers were combined and ethyl acetate was recovered at a temperature of 76-78 C. at atmospheric pressure leaving inside a total volume of about 160 ml. The contents were cooled to 20-25C. Acetone (200 ml) was then added to the reaction mixture and it was stirred for 3 hours. The reaction mixture was then cooled to 0-5 C., filtered, washed with pre-cooled mixture of acetone and ethyl acetate and dried under reduced pressure at 50-55 C. to obtain Form 1 of des<strong>[79794-75-5]loratadine</strong> essentially free of Form 2. Yield: 68 g HPLC Purity: 99.5% | |
With sodium hydroxide;tetrabutylammomium bromide; In water; at 130 - 140℃; under 2206.72 Torr; for 5 - 6h;Product distribution / selectivity; | EXAMPLE 2 Process for the Preparation of Des<strong>[79794-75-5]loratadine</strong> Using Water as Solvent Sodium hydroxide (51 g), water (200 ml), tertiary-butyl ammonium bromide (12.5 g) and 4-(8-chloro-5 6-dihydro-11 h-benzo-(56)-cyclohepta-(1,2b)-pyridin-11-ylidene-1-piperidiniecarboxylic acid ethyl ester (50 g) were taken into a clean and dry autoclave vessel followed by heating to about 130 to about 140 C. The resultant reaction mixture was agitated at about 3 Kg/cm2 of atmospheric pressure for about 5 to about 6 hours. After completion of the reaction, the reaction mass was cooled to about 65 C., and water (400 ml) was added. The reaction mass was stirred for about 30 minutes followed by extraction with toluene (2*100 ml) and the combined organic phase was washed with water (200 ml). The obtained neat organic phase was distilled to about 70% to about 75% of its original volume (260 ml) and the resultant suspension was cooled to about 0 to about 5 C. followed by stirring for about 45 minutes. The separated solid was filtered and the solid was washed with toluene to afford the title compound. | |
With sodium hydroxide; In water; toluene; at 25 - 35℃; for 0.5h;pH > 9.0;Product distribution / selectivity; | Toluene (365 liters) was taken into a reactor and 8-chloro-6,11-dihydro-11-(1-methyl-1-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (27 kg) was added to it at about 25 to about 35 C. The reaction mass was maintained at about 25 to about 35 C. for about 20 minutes. Triethyl amine (41 liters) was added to the above reaction mass at about 25 to about 35 C., and the reaction mass was heated to a temperature of about 75 C. A solution of ethylchloroformate (79 liters) and toluene (41 liters) was prepared and then added to the above reaction mass at a temperature of about 75 C. The reaction mass was then maintained at about 75 C. for about 90 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to a temperature of about 25 C. and water (203 liters) was added followed by addition of caustic lye (11 liters). The reaction mass was stirred at about 25 to about 35 C. about 30 minutes. The pH of the reaction mass was ensured to be above 9.0, and the layers were separated. The aqueous layer was extracted into 135 liters of toluene. The combined organic layer was washed with water (406 liters) in two equal lots. The organic layer was distilled off at about 70 C. under a vacuum of about 600 mm/Hg until about 400 liters of toluene was distilled off. The remaining residue was cooled to about 35 C. and further subjected to distillation in an ATFD at about 65 C. and a vacuum of about 650 mm/Hg to distill off the solvent completely.The dried powder obtained from ATFD was collected and cyclohexane (250 liters) was added. The mixture was heated to about 75 C. and checked for clear dissolution. After clear dissolution was obtained, the solution was cooled to about 45 C. and maintained for about 25 minutes. Then the reaction mass was then cooled to about 35 C. and maintained for about 30 minutes. The reaction mass was then further cooled to about 12 C. and maintained for about 30 minutes, and then filtered. The filtered solid was washed with cyclohexane (20 liters). The wet solid was dried at about 65 C. under a vacuum of about 600 mm/Hg for about 3 hours. The dry material was then milled in a multi mill to yield 25 kg of the title compound.Purity by HPLC: 99.9%. | |
[1227] Loratadine (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCl (1.4 L conc.HCl in 600 ml H2O) for 12 h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2Cl2 (1×4L, and 2×2.5L). The organic phase was washed with brine, dried over Na2SO4 and MgSO4 and then filtered. All the volatiles were then removed to give 368 g of the title compound (2). MH+=311 | ||
[1777] Loratadine (448 g, 1.17 mol) was refuxed in 2 L of 70% aqueous HCl (1.4 L conc. HCl in 600 ml H2O) for 12 h. The reaction mixture was then cooled and poured into ice. It was then basified with 950 mL of 50% NaOH followed by extraction with CH2Cl2 (1×4L, and 2×2.5L). The organic phase was washed with brine, dried over Na2SO4 and MgSO4 and then filtered. All the volatiles were then removed to give 368 g of the title compound (2). MH+=311 | ||
With potassium hydroxide; ethanol; water; at 25 - 40℃; for 22.33h;Heating / reflux; | a) Ethanol (100 ml) is added to 11-[N-(ethoxycarbonyl)-4-piperidylidene]-8-chloro-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridine (15 gm) and then potassium hydroxide solution (22.5 gm of KOH in 90 ml of water) is added for 20 minutes at 25-40 C. The contents are heated to reflux, stirred for 22 hours and distilled off ethanol under vacuum below 50 C. To the aqueous part is added sodium chloride (15 gm), extracted three times with ethyl acetate (each time 50 ml), dried and distilled off the ethyl acetate layer. Acetonitrile (20 ml) is added to the residual solid and stirred for 30 minutes at 10-15 C. Filter the solid, washed with 5 ml of acetonitrile and dried to give 10.5 gm of 8-Chloro-11-(4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (HPLC purity: 99.5%). | |
With lithium hydroxide monohydrate; sodium hydroxide; In ethanol; water; at 35℃;Reflux; | Example: Preparation of Des<strong>[79794-75-5]loratadine</strong>Ethane (600 mL) was added to a clear solution containing sodium hydroxide (11 g) in de-ionized water (400 mL) at a temperature of about 3O0C to 320C. Lithium hydroxide monohydrate (131 g) was added. The contents were stirred for about 5 to 10 minutes to obtain a uniform mixture. Loratadine (100 g) was added to the mixture at a temperature of about 350C to 450C. The temperature of the reaction mixture was raised to reflux temperature. The reaction mixture was stirred for about 34 to 40 hours. The reaction mixture was slowly cooled to about 4O0C to 450C in about 30 minutes to 40 minutes. De- ionized water (660 mL) was added. Ethanol was completely recovered under reduced pressure. The contents were cooled to about 1O0C to 150C in about 30 to 40 minutes. Ethyl acetate (500 rnL) was added. The contents were stirred for about 15 to 20 minutes, filtered through celite and the bed was washed with ethyl acetate. The layers were separated and ethyl acetate (200 mL) was added to the aqueous layer. The contents were stirred for about 15 to 20 minutes at ambient temperature and the layers were separated. 10% aqueous sodium chloride solution (400 mL) was added to the combined organic layers; this was stirred for 5 to 10 minutes and the layers were separated. The organic layer was treated with activated carbon, stirred for about 60 minutes, filtered and washed with ethyl acetate. Organic layers were combined and ethyl acetate was recovered completely at a temperature of about 8O0C to 9O0C under atmospheric pressure. The residue was cooled to about 2O0C to 250C and acetone (200 mL) was added. The contents were stirred for about 15 hours, filtered, washed with chilled acetone at a temperature of about O0C to 50C and dried. De-ionized water (300 mL) was added to the wet cake. The contents were stirred for about 2 hours, filtered and dried in an air oven to obtain des<strong>[79794-75-5]loratadine</strong>.Yield: 60.9gTotal Related Substances by HPLC: 0.266% w/wIsomer of Formula II: 0.051% w/w | |
With potassium hydroxide; ethanol; water; at 25 - 40℃; for 22.3333h;Heating / reflux; | Example 1 a) Ethanol (100 ml) is added to 11-[Lambda/-(ethoxycarbonyl)-4-piperidylidene]-8- chloro-ThetaJ I-dihydro-deltaH-benzo-Idelta^cycloheptati ^-bJpyridine (15 gm) and then potassium hydroxide solution (22.5 gm of KOH in 90 ml of water) is added for 20 minutes at 25 - 400C. The contents are heated to reflux, stirred for 22 hours and distilled off ethanol under vacuum below 500C. To the aqueous part is added sodium chloride (15 gm), extracted three times with ethyl acetate (each time 50 ml), dried and distilled off the ethyl acetate layer. Acetonitrile (20 ml) is added to the residual solid and stirred for 30 minutes at 10 - 150C. Filter the solid, washed with 5 ml of acetonitrile and dried to give 10.5 gm of 8-Chloro-11-(4- piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (HPLC purity: 99.5%). | |
