* 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.
Example 2Preparation of 8-chloro-6, ll-dihydro-ll-(N-methyl-4-piperidinylidene)-5H-benzo [5,6] cyclohepta [1, 2-b] pyridine (XII)Compound XIII (100 g) prepared as per standard process given in US patent no4,659,716 after azeotropic water removal in toluene instead of drying is heated withboric acid (115 g) in cone, sulfuric acid (415 g) for 4-8 hrs at 105-11Q°C, Reactionmass is poured in chilled water and extracted with ethyl acetate. Solvent is removed toget the title compound as a solid in 85percent yield having assay 99.5percent (OAB, HPLC)
HPLC purity: 95%
With boron trifluoride In HF; hexane
E. 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR66 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in HF (120 mL, 120 g, 6.0 mole) at -35° C. and add BF3 (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
HPLC purity 80%
With hydrogenchloride; sodium hydroxide In ice-water; hexane; trifluorormethanesulfonic acid
Alternative Step E: 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with BaCO3. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1 N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
HPLC purity: 95%
With boron trifluoride In hexane; hydrogen fluoride
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR69 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
HPLC purity 80%
With hydrogenchloride; sodium hydroxide In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; trifluorormethanesulfonic acid
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
HPLC purity: 95%
With boron trifluoride In hexane; hydrogen fluoride
E. 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR67 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
HPLC purity 80%
With hydrogenchloride; sodium hydroxide In ice-water; hexane; trifluorormethanesulfonic acid
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
HPLC purity 80%
With hydrogenchloride; sodium hydroxide In ice-water; hexane; trifluorormethanesulfonic acid
Alternative Step E: 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1. liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
HPLC purity 80%
With hydrogenchloride; sodium hydroxide In ice-water; hexane; trifluorormethanesulfonic acid
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA [1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with BaCO3. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
HPLC purity: 95%
With boron trifluoride In hexane; hydrogen fluoride
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6.11-DIHYDRO-5H-BENZO[5.6]CYCLOHEPTA[1,2-b]PYRIDINE STR97 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
HPLC purity: 95%
With boron trifluoride In HF; hexane
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR66 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in HF (120 mL, 120 g, 6.0 mole) at -35° C. and add BF3 (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[2] Patent: WO2006/6184, 2006, A2, . Location in patent: Page/Page column 17
[3] Patent: US6075025, 2000, A,
[4] Patent: US6075025, 2000, A,
[5] Patent: US5422351, 1995, A,
[6] Patent: US5422351, 1995, A,
[7] Patent: US5661152, 1997, A,
[8] Patent: US5719148, 1998, A,
[9] Patent: US5661152, 1997, A,
[10] Patent: US5721236, 1998, A,
[11] Patent: US5719148, 1998, A,
[12] Patent: US5721236, 1998, A,
2
[ 38089-93-9 ]
[ 38092-89-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 35 - 45℃; for 2 - 3 h;
A mixture of L L-(N-METHYL-4-PIPERIDINYL)-11-HYDROXY-8-CHLORO-6, 11-DIHYDRO-5H- BENZO (5,6) cyclohepta (1,2-b) pyridine (carbinol) of formula IV (1.0 kg, 0.0029 mole) and concentrated sulphuric acid (3.68 kg, 0.0375 mole) is stirred at 35 to 45°C for 2 to 3 hrs. the reaction mixture is poured in chilled water and the product (olefin) is extracted in ethyl acetate at 8-9 pH. The organic phase is dried over anhydrous sodium sulphate and solvent is removed, The residue is crystallized in hexane to give 0.8 kg of olefin of formula V (80percent) with a purity of >98percent (ODB, HPLC).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2701 - 2704
[2] Patent: WO2004/80997, 2004, A1, . Location in patent: Page 9
[3] Patent: WO2006/6184, 2006, A2, . Location in patent: Page/Page column 16-17
3
[ 119770-60-4 ]
[ 119770-61-5 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
4
[ 32998-95-1 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[2] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[3] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
5
[ 31255-57-9 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[2] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[3] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
6
[ 107285-30-3 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[2] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[3] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
7
[ 63463-36-5 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[2] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[3] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2701 - 2704
8
[ 20970-75-6 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[2] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[3] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