With lithium hydroxide monohydrate; water; sodium hydroxide; In ethanol; at 35℃;Reflux; | Example: Preparation of Des<strong>[79794-75-5]loratadine</strong>Ethane (600 mL) was added to a clear solution containing sodium hydroxide (11 g) in de-ionized water (400 mL) at a temperature of about 30 C. to 32 C. Lithium hydroxide monohydrate (131 g) was added. The contents were stirred for about 5 to 10 minutes to obtain a uniform mixture. Loratadine (100 g) was added to the mixture at a temperature of about 35 C. to 45 C. The temperature of the reaction mixture was raised to reflux temperature. The reaction mixture was stirred for about 34 to 40 hours. The reaction mixture was slowly cooled to about 40 C. to 45 C. in about 30 minutes to 40 minutes. De-ionized water (660 mL) was added. Ethanol was completely recovered under reduced pressure. The contents were cooled to about 10 C. to 15 C. in about 30 to 40 minutes. Ethyl acetate (500 mL) was added. The contents were stirred for about 15 to 20 minutes, filtered through celite and the bed was washed with ethyl acetate. The layers were separated and ethyl acetate (200 mL) was added to the aqueous layer. The contents were stirred for about 15 to 20 minutes at ambient temperature and the layers were separated. 10% aqueous sodium chloride solution (400 mL) was added to the combined organic layers; this was stirred for 5 to 10 minutes and the layers were separated. The organic layer was treated with activated carbon, stirred for about 60 minutes, filtered and washed with ethyl acetate. Organic layers were combined and ethyl acetate was recovered completely at a temperature of about 80 C. to 90 C. under atmospheric pressure. The residue was cooled to about 20 C. to 25 C. and acetone (200 mL) was added. The contents were stirred for about 15 hours, filtered, washed with chilled acetone at a temperature of about 0 C. to 5 C. and dried. De-ionized water (300 mL) was added to the wet cake. The contents were stirred for about 2 hours, filtered and dried in an air oven to obtain des<strong>[79794-75-5]loratadine</strong>.Yield: 60.9 gTotal Related Substances by HPLC: 0.266% w/wIsomer of Formula II: 0.051% w/w | |
With potassium hydroxide; In ethanol; water; at 80℃; for 0.5h; | 0.1 mol of 3,5-lutidine is dissolved in 200 mL of carbon tetrachloride, and is completely dissolved and loaded in the first raw material storage tank;0.12 mol of N-bromosuccinimide (NBS) was dissolved in 200 mL of carbon tetrachloride, and was completely dissolved and loaded in a second raw material storage tank;Taking 0.052 mol of <strong>[79794-75-5]loratadine</strong> dissolved in 100 mL of ethanol, and after being completely dissolved, loading in a third raw material storage tank;0.893 mol of KOH is dissolved in 200 mL of water, and after being completely dissolved, it is loaded in a fourth raw material storage tank;Loading 200 mL of carbon tetrachloride solution in a fifth raw material storage tank;50 mL of the triethylamine solution is loaded in the sixth raw material storage tank;Taking 0.05 mol of dimethylaminopyridine before the third microreactor;That is, the molar ratio of 3,5-dimethylpyridine, brominating agent (N-bromosuccinimide), <strong>[79794-75-5]loratadine</strong>, alkali (potassium hydroxide), and catalyst (dimethylaminopyridine) is 1:1.2: 0.5:9:0.5; the feed liquid is simultaneously pumped into the microchannel reaction device through the first feed pump 1 and the second feed pump 2, and after being mixed by the first mixer 7, the first microreaction having a coil inner diameter of 0.5 mm is entered. In the reactor, the micro-reaction parameters were set: the flow rate of the carbon tetrachloride solution of 3,5-lutidine was 0.5 mL/min, and the flow rate of the carbon tetrachloride solution of NBS was 0.5 mL/min. The flow rate is 1.0 mL/min, the reaction temperature is controlled at 50 C, and the residence time is 30 min. The reaction mainly produces a solution of 5-bromomethyl-3-methylpyridine in carbon tetrachloride;At the same time, the feed liquid is simultaneously pumped into the microchannel reaction device through the third feed pump 3 and the fourth feed pump 4, and after being mixed by the second mixer 8, it is introduced into the second microreactor having a coil inner diameter of 0.5 mm. Reaction, setting the micro-reaction parameters: the flow rate of the ethanol solution of <strong>[79794-75-5]loratadine</strong> is 0.5 mL/min, the flow rate of the aqueous solution of KOH is 0.8 mL/min, the flow rate of the continuous flow in this step is 1.3 mL/min, and the reaction temperature is controlled at 80 C. , the residence time is 30 min, the reaction mainly produces <strong>[79794-75-5]loratadine</strong>;When the second microreactor has a reaction liquid flowing out, the fifth feed pump 5 pumps the carbon tetrachloride solution into the microchannel reaction device, and after mixing through the third mixer 9 and the reaction liquid obtained in the second microreactor, In the oil-water separator 12, during the mixing process, the chlorhexidine is extracted from the reaction liquid by the carbon tetrachloride solution, and after entering the oil-water mixer, the aqueous phase is removed from the outlet, and the obtained des<strong>[79794-75-5]loratadine</strong> solution is separated from the oil-water. The bottom of the device enters the next reaction, and the microreactor parameters are set: the flow rate of the carbon tetrachloride solution is 1.0 mL/min;The effluent obtained by separating the effluent obtained from the first microreactor and the oil-water separator is simultaneously pumped into the fourth mixer 10, and the solution after mixing the fourth mixer 10 and the third in the sixth raw material storage tank The ethylamine solution is simultaneously pumped into the fifth mixer 11 and mixed into the coil inner diameter of 0.5 mm.The reaction was mixed in a third microreactor carrying a catalyst (dimethylaminopyridine), and the microreactor parameters were set: the flow rate of the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine was 1.0 mL/min. The flow rate of <strong>[79794-75-5]loratadine</strong> in a carbon tetrachloride solution was 1.0 mL/min. The flow rate of this continuous flow was 2.0 mL/min, and the flow rate of the triethylamine solution was 0.3 mL/min. The flow rate of this continuous flow was 2.3. mL/min, staying for 20 min, the reaction mainly produces rupatadine. The reaction liquid was collected by the receiver 13, washed with water, dried, filtered, and a solution of fumaric acid dissolved in methanol was added thereto, and the mixture was heated to reflux, and slowly cooled to room temperature, and placed in a refrigerator for 12 hours.Precipitating a white solid compound, which is rupatadine fumarate, yield 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With boric acid; In toluene;Reflux; | To a 500 mL reaction flask was added 280 mL of toluene, 31.1 g (100 mmol) of 8-chloro-6,11-dihydro-11-(4-piperidine).Benzo [5,6] -cyclohepta [1,2-b] pyridine (II) and 0.9 g (15 mmol) of boric acid were added and the mixture was stirred well.Into 16.5g (120mmol) of <strong>[3222-49-9]5-methylnicotinic acid</strong> (), after the addition began to heat up to reflux, points to return to the water, keep the reaction 6-8 hours,The reaction was allowed to cool to room temperature.The reaction solution was concentrated under reduced pressure until almost no solvent was added, and 250 g of ethyl acetate was added to warm up to dissolve all the solids.Saturated aqueous sodium carbonate solution pH = 8 or so, standing stratification, points to the water layer, the organic layer placed in a 500mL reaction flask,While stirring, cool down to 8~10C, a large amount of solids precipitated, keep crystallization for 2 hours, filter and dry to obtain white solid40.8 g, yield 95.0%, melting point 124-126C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 18h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane for 18h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; tetrabutylammomium bromide; In tetrachloromethane; water; at 20℃; for 6 - 8h;Product distribution / selectivity; | (b) 3.7 L of the solution from product of Example 4 (a) is stirred with 60 Gms Desloratadine , 7.6 gms Tetrabutyl ammonium bromide. To it aqueous solution of sodium hydroxide(18.66 gms sodium hydroxide in 100 ml water) is added at room temperature. And the reaction mass is stirred for 6-8 hours at room temperature. Stirring is stopped and the reaction mass is allowed to settle and layers are separated . The organic layer is charged in round bottom flask and 500 ml water is added to it. The reaction mass is stirred for 15 to 20 minutes and allowed to settle. The layers are separated. The aqueous layer is discarded. The organic phase is dried over anhydrous sodium sulfate. The organic phase is filtered and solvent is distilled under vacuum at 35-400C. Weight of residue is 110 gms. To it 560 ml acetone is added at room temperature and stirred to dissolve it. 160 gms silica gel is added to it and stirred for one hour at room temperature. The silica gel is removed by filtration and washed with acetone and solvent is removed to give Rupatadine.Weight of Rupatadine obtained = 60 gms. | |
With dmap; triethylamine; In chloroform; at 25 - 30℃; for 18h; | To the filtrate is added 8-Chloro-11-(4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (10 gm) obtained in (a) above, chloroform (100 ml), triethylamine (17 gm) and dimethylaminopyridine (0.5 gm), and stirred for 18 hours at 25-30 C. Then 5% NaHCO3 solution (300 ml) is added to the reaction mass, stirred for 15 minutes, separated the layers and the organic layer is washed two times with water (each time 300 ml). The organic layer is separated and distilled under vacuum below 50 C. to give 15 gm of rupatadine as a residue (HPLC purity: 86.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine In tetrachloromethane; chloroform for 18h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide for 18h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 4℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine; at -5℃; for 12h; | II-1 (50g, 161mmol) in 250 ml in the reaction bottle, adding pyridine (150 ml), stirring to dissolve the same, -5 C lower stirring, by adding intermediate III-2 in batches (35.7g, 161mmol), keeping the temperature and mixing and 12h, TLC detection display reaction is ended (developing agent ethyl acetate: petroleum ether = 1:3). The reaction the fluid plunges 4500 ml of cold water, stirring, a solid precipitated. Filtering, the filter cake washing, drying, crocatus solid crude product obtained. The crude product is recrystallized with ethanol, to obtain the yellow solid 76.7 g. Purity 98.9% (normalization HPLC), yield 96.0%. ESI-MS: 496.1. |