9
[ 100643-71-8 ]
[ 74-88-4 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9473 - 9479
10
[ 75-75-2 ]
[ 119770-60-4 ]
[ 119770-62-6 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
11
[ 130642-50-1 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
12
[ 620-20-2 ]
[ 38092-89-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
13
[ 31251-41-9 ]
[ 38092-89-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2701 - 2704
14
[ 38092-89-6 ]
[ 100643-71-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
[2] Patent: US5089496, 1992, A,
[3] Patent: US4826853, 1989, A,
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2701 - 2704
15
[ 541-41-3 ]
[ 38092-89-6 ]
[ 79794-75-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-ethyl-N,N-diisopropylamine In toluene at 60 - 75℃; for 1 - 2 h;
To a mixture of 8-CHLORO-6, 11-DIHYDRO-11-(N-METHYL-4-PIPERIDINYLIDENE)-5H- benzo (5, 6) cyclohepta (1,2-b) pyridine (olefin) of formula V (1. 0 KG, 0. 0031 mole) and diisopropylethylamine (0. 074 KG, 0.00057 mole) in TOLUENE (6 Lt) under nitrogen atmosphere, ETHYLCHLOROFORMATE (0. 775 kg, 0.0071 mole) is added slowly at 60 to 65°C and stirred for 1 to 2 hrs, at 70-75°C. Reaction mixture cooled to room temperature and water (5. 0 Lt) is added. The mixture is adjusted to 5. 0-5.5 pH with hydrochloric acid. The organic phase is washed with water and the solvent is removed. The residue is purified in isopropyl ether followed by CRYSTALLIZATION in acetonitrile to get 0. 9 kg loratadine (90percent) with a purity of >99percent (ODB, HPLC).
73%
Stage #1: With N-ethyl-N,N-diisopropylamine In toluene at 60 - 75℃; for 1 - 2 h; Stage #2: With hydrogenchloride In water; toluene
Step 10; Preparation of Loratadine (I)To the above toluene layer from example 16, containing compound XII (-93 gm, 0.29 mole) is added di isopropyl ethylamine (11.1 gm, 0.09 mole) under nitrogen atmosphere followed by slow addition of ethyl chloroformate (82 gm, 0.71 mole) at 60-65°C and stirred for 1-2 hrs at 70-75°C. Reaction mixture is cooled to room temperature and water (600 ml) is added. The mixture is adjusted to pH 5.0 -5.5 with hydrochloric acid. The organic phase is washed with water and the solvent is removed to get residue as crude Loratadine .The crude Loratadine is purified in isopropyl ether followed by crystallization in acetonitrile to get 81.5 gm Loratadine of formula I (73percent) with a purity of >99.4percent (ODB,HPLC).
HPLC purity 97.4%
With N-ethyl-N,N-diisopropylamine In toluene; acetonitrile
F. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR70 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
HPLC purity 97.4%
With N-ethyl-N,N-diisopropylamine In toluene; acetonitrile
F. 8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidylidene)6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR68 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound, (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
HPLC purity 97.4%
With N-ethyl-N,N-diisopropylamine In toluene; acetonitrile
F. 8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR81 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution, with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
HPLC purity 97.4%
With N-ethyl-N,N-diisopropylamine In toluene; acetonitrile
F. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR98 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
Reference：
[1] Patent: WO2004/80997, 2004, A1, . Location in patent: Page 9
[2] Patent: WO2006/6184, 2006, A2, . Location in patent: Page/Page column 17
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2701 - 2704
[4] Arzneimittel-Forschung/Drug Research, 1986, vol. 36, # 9, p. 1311 - 1314
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 457 - 461
[6] Journal of Organic Chemistry, 1989, vol. 54, # 9, p. 2242 - 2244
[7] Patent: US5422351, 1995, A,
[8] Patent: US5661152, 1997, A,
[9] Patent: US5700806, 1997, A,
[10] Patent: US5719148, 1998, A,
[11] Patent: US2008/194823, 2008, A1, . Location in patent: Page/Page column 4
[12] Patent: US2008/194823, 2008, A1, . Location in patent: Page/Page column 5
[13] Patent: US2008/287481, 2008, A1, . Location in patent: Page/Page column 4-5
16
[ 541-41-3 ]
[ 7087-68-5 ]
[ 38092-89-6 ]
[ 79794-75-5 ]
Reference：
[1] Patent: US6075025, 2000, A,
[2] Patent: US5721236, 1998, A,
With N-ethyl-N,N-diisopropylamine; In toluene; at 60 - 75℃; for 1 - 2h;
To a mixture of 8-CHLORO-6, 11-DIHYDRO-11-(N-METHYL-4-PIPERIDINYLIDENE)-5H- benzo (5, 6) cyclohepta (1,2-b) pyridine (olefin) of formula V (1. 0 KG, 0. 0031 mole) and diisopropylethylamine (0. 074 KG, 0.00057 mole) in TOLUENE (6 Lt) under nitrogen atmosphere, ETHYLCHLOROFORMATE (0. 775 kg, 0.0071 mole) is added slowly at 60 to 65°C and stirred for 1 to 2 hrs, at 70-75°C. Reaction mixture cooled to room temperature and water (5. 0 Lt) is added. The mixture is adjusted to 5. 0-5.5 pH with hydrochloric acid. The organic phase is washed with water and the solvent is removed. The residue is purified in isopropyl ether followed by CRYSTALLIZATION in acetonitrile to get 0. 9 kg loratadine (90percent) with a purity of >99percent (ODB, HPLC).
73%
Step 10; Preparation of Loratadine (I)To the above toluene layer from example 16, containing compound XII (-93 gm, 0.29 mole) is added di isopropyl ethylamine (11.1 gm, 0.09 mole) under nitrogen atmosphere followed by slow addition of ethyl chloroformate (82 gm, 0.71 mole) at 60-65°C and stirred for 1-2 hrs at 70-75°C. Reaction mixture is cooled to room temperature and water (600 ml) is added. The mixture is adjusted to pH 5.0 -5.5 with hydrochloric acid. The organic phase is washed with water and the solvent is removed to get residue as crude Loratadine .The crude Loratadine is purified in isopropyl ether followed by crystallization in acetonitrile to get 81.5 gm Loratadine of formula I (73percent) with a purity of >99.4percent (ODB,HPLC).
42.4 g (HPLC purity 97.4%)
With N-ethyl-N,N-diisopropylamine; In toluene; acetonitrile;
F. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR70 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
42.4 g (HPLC purity 97.4%)
With N-ethyl-N,N-diisopropylamine; In toluene; acetonitrile;
F. 8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidylidene)6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR68 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound, (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
42.4 g (HPLC purity 97.4%)
With N-ethyl-N,N-diisopropylamine; In toluene; acetonitrile;
F. 8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR81 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution, with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
42.4 g (HPLC purity 97.4%)
With N-ethyl-N,N-diisopropylamine; In toluene; acetonitrile;
F. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR98 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitrile (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70° C. to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
EXAMPLE 1; Preparation of Loratadine Polymorphic Form I Substantially Free of Polymorphic Form II27 Kg of 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine was taken into a reactor containing 365 liters of toluene and stirred for about 15 minutes. 41 liters of triethylamine was added to the reactor and the contents were heated to 72.5° C. A mixture of 79 liters of ethylchloroformate and 41 liters of toluene was added to the reaction mass at 70 to 75° C. The reaction mass was stirred for 1 hours 30 minutes at 72-74° C. Reaction completion was confirmed by thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 33.5° C. and 205 liters of water was added slowly. The pH of the reaction mixture was adjusted to 9.3 with 14 liters of 50percent aqueous sodium hydroxide solution and stirred for 20 minutes. The aqueous layer was separated and extracted with 135 liters of toluene. The combined organic layer was washed with 410 liters of water in two equal lots. The organic layer was heated to 72° C. and distilled off under a vacuum of 650 mm Hg until 145 liters of the organic layer was left in the reactor. The organic layer was cooled to 40° C. and the solvent was removed completely by using an agitated thin film dryer (ATFD) with an Inlet temperature of 70° C., outlet temperature of 65.7° C., a feed rate of 20-30 L per hour, and a vacuum of 710 mm Hg to get 31.5 Kg of crude loratadine.