88% | General procedure: Compound 4c was prepared using a similar method as for 4a. Yield: 88%,m.p.: >230 C; 1H-NMR (CDCl3): delta 2.34-2.39 (m, 2H), 2.46-2.49 (m, 1H), 2.60-2.62 (m, 1H),2.72-2.81 (m, 2H), 2.99-3.03 (m, 2H), 3.20-3.33 (m, 4H), 6.98 (d, J = 8.4 Hz, 1H), 7.05-7.13 (m, 3H),7.39 (d, J = 7.6 Hz, 1H), 7.91-7.94 (m, 2H), 8.33-8.37 (m, 3H). | |
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[1228] To the title compound from Preparative Example 1, Step A (363 g, 1.17 mol) was added trifuromethane sulfonic acid (1.8 Kg) under N2. The reaction mixture was refluxed at 170 C. The progress of the reaction was monitored by 1H NMR. After 4 days the reaction was only 63% complete. After 8 days the reaction was found to be 80% complete according to 1H NMR; thus another 130 mL of CF3SO3H were added and refuxing continued for another 24 h. It was then poured into ice and basified with 800 mL of NaOH (50%) and extracted twice with CH2Cl2(1×8L then 1×7L). The organic phase was combined, washed with H2O and filtered through celite. It was then dried over MgSO4 and Na2SO4 and again filtered through celite. The filtrate was concentrated to give a black brown semi-solid that was pre adsorbed on 600 g of silica gel and then chromatographed on 2.3 Kg of silica gel eluting first with 5% CH30H-CH2Cl2 (saturated with ammonia) and then with 10% CH30H-CH2Cl2 (saturated with ammonia) to give 102 g of the title compound (3) as a solid. mp=73-75; MS (FAB) m/z 483 (MH+). | ||
[1778] To the title compound from Preparative Example 1, Step A (363 g, 1.17 mol) was added trifuromethane sulfonic acid (1.8 Kg) under N2. The reaction mixture was refluxed at 170 C. The progress of the reaction was monitored by 1H NMR. After 4 days the reaction was only 63% complete. After 8 days the reaction was found to be 80% complete according to 1H NMR; thus another 130 mL of CF3SO3H were added and refuxing continued for another 24 h. It was then poured into ice and basified with 800 mL of NaOH (50%) and extracted twice with CH2Cl2(1×8L then 1×7L). The organic phase was combined, washed with H2O and filtered through celite. It was then dried over MgSO4 and Na2SO4 and again filtered through celite. The filtrate was concentrated to give a black brown semi-solid that was pre adsorbed on 600 g of silica gel and then chromatographed on 2.3 Kg of silica gel eluting first with 5% CH3OH-CH2Cl2 (saturated with ammonia) and then with 10% CH3OH-CH2Cl2 (saturated with ammonia) to give 102 g of the title compound (3) as a solid. mp=73-75; MS (FAB) m/z 483 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.8% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 20h;Inert atmosphere; | S4, preparation of rupatadine:In charge N2 environment,According to the molar portion will be 1 to dertat,2.5 parts of potassium carbonate,N, N-dimethylformamide and 2 parts of 3-methyl-5-chloromethylpyridine hydrochloride obtained in S3,Warmed to 50 ,Insulation 20h,Insulation kept stirring process,After adding water and mixing,Add dichloromethane extraction 5 times,The combined dichloromethane phases then give solution E,Solution E was washed twice with water,Take the supernatant to obtain a solution F,Then the supernatant is solution G,Add dichloromethane to solution F for extraction,Remove the supernatant to obtain a solution H,The solution H and solution G mixed,Add anhydrous sodium sulfate dried to a moisture content of 0.3wt%Filtration, rotary evaporation to give rupatadine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; | G. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR71 Hydrolize the title compound of Preparative Example 1E, 8-chloro-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in ethanol (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the ethanol and dilute the residue with brine, and extract with ethylacetate (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77percent, melting point 154°-155° C.). | |
With potassium hydroxide; In ethanol; water; | G. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE Hydrolize the title compound of Preparative Example 1E, 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (39 g, 0.101 mole) with KOH (50 g) in ethanol (305 mL) and water (270 mL) at reflux under an argon atmosphere for 64 hours. Partially distill off the ethanol and dilute the residue with brine, and extract with ethylacetate (3*). Wash the combined organic phases with water and dry with Na2 SO4. Remove the solvent to give a solid which can be recrystallized from toluene to give the title compound as a white solid. (Yield: 24.5 g, 77percent, melting point 154°-155° C.). By substituting in step 1B above, an appropriately substituted benzylhalide listed in Table 1 below for meta-chlorobenzylchloride, and employing basically the same methods as steps C through G, the products listed in Table 1 are prepared by the process of Preparative Example 1 above. Reaction times are determined by TLC or HPLC. In some instances purification of the product by chromatography is necessary. Preparative Example 2A through 2G follows the reaction sequence shown below. STR35 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With lithium aluminium tetrahydride; In toluene;Heating / reflux; | Combine 82.0 g (0.26 mole) of the product of Preparative Example 1, Step G, of WO 95/10516, and 1 L of toluene, then add 20.06 g (0.53 mole) of LiAlH4 and heat the reaction mixture at reflux overnight. Cool the mixture to room temperature and add ?1 L of Et2O, followed by dropwise addition of saturated Na2SO4 (aqueous) until a precipitate forms. Filter and stir the filtrate over MgSO4 for 30 minutes, then concentrate in vacuo to give the product compound in 83% yield. Mass Spec.: MH+ = 313 |
With ammonia; magnesium sulfate; sodium sulfate; In tetrahydrofuran; diethyl ether; dichloromethane; | PREPARATIVE EXAMPLE 2 8-Chloro-6,11-Dihydro-11-(4-Piperidinyl)-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine (Product A) and 6,11-Dihydro-11-(4-Piperidinyl)-5H-Benzo[5,6]-Cyclohepta[1,2-b]Pyridine (Product B) STR70 To a solution 66.27 g (0.21 mole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta(1,2-b]pyridin-11-ylidene)-piperidine (product from Preparative Example 1 Example, step G), in THF (1 L) was added lithium aluminum hydride (24.32 g, 0.64 mole) and the reaction mixture was heated to reflux overnight. The reaction mixture was then cooled to room temperature and ~3 L of diethyl ether is added followed by dropwise addition of saturated sodium sulfate until a white gray precipitate forms. Magnesium sulfate was then added to the separated organic layer and stirred for 30 minutes. All the volatiles were then removed and the resulting crude mixture was chromatographed on a silica gel column eluding with 10% methanol saturated with ammonia in methylene chloride. The material obtained contained both the desired compound and the des-chloro compound. Separation on HPLC using reverse phase column and eluding with 40% methanol-water afforded the desired compounds as white solids (Product A's mp=95.2-96.1 C., Product B's mp=145.1-145.7 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; In dichloromethane; | EXAMPLE 1 1-(4-PYRIDYLACETYL)-4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-YLIDENE)PIPERIDINE STR256 To a mixture of 528 mg (1.7 mmol) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine (product from Preparative Example 1, Step G), 274 mg (1.7 mmol) of 4-pyridylacetic acid hydrochloride, and 242 mg (1.8 mmol) of HOBT in 5 mL of dry CH2 Cl2 at -15 C. and under a nitrogen atmosphere was added dropwise 0.17 mL (1.5 mmol) of Et3 N followed by a solution of 363 mg (1.9 mmol) of DEC in 5 mL of dry CH2 Cl2. The reaction mixture was slowly allowed to warm to room temperature. After 4 hours the minute was poured into water and extracted several times with CH2 Cl2. The combined organic potions were dried over MgSO4, filtered, and concentrated in vacuo to give a product which was purified via flash chromatography (3% MeOH saturated with ammonia in CH2 Cl2) 155 mg of 1-(4-pyridylacetyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine as a solid: mp 152-155 C. | |
With benzotriazol-1-ol; In dichloromethane; | EXAMPLE 1 1-(4-PYRIDYLACETYL)-4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-YLIDENE)PIPERIDINE STR273 To a mixture of 528 mg (1.7 mmol) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine (product from Preparative Example 1, Step G), 274 mg (1.7 mmol) of 4-pyridylacetic acid hydrochloride, and 242 mg (1.8 mmol) of HOBT in 5 mL of dry CH2 Cl2 at -15 C. and under a nitrogen atmosphere was added dropwise 0.17 mL (1.5 mmol) of Et3 N followed by a solution of 363 mg (1.9 mmol) of DEC in 5 mL of dry CH2 Cl2. The reaction mixture was slowly allowed to warm to room temperature. After 4 hours the mixture was poured into water and extracted several times with CH2 Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to give a product which was purified via flash chromatography (3% MeOH saturated with ammonia in CH2 Cl2) 155 mg of 1-(4-pyridylacetyl)-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine as a solid: mp 152-155 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In tetrahydrofuran; | EXAMPLE 13 2-[4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-piperidin-1-yl]-N-(4-methyl-2-{methyl-[4-(1H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonyl]-amino}-pentyl)-acetamide. STR22 (a) Methyl-[4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11ylidene}-piperidin1-yl]acetate Methylbromoacetate (0.17 ml, 1.77 mmol) was added dropwise to a solution of 4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidine (0.50 g, 1.61 mmol) and triethylamine (0.45 ml, 3.22 mmol) in THF (15 ml) under an inert atmosphere. The reaction was left to stir for 18 hours. THF was removed under reduced pressure and the product purified by column chromatography on silica gel, eluding with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield methyl-[4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidin-1-yl]acetate as an orange solid (550 mg, 90%). 1 H-NMR; delta (CDCl3), 8.40 (1H, m), 7.42 (1H, m), 7.09 (4H, m), 3.71 (3H, s), 3.37 (2H, m), 3.24 (2H, s), 2.79 (4H, m), 2.57 (1 H, m), 2.47 (1 H, m), and 2.37 (4H, m). 13 C-NMR; delta (CDCl3), 170.9, 157.5, 146.6, 139.5, 138.1, 137.7, 137.2, 133.4, 133.0, 132.7, 130.8, 128.9, 126.0, 122.1, 59.3, 54.6, 51.7, 31.8, 31.4, 30.8 and 30.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.66% | With sodium hydroxide; tetrabutylammomium bromide; In dichloromethane; water; at 0 - 20℃; for 13h;Product distribution / selectivity; | A mixture of desloratadine (5.0gm, 0.016mol), methylene chloride (15ml), tetrabutylammonium bromide (0.575gm, 0.0018mol) and sodium hydroxide solution (2.5gm, 0.064mol in 8ml water) is cooled to 0 to 50C. 3-bromomethyl-5- methylpyridine hydrochloride (7.18gm, 0.032mol) in methylene chloride (35ml) is EPO <DP n="8"/>added to above mixture. The reaction mixture is stirred at 0 to 50C for 1 hour and at room temperature for 12 hours. Layers are separated and organic layer is washed with dilute HCl solution and water. Methylene chloride is distilled. Yield = 9.5g %Yield =67.66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With pyridine; In dichloromethane; pentane; | EXAMPLE 1 8-CHLORO-11-(1-METHOXYACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]-CYCLOHEPTA[1,2-b]-PYRIDINE STR40 Dissolve the title compound of Preparative Example 1G above, 8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (3.00 gm, 9.7 mmol) and 1.2 mL (14.8 mmol) of pyridine in dry methylene chloride (20 mL) at 0 C. under an argon atmosphere. Add methoxyacetyl chloride (1.1 mL, 12.0 mmol) dropwise, and slowly warm to room temperature. After 1.5 hours take up the mixture in methylene chloride and wash with brine. Dry over Na2 SO4, filter, and concentrate in vacuo to give a residue and purify via flash chromatography. Triturate the product with pentane and recrystallize from ethyl acetate/pentane to give the title compound as a white solid. (1.89 g, Yield 66%, m.p. 104-106 C.). |
With pyridine; In dichloromethane; pentane; | EXAMPLE 1 8-CHLORO-11-(1-METHOXYACETYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR124 Dissolve the title compound of Preparative Example 1G above, 8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (3.00 gm, 9.7 mmol) and 1.2 mL (14.8 mmol) of pyridine in dry methylene chloride (20 mL) at 0 C. under an argon atmosphere. Add methoxyacetyl chloride (1.1 mL, 12.0 mmol) dropwise, and slowly warm to room temperature. After 1.5 hours take up the mixture in methylene chloride and wash with brine. Dry over Na2 SO4, filter, and concentrate in vacuo to give a residue and purify via flash chromatography. Triturate the product with pentane and recrystallize from ethyl acetate/pentane to give the title compound as a white solid. (1.89 g, m.p. 104-106 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; In acetonitrile; | This mutual prodrug was synthesized as depicted in Scheme 21. The compound I-AA-MPD1 was obtained as a colorless gum. 1H-NMR (300 MHz, CDCl3): delta 1.00 (d, 3H, J=6.9 Hz), 2.27-2.51 (m, 4H), 2.74-2.97 (m, 9H), 3.28-3.41(m, 4H), 3.79 (bs, 2H), 4.28-4.30 (m, 4H), 4.57 (m, 1H), 7.04-7.44 (m, 9H), 8.26-8.33 (m, 2H). MS (m/z): 682 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
b) N-Bromosuccinamide (30 gm) and 2,2'-azobisisobutyronitrile (1 gm) are added to a solution of 3,5-lutidine (17 ml) in 200 ml of carbontetrachloride, heated to 750C and stirred for 1 hour 30 minutes at 75 - 800C. The reaction mass is cooled to 250C and filtered the cake. To the filtrate is added 8-Chloro-11-(4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1 ,2-b]pyridine (10 gm) obtained in (a) above, chloroform (100 ml), triethylamine (17 gm) and dimethylaminopyridine (0.5 gm), and stirred for 18 hours at 25 - 300C. Then 5%, NaHCO3 solution (300 ml) is added to the reaction mass, stirred for 15 minutes, separated the layers and the organic layer is washed two times with water (each time 300 ml). The organic layer is separated and distilled under vacuum below500C to give 15 gm of rupatadine as a residue (HPLC purity: 86.0%). EPO <DP n="8"/>The residue is suspended in with cyclohexane (50 ml), stirred for 6 hours at 15 - 250C, filtered the solid and dried at 40 - 500C to give 6.5 gm of crystalline rupatadine form-B (HPLC purity: 99.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethanol; at 20℃; for 1h; | General procedure:The flask was charged with 10 mLof absolute ethanol, 1.0 g (3.4 mmol) of desloratadine and 6.8 mmol of RNCS.The resulting solution was stirred at rt for over 1 h. Then the white suspension was filtered under suction and the solid was washed with a small amount of cold ethanol to obtain the white product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | In ethanol; at 20℃; for 2h; | The flask was charged with 60 mL of absolute ethanol, 6.0 g (19.3 mmol) of 1 (desloratadine) and 2.9 g (20 mmol) of dimethyl cyanocarbonimidodithioate. The resulting solution was stirred at rt for over 2 h. Then the white suspension was filtered under suction and the solid was washed with a small amount of cold ethanol to give the white product 4 (6.4 g). Yield: 81.2% of a white solid; mp: 162-164 C. ESI-MS: 409.0 [M+H]+. IR (cm-1): 3080, 2929, 2894, 2852, 2180, 1548, 1540, 1456, 1434, 991, 834. 1H NMR (CDCl3) delta: 2.36-2.44 (m, 2H, =C(CH2)2); 2.47-2.72 (m, 2H, =C(CH2)2); 2.76 (s, 3H, SCH3); 2.78-2.90 (m, 2H, N(CH2)2); 3.28-3.39 (m, 2H, N(CH2)2); 3.50-3.60 (m, 2H, PhCH2); 4.03-4.15 (m, 2H, CH2); 7.09-7.18 (m, 3H, Ar-H); 7.26 (m, 1H, pyridine-H); 7.47 (dd, 1H, J = 7.3 Hz, pyridine-H); 8.40 (dd, 1H, J = 4.7 Hz, pyridine-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; | The compound (120 mg, 0.39 mmol) obtained in Production Example 92 was dissolved in N,N-dimethylformamide, and methyl 3-bromomethylbenzoate (99 mg, 0.43 mmol) and potassium carbonate (59 mg, 0.43 mmol) were added thereto. The mixture was stirred at 70 C. overnight. After the solvent was distilled off, ethyl acetate was added to the residue. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. The solvent was distilled off, and then the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate 5:1) to give the title compound (170 mg, 95.0%) as an oily substance. 1H-NMR (CDCl3, delta): 2.1-2.5 (6H,m), 2.7-2.9 (4H,m), 3.3-3.5 (2H,m), 3.54 (2H,s), 3.91 (3H,s), 7.1-7.2 (4H,m), 7.3-7.4 (2H,m) 7.5-7.6 (1H,m), 7.9-8.0 (2H,m), 8.39 (1H,dd,J=1.9 Hz, 4.9 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0°C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To a solution of desloratadine (100 g, 322 mmol) in CH2Cl2 (500 mL), Et3N(48 g, 480 mmol) was added and the mixture was stirred at 0 C for 10 min. Then 2a (59.8 g,322 mmol) dissolved in CH2Cl2 (200 mL) was added dropwise into the mixture and stirring was continuedfor another 2 h. The reaction misxture was washed successively with 1 mol/L hydrochloric acid andwater. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give thecrude product as a yellow powder, which was recrystallized from ethanol affording 4a as a white powder.Yield: 95%; m.p.: 188.2-189.0 C; 1H-NMR (400 MHz, DMSO-d6): delta 2.18-2.32 (m, 2H), 2.41 (br s, 1H),2.79-2.84 (m, 2H), 3.17-3.36 (m, 6H), 3.97 (br s, 1H), 7.05-7.32 (m, 4H), 7.54-7.57 (m, 1H), 7.68 (d,J = 8.4 Hz, 2H), 8.25-8.36 (m, 3H). | |
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | General procedure: Compound 4b was prepared using a similar method as for 4a. Yield: 97%, m.p.:221.7-222.8 C; 1H-NMR (CDCl3): delta 2.40-2.41 (m, 2H), 2.50-2.57 (m, 1H), 2.62-2.68 (m, 1H),2.71-2.86 (m, 2H), 3.09-3.15 (m, 2H), 3.22-3.36 (m, 4H), 7.01 (d, J = 8.0 Hz, 2H), 7.11-7.15 (m, 3H),7.45 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 8.07-8.10 (m, 1H), 8.37 (d, J = 6.4 Hz, 1H),8.44-8.59 (m, 1H), 8.59 (d, J = 2.0 Hz, 1H). | |
97.2% | With triethylamine; In dichloromethane; at 20℃; for 6h; | II-1 (50g, 161mmol) in 1000 ml in the reaction bottle, by adding CH 2 Cl 2 (300 ml) stirring dissolved, add triethylamine (49g, 483mmol), stirring at room temperature, adding intermediate III-1 in batches (35.7g, 161mmol), maintaining the temperature to stir 6h, TLC detection display reaction is ended (developing agent ethyl acetate: petroleum ether = 1:3). The reaction the fluid plunges 200 ml of cold water, full oscillation layered, obtaining organic layer, so the continuous washing three times. The organic layer is dried with anhydrous sodium sulfate, placing sleepovers. Filtration, solvent evaporation to dryness under reduced pressure, to obtain light yellow solid crude product. The resulting crude product is recrystallized with ethanol, to obtain white solid 77.6 g. Purity 98.5% (normalization HPLC), the yield is 97.2%. ESI-MS: 496.1. |