EXAMPLE 3; Preparation of Loratadine Polymorphic Form I Substantially Free of Polymorphic Form II Using Acetonitrile as the Solvent1000 ml of toluene was taken into a round bottom flask and 100 g of 8-Chloro-11-(1-methyl-4-piperidine)-6,11-dihydro-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridine was added. 38 g of triethylamine was added to the reaction mixture and the reaction mass was heated to 65° C. 143 ml of ethyl chloroformate was then added to the reaction mass through a pressure equalizing funnel at 69 to 75° C. The temperature of the reaction mass was then increased to 77° C. and maintained for 2 hours and 15 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the toluene was distilled at a temperature of 75° C. under a vacuum of below 700 mm Hg. 900 ml of toluene was then added to the residue obtained after distillation. The toluene layer was washed with 500 ml of water followed by washing with 1400 ml of 10percent aqueous solution of sodium bicarbonate in two equal lots. Finally, the organic layer was washed with 500 ml of water. The organic layer was distilled completely under a vacuum of 700 mm Hg at 70° C. The residue was then co-distilled with 300 ml of acetonitrile in 3 equal lots at 69° C. 300 ml of acetonitrile was added to the resulting residue and 10 g of carbon was added to it and stirred at 77° C. for 30 minutes. The mass was filtered under a hot condition at 75° C. The filter bed was washed with 100 ml of acetonitrile. As the filtrate cooled, a precipitate formed, so the filtrate was reheated to 78° C. for clear dissolution and then was gradually cooled to 30° C. and maintained for 1 hour. The mass was further cooled to 2° C. and maintained for 2 hours. The separated solid was filtered and washed with 50 ml of chilled acetonitrile. The wet solid was dried at about 60° C. to yield 103 g of the title compound. EXAMPLE 4Preparation of Loratadine Polymorphic Form I Substantially Free of Polymorphic Form II1000 ml of toluene was taken into a round bottom flask and 100 g of 8-Chloro-11-(1-methyl-4-piperidine)-6,11-dihydro-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridine was added and the reaction mass was stirred at 30° C. for 15 minutes to get a clear solution. 38 g of triethylamine was added to the reaction mixture, and then the reaction mass was heated to 66° C. 143 ml of ethyl chloroformate was then added to the reaction mass at 66° C. The temperature of the reaction mass was then increased to 78° C. and maintained for 4 hours, 15 minutes. Reaction progress was monitored using thin layer chromatography. After the reaction completed, the toluene was distilled at a temperature of 65° C. under a vacuum below 700 mm Hg. 900 ml of toluene was then added to the residue obtained after distillation. The toluene layer was washed with 500 ml of water followed by washing with 1400 ml of a 10percent aqueous solution of sodium bicarbonate in two equal lots. Finally, the organic layer was washed with 500 ml of water. The organic layer was distilled completely under a vacuum of 700 mm Hg at 70° C. The residue was then co-distilled with 300 ml of cyclohexane in 3 equal lots at 69° C. 500 ml of cyclohexane was added to the resulting residue and 10 g of carbon was added and stirred at 76° C. for 20 minutes. The mass was filtered in a hot condition at 75° C. The filter bed was washed with 100 ml of cyclohexane. The reaction mass was gradually cooled to 30° C. and maintained for 1 hour. The reaction mass was further cooled to 5° C. and maintained for 2 hours. The separated solid was filtered and washed with 50 ml of chilled cyclohexane. The wet solid was dried at about 55° C. for 2.5 hours to yield 106 g of the title compound.
With triethylamine; In toluene; at 25 - 75℃; for 1.5h;
EXAMPLE 1 Preparation of Desloratadine 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.
With sulfuric acid; boric acid; at 105 - 110℃; for 4 - 8h;Product distribution / selectivity;
Example 2Preparation of 8-chloro-6, ll-dihydro-ll-(N-methyl-4-piperidinylidene)-5H-benzo [5,6] cyclohepta [1, 2-b] pyridine (XII)Compound XIII (100 g) prepared as per standard process given in US patent no4,659,716 after azeotropic water removal in toluene instead of drying is heated withboric acid (115 g) in cone, sulfuric acid (415 g) for 4-8 hrs at 105-11Q°C, Reactionmass is poured in chilled water and extracted with ethyl acetate. Solvent is removed toget the title compound as a solid in 85percent yield having assay 99.5percent (OAB, HPLC)
45.7 g (HPLC purity: 95%)
With boron trifluoride; In HF; hexane;
E. 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR66 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in HF (120 mL, 120 g, 6.0 mole) at -35° C. and add BF3 (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
126 g (HPLC purity 80%)
With hydrogenchloride; sodium hydroxide; In ice-water; hexane; trifluorormethanesulfonic acid;
Alternative Step E: 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with BaCO3. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1 N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
45.7 g (HPLC purity: 95%)
With boron trifluoride; In hexane; hydrogen fluoride;
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR69 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
126 g (HPLC purity 80%)
With hydrogenchloride; sodium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; trifluorormethanesulfonic acid;