With triethylamine; In dichloromethane; at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0℃; for 2h; | General procedure: The syntheses of the compounds are illustrated in Schemes 1 and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and was then stirred at 0°C for 10min. Then 1 or 2 (or their solutions in CH2Cl2) was added dropwise into the mixture and stirred for another 2h. The reaction solution was concentrated under reduced pressure to get yellow powder as a crude product. The crude product was then purified by silica gel column chromatography (methanol/dichloromethane=1/10) to give object compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example-3Synthesis of Rupatadine base (Formula-4) from <strong>[102074-19-1]5-methylpyridine-3-methanol</strong> (Formula-9)Take <strong>[102074-19-1]5-methylpyridine-3-methanol</strong> (Formula-9, 51 gm) in toluene (255 ml) and add slowly thionyl chloride (36.5 ml) between 20-40C. On completion of thionyl chloride addition, reflux the reaction mixture at 60C for 2 hrs. On the completion of reaction toluene is distilled toluene under vacuum. Toluene (250 ml) and water (25 ml) added to the reaction mixture. Stir it between below 20C temperature. Adjust the pH by using 35% NaOH solution and again stir the reaction to separate the layers. Desloratadine (95g) is added to the in the separated organic layers at 25-30C. Then add Potassium carbonate (100g), TBAB (5g) and water (200 ml) is added to the reaction mass followed by reflux at 65-70C for 2 hrs. On the completion of reaction, separate lower aq. Layer and impurity layer using toluene. 10% solution of potassium dihydrogen phosphate (100 ml) is added with stirring for 1 hr. The layers are allowed to separate followed by addition of charcoal in the reaction mass and heat the reaction mass at 40-45C for 2 hrs. Then filter through hyflow bed and evaporate solvent under reduce pressure. Followed by dissolving the oily mass in SDS (300 ml). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 1 Example 1 Synthesis of compound of formula (1) To the ground desloratadine 5.00 g, lactose 5.47 g, sodium bicarbonate 1.35 g and 20 ml DMF were added to the reaction flask, The temperature was raised to 80 ° C stirring reaction; HPLC monitoring reaction progress, reaction 3 h, the impurity purity35%Stop the heating reaction; the reaction solution cooled to 5 ~ 10 ° C, add 40 ml of pure water stir are hook; ethyl acetate 50 ml X3 times extraction, 1: 1 ethyl acetate-isopropyl alcohol 50 ml X 2 extraction, dichloromethane 50 ml extraction time; HPLCDetection of water layer, impurity purity of 96.8%, the water layer by adding solid NaCl to saturation, add 50 mlN-butanol extraction time; n-butanol extract concentrated in half the volume of the solution, the solution precipitation of solid salt, filtered and concentrated to a solid precipitation, the volume of about 15 ml, hot by adding 30 ml of ethyl acetate,Stirring down to room temperature crystallization. Filter, filter cake with ethyl acetate leaching,Dried under reduced pressure to give off-white solid 1.2 g APLC purity 98.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: To solution of desloratadine (8, 10 mmol) in dichloromethane (DCM, 30 mL) added Et3N and stirred at 0 C for 10-15 min. To this solution, 10 mmol of benzyl/benzoyl bromide (21-25) dissolved in15 mL of DCM was added drop-wise and then heated to reflux until the completion of reaction (TLC). After the completion of reaction, mixture was poured into ice, filtered and recrystallized from ethanol. 4.2.1. 11-(1-benzylpiperidin-4-ylidene)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (1a)1a was synthesized according to general procedure by using 8 andbenzyl chloride (21). Rf 0.44 (n-hexane/ethyl acetate 6:1). Yield 73%,m.p. 156-155 C. 1H NMR (300 MHz, CDCl3): delta 8.39 (d, 1H, J=7.5 Hz,Ar-H), 7.48 (d, 1H, J=7.8 Hz, Ar-H), 7.20-7.15 (m, 4H, Ar-H),7.10-7.06 (m, 5H, Ar-H), 3.66 (s, 2H, CH2), 3.10-3.01 (m, 2H, CH2),2.83-2.73 (m, 2H, CH2), 2.61-2.59 (m, 2H, CH2), 2.40-237 (m, 2H,CH2), 2.18-2.08 (m, 4H, 2×CH2); 13C NMR (75 MHz, CDCl3): 153.2,143.9, 137.5, 136.4, 133.5, 133.2 (2C), 132.2, 129.9, 126.6 (2C), 126.2(2C), 124.5, 124.2 (2C), 123.7, 117.7, 114.2, 62.5, 57.5 (2C), 31.7 (2C),29.9, 28.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: To solution of desloratadine (8, 10 mmol) in dichloromethane (DCM, 30 mL) added Et3N and stirred at 0 C for 10-15 min. To this solution, 10 mmol of benzyl/benzoyl bromide (21-25) dissolved in15 mL of DCM was added drop-wise and then heated to reflux until the completion of reaction (TLC). After the completion of reaction, mixture was poured into ice, filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | General procedure: To solution of desloratadine (8, 10 mmol) in dichloromethane (DCM, 30 mL) added Et3N and stirred at 0 C for 10-15 min. To this solution, 10 mmol of benzyl/benzoyl bromide (21-25) dissolved in15 mL of DCM was added drop-wise and then heated to reflux until the completion of reaction (TLC). After the completion of reaction, mixture was poured into ice, filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | General procedure: To solution of desloratadine (8, 10 mmol) in dichloromethane (DCM, 30 mL) added Et3N and stirred at 0 C for 10-15 min. To this solution, 10 mmol of benzyl/benzoyl bromide (21-25) dissolved in15 mL of DCM was added drop-wise and then heated to reflux until the completion of reaction (TLC). After the completion of reaction, mixture was poured into ice, filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: To solution of desloratadine (8, 10 mmol) in dichloromethane (DCM, 30 mL) added Et3N and stirred at 0 C for 10-15 min. To this solution, 10 mmol of benzyl/benzoyl bromide (21-25) dissolved in15 mL of DCM was added drop-wise and then heated to reflux until the completion of reaction (TLC). After the completion of reaction, mixture was poured into ice, filtered and recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | General procedure: A mixture of desloratadine/carbazole (2.0 eq; 8.686 mmol) and K2CO3 (2.0 eq; 17.373 mmol) in DMF (10 mL) at 0 C under N2. Stirred the mixture for 20 min and then add dihalo-compounds (27-30, 1.0 eq;) in the reaction mixture drop wise at 0 C. Then stay room temperature and maintain the temperature at 70-80 C and reflux the mixture for 5-6 h. The reaction was monitored by TLC. The extraction was done with water and chloroform (3 times in 50 mL/10 mL ratio). Anhydrous sodium sulfate is added to dry off the mixture. The solvent was evaporated and crude was obtained. Further, crude mixture was purified by silica gel column chromatography (n-hexanes/ethyl acetate). 4.4.1. Synthesis of Bis-desloratadine derivatives (2b-e)4.4.1.1. 2-(4-{13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ylidene} piperidin-1-yl)-1-(4-{13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3(8),4,6,11,13-hexaen-2-ylidene}piperidin-1-yl)ethan-1-one (2b). 2b was synthesized according togeneral procedure by using 8 and bromoacetyl bromide (27). Purifiedby silica gel column chromatography (n-hexanes/ethyl acetate 5:1).Yield=69%; Rf=0.43 (n-hexane/ethyl acetate 7:1); m.p. 215-219 C;1H NMR (300 MHz, CDCl3): delta 8.29 (d, 2H, J=4.2 Hz, Ar-H), 7.43 (d,2H, J=6.9 Hz, Ar-H), 7.09-7.01 (m, 8H), 3.43-3.20 (m, 4H), 3.16 (t,4H, J=12.6 Hz), 3.01 (s, 2H), 2.88-2.76 (m, 8H), 2.59-2.35 (m, 8H).13C NMR (75 MHz, CDCl3): 163.9, 157.4 (2C), 145.1 (2C), 137.6 (2C),134.5 (2C), 134.0 (4C), 133.4 (2C), 131.6 (2C), 131.1 (2C), 129.1 (2C),126.5 (2C), 126.0 (2C), 123.4 (2C), 119.6 (2C), 114.1 (2C), 57.9 (2C),55.5, 46.5 (2C), 32.4 (2C), 32.0 (2C), 30.1 (2C). LC-MS found forC40H38Cl2N4O (m/z)=661.2 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: A mixture of desloratadine/carbazole (2.0 eq; 8.686 mmol) and K2CO3 (2.0 eq; 17.373 mmol) in DMF (10 mL) at 0 C under N2. Stirred the mixture for 20 min and then add dihalo-compounds (27-30, 1.0 eq;) in the reaction mixture drop wise at 0 C. Then stay room temperature and maintain the temperature at 70-80 C and reflux the mixture for 5-6 h. The reaction was monitored by TLC. The extraction was done with water and chloroform (3 times in 50 mL/10 mL ratio). Anhydrous sodium sulfate is added to dry off the mixture. The solvent was evaporated and crude was obtained. Further, crude mixture was purified by silica gel column chromatography (n-hexanes/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A mixture of desloratadine/carbazole (2.0 eq; 8.686 mmol) and K2CO3 (2.0 eq; 17.373 mmol) in DMF (10 mL) at 0 C under N2. Stirred the mixture for 20 min and then add dihalo-compounds (27-30, 1.0 eq;) in the reaction mixture drop wise at 0 C. Then stay room temperature and maintain the temperature at 70-80 C and reflux the mixture for 5-6 h. The reaction was monitored by TLC. The extraction was done with water and chloroform (3 times in 50 mL/10 mL ratio). Anhydrous sodium sulfate is added to dry off the mixture. The solvent was evaporated and crude was obtained. Further, crude mixture was purified by silica gel column chromatography (n-hexanes/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: A mixture of desloratadine/carbazole (2.0 eq; 8.686 mmol) and K2CO3 (2.0 eq; 17.373 mmol) in DMF (10 mL) at 0 C under N2. Stirred the mixture for 20 min and then add dihalo-compounds (27-30, 1.0 eq;) in the reaction mixture drop wise at 0 C. Then stay room temperature and maintain the temperature at 70-80 C and reflux the mixture for 5-6 h. The reaction was monitored by TLC. The extraction was done with water and chloroform (3 times in 50 mL/10 mL ratio). Anhydrous sodium sulfate is added to dry off the mixture. The solvent was evaporated and crude was obtained. Further, crude mixture was purified by silica gel column chromatography (n-hexanes/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: A mixture of desloratadine/carbazole (2.0 eq; 8.686 mmol) and K2CO3 (2.0 eq; 17.373 mmol) in DMF (10 mL) at 0 C under N2. Stirred the mixture for 20 min and then add dihalo-compounds (27-30, 1.0 eq;) in the reaction mixture drop wise at 0 C. Then stay room temperature and maintain the temperature at 70-80 C and reflux the mixture for 5-6 h. The reaction was monitored by TLC. The extraction was done with water and chloroform (3 times in 50 mL/10 mL ratio). Anhydrous sodium sulfate is added to dry off the mixture. The solvent was evaporated and crude was obtained. Further, crude mixture was purified by silica gel column chromatography (n-hexanes/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.6% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; | Add SM2 (146mg, 0.47mmol) to the thumb bottle,Potassium carbonate (162 mg, 1.18 mmol),DMF (2 mL) and Intermediate 1 (67 mg, 0.47 mmol), under nitrogen,The reaction was carried out at 80 C for 3 h. After TLC (DCM: MeOH = 20:1) was monitored,The reaction solution was cooled to room temperature, then water (6 mL)Combine the organic layers. The saturated sodium chloride solution (5 mL x 3) was washed and the organic phase was collected.Dry over anhydrous magnesium sulfate, suction filtration, concentration,Preparative plate purification (DCM: MeOH = 20:1)Obtained LP-1 (60 mg, 30.6% yield, 98% purity), yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With di-isopropyl azodicarboxylate; triphenylphosphine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere; | In a 250 ml round bottom flask, an inert atmosphere N2 was introduced and kept, and added.4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptane[1,2-b]pyridin-11-yl)piperidine(Raw material C, 5 g, 16.09 mmol, 1.00 equiv), 1-(2-carboxyethyl)-3-hydroxymethyl-5-methylpyridine-1-indole (intermediate compound, 3.74 g, 19.16 mmol, 1.20 equiv), PPh3 (8.38 g, 31.95 mmol, 2.00 equiv), and 50 ml of N,N-dimethylformamide, followed by stirring at 0-10 CDIAD (6.46g, 31.95mmol, 2.00equiv), the obtained solution was stirred at room temperature for 16 hours, the reaction was carried out in parallel twice, then 50 ml of ice water was added dropwise to quench the reaction, and the obtained solution was extracted with 3×50 ml of ethyl acetate. It was concentrated in vacuo. The crude product was purified by Prep-HPLC under the following conditions: XBridge Prep PR Column 5um, 19*150mm; mobile phase, water (0.05% NH4OH) and acetonitrile; gradient: acetonitrile 28% to 32% within 8 min, rise to 100 in 2 min %, down to 10% within 2min; detector, waters 2545UV Detector 254 & 220nm,3.8919g (25%, purity 99.6% is obtained, it should be noted that the yield here refers to the total yield of the reaction between the raw material A and the raw material B to form an intermediate compound, and then the intermediate compound and the raw material C are reacted). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With triethylamine; In acetonitrile; at 0 - 20℃; for 16h; | in 250 ml of three round-bottom flask is added 3 - chloro methyl -5 - methyl -1 - [(5 - methyl pyridine -3 - yl) methyl] pyridine hydrochloride (6 g, 18.77 mmol, 1.00 equiv.), acetonitrile (100 ml), 8 - chloro - 6, 11 - dihydro -11 - (4 - sub-piperidinyl) - 5H - benzo [5, 6] cyclohepta [1, 2 - b] pyridine (5.2 g, 16 . 73 mmol, 0 . 90 equiv.). Subsequently in the 0 - 5 C, under the condition of stirring, add triethylamine (5.68 g, 56 . 13 mmol, 3 . 00 equiv.). The reaction system is heated up to room temperature, stirring 16 h after, concentrate in vacuo, to obtain crude product. The above-mentioned crude product is dispersed to 60 ml water, purified using reversed phase chromatography, to obtain rupatadine fumarate impurity S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 0.1 mol of 3,5-lutidine is dissolved in 200 mL of carbon tetrachloride, and is completely dissolved and loaded in the first raw material storage tank;0.12 mol of N-bromosuccinimide (NBS) was dissolved in 200 mL of carbon tetrachloride, and was completely dissolved and loaded in a second raw material storage tank;Taking 0.052 mol of loratadine dissolved in 100 mL of ethanol, and after being completely dissolved, loading in a third raw material storage tank;0.893 mol of KOH is dissolved in 200 mL of water, and after being completely dissolved, it is loaded in a fourth raw material storage tank;Loading 200 mL of carbon tetrachloride solution in a fifth raw material storage tank;50 mL of the triethylamine solution is loaded in the sixth raw material storage tank;Taking 0.05 mol of dimethylaminopyridine before the third microreactor;That is, the molar ratio of 3,5-dimethylpyridine, brominating agent (N-bromosuccinimide), loratadine, alkali (potassium hydroxide), and catalyst (dimethylaminopyridine) is 1:1.2: 0.5:9:0.5; the feed liquid is simultaneously pumped into the microchannel reaction device through the first feed pump 1 and the second feed pump 2, and after being mixed by the first mixer 7, the first microreaction having a coil inner diameter of 0.5 mm is entered. In the reactor, the micro-reaction parameters were set: the flow rate of the carbon tetrachloride solution of 3,5-lutidine was 0.5 mL/min, and the flow rate of the carbon tetrachloride solution of NBS was 0.5 mL/min. The flow rate is 1.0 mL/min, the reaction temperature is controlled at 50 C, and the residence time is 30 min. The reaction mainly produces a solution of 5-bromomethyl-3-methylpyridine in carbon tetrachloride;At the same time, the feed liquid is simultaneously pumped into the microchannel reaction device through the third feed pump 3 and the fourth feed pump 4, and after being mixed by the second mixer 8, it is introduced into the second microreactor having a coil inner diameter of 0.5 mm. Reaction, setting the micro-reaction parameters: the flow rate of the ethanol solution of loratadine is 0.5 mL/min, the flow rate of the aqueous solution of KOH is 0.8 mL/min, the flow rate of the continuous flow in this step is 1.3 mL/min, and the reaction temperature is controlled at 80 C. , the residence time is 30 min, the reaction mainly produces loratadine;When the second microreactor has a reaction liquid flowing out, the fifth feed pump 5 pumps the carbon tetrachloride solution into the microchannel reaction device, and after mixing through the third mixer 9 and the reaction liquid obtained in the second microreactor, In the oil-water separator 12, during the mixing process, the chlorhexidine is extracted from the reaction liquid by the carbon tetrachloride solution, and after entering the oil-water mixer, the aqueous phase is removed from the outlet, and the obtained desloratadine solution is separated from the oil-water. The bottom of the device enters the next reaction, and the microreactor parameters are set: the flow rate of the carbon tetrachloride solution is 1.0 mL/min;The effluent obtained by separating the effluent obtained from the first microreactor and the oil-water separator is simultaneously pumped into the fourth mixer 10, and the solution after mixing the fourth mixer 10 and the third in the sixth raw material storage tank The ethylamine solution is simultaneously pumped into the fifth mixer 11 and mixed into the coil inner diameter of 0.5 mm.The reaction was mixed in a third microreactor carrying a catalyst (dimethylaminopyridine), and the microreactor parameters were set: the flow rate of the carbon tetrachloride solution of 5-bromomethyl-3-methylpyridine was 1.0 mL/min. The flow rate of loratadine in a carbon tetrachloride solution was 1.0 mL/min. The flow rate of this continuous flow was 2.0 mL/min, and the flow rate of the triethylamine solution was 0.3 mL/min. The flow rate of this continuous flow was 2.3. mL/min, staying for 20 min, the reaction mainly produces rupatadine. The reaction liquid was collected by the receiver 13, washed with water, dried, filtered, and a solution of fumaric acid dissolved in methanol was added thereto, and the mixture was heated to reflux, and slowly cooled to room temperature, and placed in a refrigerator for 12 hours.Precipitating a white solid compound, which is rupatadine fumarate, yield 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With europium(III) trifluoromethanesulfonate In acetonitrile at 50℃; for 24h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With copper diacetate In dimethyl sulfoxide at 60℃; | General procedure for the reactions of 3,4-dihydroquinoxalin-2(1H)-ones with amines. General procedure: To a stirred solution of 3,4-dihydroquinoxalin-2(1H)-ones (1, 0.2 mmol) and amines (2, 3 equiv.) inDMSO (1 mL), and Cu(OAc)2 (10 mol%) were added. The reactions were performed at 60oC under air(open flask) and completed as monitored by TLC. The products (3) were isolated by flash columnchromatographic separation (EtOAc/petroleum ether = 1:20 to 1:10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: descarboethoxyloratadine With ethylmagnesium bromide In tetrahydrofuran; diethyl ether at 0℃; for 0.25h; Inert atmosphere; Sealed tube; Stage #2: tert-butyl 2,6-dimethylbenzoperoxoate In tetrahydrofuran; hexane at 0℃; for 0.25h; Inert atmosphere; Sealed tube; | |