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
45.7 g (HPLC purity: 95%)
With boron trifluoride; In hexane; hydrogen fluoride;
E. 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR67 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
126 g (HPLC purity 80%)
With hydrogenchloride; sodium hydroxide; In ice-water; hexane; trifluorormethanesulfonic acid;
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
126 g (HPLC purity 80%)
With hydrogenchloride; sodium hydroxide; In ice-water; hexane; trifluorormethanesulfonic acid;
Alternative Step E: 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1. liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
126 g (HPLC purity 80%)
With hydrogenchloride; sodium hydroxide; In ice-water; hexane; trifluorormethanesulfonic acid;
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA [1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with BaCO3. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
45.7 g (HPLC purity: 95%)
With boron trifluoride; In hexane; hydrogen fluoride;
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6.11-DIHYDRO-5H-BENZO[5.6]CYCLOHEPTA[1,2-b]PYRIDINE STR97 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
45.7 g (HPLC purity: 95%)
With boron trifluoride; In HF; hexane;
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR66 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in HF (120 mL, 120 g, 6.0 mole) at -35° C. and add BF3 (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
E. 8-Chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta [1,2-b]pyridine To a solution of [3-[2-(3-chlorophenyl)ethyl]-2-pyridinyl]-1-methyl-4-piperidinyl methanone hydrochloride (59.0 g; 0.15 mol) in 120 mL (120 g; 6.0 mol) of hydrofluoric acid at -35° C. was added boron trifluoride (44.3 g; 0.66 mol) over 1 h. The reaction was quenched using ice water and potassium hydroxide to a final pH of 10. The product was extracted into toluene which was washed with water and brine. The toluene solution was concentrated to a residue which was triturated with hot hexanes. Insoluble salts were removed by filtration and the filtrate was concentrated to give as a main product 45.7 g (HPLC purity 96percent, yield 91percent) of 8-chloro-6,11-dihydro- 11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine as an off-white solid: mp 116°-119° C.; NMR (200 MHz, CDCl3)delta2.0-2.2 (m,2H), 2.27 (s,3H), 2.3-2.6 (m,4H), 2.6-3.0 (m,4H), 3.3-3.6 (m,2H), 7.0-7.2 (m,4H), 7.44 (dd,1H,J=8, 2 Hz), 8.42 (dd,1H,J=3, 2 Hz); mass spectrum, m/e (rel intensity) 327M+3 (28), 325M+1 (100) Anal. Calcd. for C20 H21 N2 Cl: C,73.94; H,6.52; N,8.63; Cl,10.92. Found: C,73.88; H,6.48; N,8.69; Cl10.80.
45.7 g (HPLC purity: 95%)
E. 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR80 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and KOH bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
126 g (HPLC purity 80%)
Alternative Step E: 8-Chloro-11-(1-Methyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with CH2 Cl2, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous NaOH (50percent), extract the product into CH2 Cl2, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
45.7 g (HPLC purity: 95%)
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR44 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin layer chromatography. Quench the reaction using ice, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
126 g (HPLC purity 80%)
Alternative Step E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
45.7 g (HPLC purity: 95%)
E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR69 Dissolve the title compound of Preparative Example 1D above (59 g, 0.15 mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and add boron trifluoridine (44.3 g, 0.66 mole) over 1 hour. Determine completeness of the reaction by thin-layer chromatography. Quench the reaction using ice, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solution to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an off-white powder. (Yield: 45.7 g (HPLC purity: 95percent), 92percent of theory).
126 g (HPLC purity 80%)
ALTERNATIVE STEP E: 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]-PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin-layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1 N HCl which is treated with 30 g of activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
Alternative Step E 8-Chloro-6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine A solution of 177 g (0.49 mole) of a product of Step D above in 480 mL (814.1 g, 5.31 mole) of trifluoromethanesulfonic acid at 90°-95° C. for 18 hours under nitrogen. Completeness of the reaction is determined by thin-layer chromatography. The cooled reaction is quenched with ice-water and the pH is adjusted to 6 with barium carbonate. The product is extracted into methylene chloride, which is concentrated under reduced pressure to about 1 liter and washed with water. The product is extracted into 1N hydrochloric acid, which is treated with 30 g of Darco, and filtered through celite. The pH of the filtrate is adjusted to 10 with 50percent aqueous sodium hydroxide and the product is extracted into methylene chloride, which is removed under reduced pressure. The residue is dissolved in hot hexane, which is filtered to remove insolubles. The filtrate is concentrated to a residual beige powder. Yield: 126 g (HPLC purity 80percent), 65percent of theory.