65% | Stage #1: descarboethoxyloratadine With ethylmagnesium bromide In tetrahydrofuran; diethyl ether for 0.25h; Stage #2: tert-butyl 2,6-dimethylbenzoperoxoate In tetrahydrofuran; diethyl ether at 0℃; for 0.25h; | 12 Synthesis of 11-(1'-(tert-butoxy)piperidin-4'-ylidene)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (4i) Following general procedure A, to a stirred solution of desloratadine (310 mg, 1.0 mmol, 2.5 eq.) in 1.0 mL anhydrous THF was added EtMgBr (3 M in diethyl ether) (267 μL, 0.8 mmol, 2.0 eq.) and the solution was stirred for 15 min. After which, 2,6-dimethyl-tert-butyl peroxybenzoate (Si) (89 mg, 0.4 mmol, 1.0 eq.) was added dropwise in 1.0 mL anhydrous THF. The solution was stirred for an additional 15 min at 0° C. Following work-up, the crude reaction mixture was purified by flash column chromatography on silica (eluent: 10:90 EtOAc:Hexanes) to afford the title compound (4j) (99 mg, 0.259 mmol, 65%) as an orange foam. TLC: Rf=0.20 (10:90 EtOAc:Hexanes; UV, CAM). 1H NMR (500 MHz, CDCl3): δ 8.38 (dd, J=4.8, 1.7 Hz, 1H), 7.43 (dd, J=7.7, 1.7 Hz, 1H), 7.12 (m, 3H), 7.07 (dd, J=7.7, 4.8 Hz, 1H), 3.37 (m, 2H), 3.09 (br s, 2H), 2.79 (m, 2H), 2.55-2.08 (m, 6H), 1.17 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 157.6, 146.7, 139.6, 138.0 (2C), 137.5, 133.5, 133.1, 132.8, 130.9, 129.1, 126.1, 122.3, 77.6, 58.9 (2C), 31.9, 31.5, 30.5, 30.3, 27.2 (3C). HRMS-ESI (m/z): [M+H]+ calculated for [C23H28ON235Cl]: 383.1885, found: 383.1881. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: descarboethoxyloratadine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Stage #2: 2-bromoethanol In dichloromethane at 20℃; for 22h; | 1.1 Step 1 ) Synthesis of 2-(4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl ethane-1-ol (2) Raw material 1 (400 mg, 1.29 mmol) and N,N-diisopropylethylamine (417 mg, 3.23 mmol) were dissolved in DCM (7 mL), and after stirring at room temperature for 30 min, 2-bromoethanol (404 mg, 3.23 mmol) was added, The reaction was stirred at room temperature for 22h. TLC (Vacetone:Vdichloromethane:Vtriethylamine=1:2:0.1) detected that the reaction of raw material 1 was complete. The reaction was stopped, the solvent was spin-dried under reduced pressure, and separated by column chromatography (V dichloromethane:V ethyl acetate:V triethylamine=2:1:0.05) to obtain 412 mg of white solid with a yield of 90.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | With triethylamine In ethyl acetate at 10 - 20℃; for 5h; Inert atmosphere; | 6-8 Example 7 Preparation of Compound III Under nitrogen protection,The compound of formula (V) (2.8g, 0.018mol, 1.5eq) was added to a 100ml reaction flask,Add 20ml of ethyl acetate, turn on stirring,The compound of formula (IV) (3.7 g, 0.012 mol, 1.0 eq) was added,Control the temperature of the reaction solution at 10-20°C,Triethylamine (2.4g, 0.024mol, 2.0eq) was added,Reaction for 5h, TLC (developing solvent, methanol:ethyl acetate=1:2,Add 2 drops of ammonia) to monitor the disappearance of the compound of formula (IV),Add buffer solution with pH value of 4-6 (mixed with sodium hydroxide, water, acetic acid) to wash twice,20ml of n-hexane was added dropwise at room temperature, the dropwise addition was completed,Cool down to 0-10°C and stir for 120min,Filtration and drying gave the compound of formula (III) (4.81 g) with a yield of 92.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With [Co(dmgH)2(Py)2]PF6; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-κN1,κN1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC]iridium hexafluorophosphate In toluene at 25℃; for 9h; Irradiation; Inert atmosphere; | Method C General procedure: A solution of amines (0.2 mmol), pinene (1 ml), [Ir(dFCF3ppy)2dtbpy)]PF6 (1 mol%) and Co(dmgBF2)2(H2O)2 (5 mol%) in degased toluene (6 ml) wasstirred under nitrogen atmosphere and irradiated by 3 W blue LEDs at 25 °C for9 h. After completion of the reaction, the solvent was removed under reducedpressure by rotary evaporation. The pure product was then obtained by flashcolumn chromatography on neutral alumina. Products 87 to 99 were obtained viaMethod C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; | 9.2 Step 2: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (120 mg, 0.313 mmol) obtained in the step 1 of Example 9 was dissolved in 2 mL ofN,N-dimethylformamide, sodium carbonate (99.43 mg, 0.938 mmol), potassium iodide (51.91 mg, 0.313 mmol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (77.74 mg, 0.344 mmol) were sequentially added, and the resultant was then heated to 80°C. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (140 mg, yield of 89%). 1H NMR (300 MHz, MeOD): δ 8.49 (dd, J=4.88, 1.22 Hz, 1H), 7.87 (d, J=7.63 Hz, 1H), 7.50-7.44 (m, 1H), 7.38 (d, J=2.14 Hz, 1H), 7.35-7.23 (m, 2H), 4.92-4.78 (m, 2H), 3.65-3.28 (m, 9H), 2.96-2.43 (m, 16H) |
89% | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; | 9.2 Step 2: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (120 mg, 0.313 mmol) obtained in the step 1 of Example 9 was dissolved in 2 mL ofN,N-dimethylformamide, sodium carbonate (99.43 mg, 0.938 mmol), potassium iodide (51.91 mg, 0.313 mmol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (77.74 mg, 0.344 mmol) were sequentially added, and the resultant was then heated to 80°C. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (140 mg, yield of 89%). 1H NMR (300 MHz, MeOD): δ 8.49 (dd, J=4.88, 1.22 Hz, 1H), 7.87 (d, J=7.63 Hz, 1H), 7.50-7.44 (m, 1H), 7.38 (d, J=2.14 Hz, 1H), 7.35-7.23 (m, 2H), 4.92-4.78 (m, 2H), 3.65-3.28 (m, 9H), 2.96-2.43 (m, 16H) |
9.2 Step 2: Step 2: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (120 mg, 0.313 mmol) obtained in the step 1 of Example 9 was dissolved in 2 mL ofN,N-dimethylformamide, sodium carbonate (99.43 mg, 0.938 mmol), potassium iodide (51.91 mg, 0.313 mmol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (77.74 mg, 0.344 mmol) were sequentially added, and the resultant was then heated to 80°C. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (140 mg, yield of 89%). 1H NMR (300 MHz, MeOD): δ 8.49 (dd, J=4.88, 1.22 Hz, 1H), 7.87 (d, J=7.63 Hz, 1H), 7.50-7.44 (m, 1H), 7.38 (d, J=2.14 Hz, 1H), 7.35-7.23 (m, 2H), 4.92-4.78 (m, 2H), 3.65-3.28 (m, 9H), 2.96-2.43 (m, 16H) |
89 % | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; | 9.2 Step 2: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (120 mg, 0.313 mmol) obtained in the step 1 of Example 9 was dissolved in 2 mL ofN,N-dimethylformamide, sodium carbonate (99.43 mg, 0.938 mmol), potassium iodide (51.91 mg, 0.313 mmol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (77.74 mg, 0.344 mmol) were sequentially added, and the resultant was then heated to 80°C. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (140 mg, yield of 89%). 1H NMR (300 MHz, MeOD): δ 8.49 (dd, J=4.88, 1.22 Hz, 1H), 7.87 (d, J=7.63 Hz, 1H), 7.50-7.44 (m, 1H), 7.38 (d, J=2.14 Hz, 1H), 7.35-7.23 (m, 2H), 4.92-4.78 (m, 2H), 3.65-3.28 (m, 9H), 2.96-2.43 (m, 16H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; | 10.3 Step 3: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (500 mg, 1.609 mmol) obtained in the step 2 of Example 10 was dissolved in 4 mL of N,N-dimethylformamide, sodium carbonate (511.49 mg, 4.826 mmol), potassium iodide (267.04 mg, 1.0609 mmol), and the compound (390.41 mg, 1.609 mmol) obtained in the step 1 of Example 10 were sequentially added, and the mixed solution was heated to 80°C. After the completion of the reaction, extraction was performed twice with ethyl acetate and brine. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (745 mg, yield of 90%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=4.58 Hz, 1H), 7.53 (d, J=7.63 Hz, 1H), 7.26 (s, 1H), 7.21-7.12 (m, 2H), 7.04 (d, J=7.93 Hz, 1H), 5.63 (d, J=4.27 Hz, 1H), 4.43-4.34 (m, 1H), 3.89-3.78 (m, 1H), 3.67-3.55 (m, 1H), 3.29 (s, 3H), 3.35-3.20 (m, 2H), 2.86-2.42 (m, 6H), 2.40-2.04 (m, 10H), 1.98-1.68 (m, 2H); LCMS [M+H] 517.2 |
90% | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; | 10.3 Step 3: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (500 mg, 1.609 mmol) obtained in the step 2 of Example 10 was dissolved in 4 mL of N,N-dimethylformamide, sodium carbonate (511.49 mg, 4.826 mmol), potassium iodide (267.04 mg, 1.0609 mmol), and the compound (390.41 mg, 1.609 mmol) obtained in the step 1 of Example 10 were sequentially added, and the mixed solution was heated to 80°C. After the completion of the reaction, extraction was performed twice with ethyl acetate and brine. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (745 mg, yield of 90%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=4.58 Hz, 1H), 7.53 (d, J=7.63 Hz, 1H), 7.26 (s, 1H), 7.21-7.12 (m, 2H), 7.04 (d, J=7.93 Hz, 1H), 5.63 (d, J=4.27 Hz, 1H), 4.43-4.34 (m, 1H), 3.89-3.78 (m, 1H), 3.67-3.55 (m, 1H), 3.29 (s, 3H), 3.35-3.20 (m, 2H), 2.86-2.42 (m, 6H), 2.40-2.04 (m, 10H), 1.98-1.68 (m, 2H); LCMS [M+H] 517.2 |
90 % | With sodium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; | 10.3 Step 3: Preparation of 3-(2-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)ethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one After the compound (500 mg, 1.609 mmol) obtained in the step 2 of Example 10 was dissolved in 4 mL of N,N-dimethylformamide, sodium carbonate (511.49 mg, 4.826 mmol), potassium iodide (267.04 mg, 1.0609 mmol), and the compound (390.41 mg, 1.609 mmol) obtained in the step 1 of Example 10 were sequentially added, and the mixed solution was heated to 80°C. After the completion of the reaction, extraction was performed twice with ethyl acetate and brine. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (745 mg, yield of 90%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=4.58 Hz, 1H), 7.53 (d, J=7.63 Hz, 1H), 7.26 (s, 1H), 7.21-7.12 (m, 2H), 7.04 (d, J=7.93 Hz, 1H), 5.63 (d, J=4.27 Hz, 1H), 4.43-4.34 (m, 1H), 3.89-3.78 (m, 1H), 3.67-3.55 (m, 1H), 3.29 (s, 3H), 3.35-3.20 (m, 2H), 2.86-2.42 (m, 6H), 2.40-2.04 (m, 10H), 1.98-1.68 (m, 2H); LCMS [M+H] 517.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 22.3 Step 3: Preparation of ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (200 mg, 0.521 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and the resultant was stirred. Sodium carbonate (209.91 mg, 1.98 mmol) and ethyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoate (246.69 mg, 0.573 mmol) were sequentially added to the reaction solution. Thereafter, the mixed solution was heated to 80°C and then stirred for 3 hours. After the completion of the reaction, brine and ethyl acetate were added to the mixed solution to perform extraction. The organic layer was treated with sodium sulfate, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain a title compound (310 mg, yield of 90%). |
90% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 22.3 Step 3: Preparation of ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (200 mg, 0.521 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and the resultant was stirred. Sodium carbonate (209.91 mg, 1.98 mmol) and ethyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoate (246.69 mg, 0.573 mmol) were sequentially added to the reaction solution. Thereafter, the mixed solution was heated to 80°C and then stirred for 3 hours. After the completion of the reaction, brine and ethyl acetate were added to the mixed solution to perform extraction. The organic layer was treated with sodium sulfate, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain a title compound (310 mg, yield of 90%). |
With sodium carbonate; sodium sulfate | 22.3 Step 3: Step 3: Preparation of ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (200 mg, 0.521 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and the resultant was stirred. Sodium carbonate (209.91 mg, 1.98 mmol) and ethyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoate (246.69 mg, 0.573 mmol) were sequentially added to the reaction solution. Thereafter, the mixed solution was heated to 80°C and then stirred for 3 hours. After the completion of the reaction, brine and ethyl acetate were added to the mixed solution to perform extraction. The organic layer was treated with sodium sulfate, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain a title compound (310 mg, yield of 90%). |
90 % | With sodium carbonate In N,N-dimethyl-formamide at 80℃; | 22.3 Step 3: Preparation of ethyl (S)-2-((t-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate 8-Chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (200 mg, 0.521 mmol) was dissolved in 4 mL of N,N-dimethylformamide, and the resultant was stirred. Sodium carbonate (209.91 mg, 1.98 mmol) and ethyl (S)-3-(4-(3-bromopropoxy)phenyl)-2-((t-butoxycarbonyl)amino)propanoate (246.69 mg, 0.573 mmol) were sequentially added to the reaction solution. Thereafter, the mixed solution was heated to 80°C and then stirred for 3 hours. After the completion of the reaction, brine and ethyl acetate were added to the mixed solution to perform extraction. The organic layer was treated with sodium sulfate, and the filtrate was concentrated and then purified by silica gel column chromatography to obtain a title compound (310 mg, yield of 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 25.3 Step 3: Preparation of (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione After the compound (200 mg, 0.521 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (165.72 mg, 1.564 mmol) and the compound (211.84 mg, 0.573 mmol) obtained in the step 2 of Example 25 were sequentially added, and the resultant was stirred at 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (250 mg, yield of 82%). 1H NMR (300 MHz, CDCl3): δ 8.47-8.32 (m, 1H), 7.42 (d, J=7.93 Hz, 1H), 7.24-7.02 (m, 4H), 4.01-3.11 (m, 4H), 2.93-0.93 (m, 32H) |
82% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 25.3 Step 3: Preparation of (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione After the compound (200 mg, 0.521 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (165.72 mg, 1.564 mmol) and the compound (211.84 mg, 0.573 mmol) obtained in the step 2 of Example 25 were sequentially added, and the resultant was stirred at 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (250 mg, yield of 82%). 1H NMR (300 MHz, CDCl3): δ 8.47-8.32 (m, 1H), 7.42 (d, J=7.93 Hz, 1H), 7.24-7.02 (m, 4H), 4.01-3.11 (m, 4H), 2.93-0.93 (m, 32H) |
82 % | With sodium carbonate In N,N-dimethyl-formamide at 80℃; | 25.3 Step 3: Preparation of (4R,7S)-2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione After the compound (200 mg, 0.521 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (165.72 mg, 1.564 mmol) and the compound (211.84 mg, 0.573 mmol) obtained in the step 2 of Example 25 were sequentially added, and the resultant was stirred at 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (250 mg, yield of 82%). 1H NMR (300 MHz, CDCl3): δ 8.47-8.32 (m, 1H), 7.42 (d, J=7.93 Hz, 1H), 7.24-7.02 (m, 4H), 4.01-3.11 (m, 4H), 2.93-0.93 (m, 32H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 26.2 Step 2: Preparation of 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3 (2H)-dione After the compound (200 mg, 0.521 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (165.72 mg, 1.564 mmol) and the compound (204.96 mg, 0.573 mmol) obtained in the step 1 of Example 26 were sequentially added, and the resultant was heated to 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (260 mg, yield of 87%). 1H NMR (300 MHz, CDCl3): δ 8.44-8.34 (m, 1H), 7.41 (d, J=7.93 Hz, 1H), 7.23-7.03 (m, 4H), 3.48-3.12 (m, 2H), 2.92-0.94 (m, 34H). |
87% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 26.2 Step 2: Preparation of 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3 (2H)-dione After the compound (200 mg, 0.521 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (165.72 mg, 1.564 mmol) and the compound (204.96 mg, 0.573 mmol) obtained in the step 1 of Example 26 were sequentially added, and the resultant was heated to 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (260 mg, yield of 87%). 1H NMR (300 MHz, CDCl3): δ 8.44-8.34 (m, 1H), 7.41 (d, J=7.93 Hz, 1H), 7.23-7.03 (m, 4H), 3.48-3.12 (m, 2H), 2.92-0.94 (m, 34H). |
87 % | With sodium carbonate In N,N-dimethyl-formamide at 80℃; | 26.2 Step 2: Preparation of 2-(((1S,2S)-2-((4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-isoindole-1,3 (2H)-dione After the compound (200 mg, 0.521 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (165.72 mg, 1.564 mmol) and the compound (204.96 mg, 0.573 mmol) obtained in the step 1 of Example 26 were sequentially added, and the resultant was heated to 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (260 mg, yield of 87%). 1H NMR (300 MHz, CDCl3): δ 8.44-8.34 (m, 1H), 7.41 (d, J=7.93 Hz, 1H), 7.23-7.03 (m, 4H), 3.48-3.12 (m, 2H), 2.92-0.94 (m, 34H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 51.2 Step 2: Preparation of cyclopentyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate After the compound (170 mg, 0.443 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (141 mg, 1.329 mmol) and the compound (219 mg, 0.465 mmol) obtained in the step 1 of Example 51 were sequentially added, and the resultant was heated to 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (270 mg, yield of 87%). |
87% | With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 51.2 Step 2: Preparation of cyclopentyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate After the compound (170 mg, 0.443 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (141 mg, 1.329 mmol) and the compound (219 mg, 0.465 mmol) obtained in the step 1 of Example 51 were sequentially added, and the resultant was heated to 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (270 mg, yield of 87%). |
87 % | With sodium carbonate In N,N-dimethyl-formamide at 80℃; | 51.2 Step 2: Preparation of cyclopentyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidin-1-yl)propoxy)phenyl)propanoate After the compound (170 mg, 0.443 mmol) obtained in the step 2 of Example 10 was dissolved in 2 mL of N,N-dimethylformamide, sodium carbonate (141 mg, 1.329 mmol) and the compound (219 mg, 0.465 mmol) obtained in the step 1 of Example 51 were sequentially added, and the resultant was heated to 80°C for 3 hours. After the completion of the reaction, extraction was performed twice with brine and ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain a title compound (270 mg, yield of 87%). |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
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P220 | Keep/Store away from clothing/combustible materials. |
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P222 | Do not allow contact with air. |
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P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
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P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
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P285 | In case of inadequate ventilation wear respiratory protection. |
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P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
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P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
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P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
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P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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