126 g (HPLC purity 80%)
Alternative Step E: 8-CHLORO-6,11-DIHYDRO-11-(1-METHYL-4-PIPERIDYLIDENE)-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]-PYRIDINE React the title compound of Preparative Example 1D above (177 g, 0.49 mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at 90°-95° C. for 18 hours under nitrogen. Determine the completeness of the reaction by thin-layer chromatography. Cool the reaction and quench the reaction with ice-water and adjust the pH to 6 with barium carbonate. Extract the product with methylene chloride, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1 N HCl which is treated with 30 g of Darco, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50percent), extract the product into methylene chloride, and remove under reduced pressure to form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80percent), 65percent of theory).
8
[ 506-68-3 ]
[ 38092-89-6 ]
[ 100643-73-0 ]
Yield
Reaction Conditions
Operation in experiment
15 grams (89%)
In water; Petroleum ether; benzene;
A. 8-chloro-6,11-dihydro-11-(1-cyano-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. Dissolve 16.2 grams (0.05 mole) of 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (prepared by the methods described in U.S. Pat. No. 3,326,924) in 300 mL of dry benzene. To this solution, add slowly under nitrogen a solution of cyanogen bromide (6.4 g) dissolved in 75 mL of benzene. Allow this mixture to stir at room temperature overnight (approximately 20 hours). Filter the solution, and concentrate the filtrate in vacuo to a small volume and precipitate the product by the addition of petroleum ether or hexane until precipitation is complete. Filter and recrystallize from ethanol/water to yield the product 15 grams (89percent), m.p. 140°-142° C. Anal. Calcd. for C20 H18 N3 Cl: C,71.53; H,5.40; N,12.51. Found, C,71.73; H,5.43; N,12.27.
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
A mixture of L L-(N-METHYL-4-PIPERIDINYL)-11-HYDROXY-8-CHLORO-6, 11-DIHYDRO-5H- BENZO (5,6) cyclohepta (1,2-b) pyridine (carbinol) of formula IV (1.0 kg, 0.0029 mole) and concentrated sulphuric acid (3.68 kg, 0.0375 mole) is stirred at 35 to 45°C for 2 to 3 hrs. the reaction mixture is poured in chilled water and the product (olefin) is extracted in ethyl acetate at 8-9 pH. The organic phase is dried over anhydrous sodium sulphate and solvent is removed, The residue is crystallized in hexane to give 0.8 kg of olefin of formula V (80percent) with a purity of >98percent (ODB, HPLC).
Step 9: Preparation of 8-chloro-6, ll-dihydro-ll-(N-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[l, 2-b]pyridine (XII); A compound of formula XI (100 gm, 0.29 mole) and concentrated sulfuric acid (368gm, 3.93mole) is stirred at 35-45°C for 2-3 hrs. The reaction mixture is poured in chilled water and the product is extracted in toluene at pH 8-9. The toluene layer in situ proceeded for further reaction to get Loratadine of formula I
F. 8-Chloro-11-(1-Ethoxycarbonyl-4-Piperidylidene)-6,11-Dihydro-5H-Benzo[5,6]Cyclohepta[1,2-b]Pyridine STR67 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethyl-amine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot CH3 CN (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0-5° C., and isolate the product by filtration. Wash with cold CH3 CN and dry the product at below 70° C. to yield compound 535.00. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
42.4 g (HPLC purity 97.4%)
In toluene; acetonitrile;
F. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE STR67 Dissolve the title compound of Preparative Example 1E above (45.6 g, 0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethyl chloroformate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80° C. for 1 hour, then add diisopropylethyl-amine (2.7 mL, 2.00 g, 0.016 mole) and additional ethyl chloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot CH3 CN (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0°-5° C., and isolate the product by filtration. Wash with cold CH3 CN and dry the product at below 70° C. to yield compound 535.00. (Yield: 42.4 g (HPLC purity 97.4percent), 80percent of theory).
F. 8-Chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine Ethyl chloroformate (40.4 mL; 45.9 g; 0.423 mol) was added slowly to a hot (-80° C) toluene solution (320 mL) of the 8-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (45.7 g; 0.141 mol) from Example 1E containing the two corresponding fluoro-substituted compounds of the invention. Following complete addition, the temperature was maintained at 80° C. for 1 h. The reaction mixture was cooled to ambient temperature and the toluene solution washed with water which was adjusted to pH 10 with aqueous sodium hydroxide. The organic layer was concentrated to a residue which was dissolved in hot acetonitrile and decolorized with charcoal. The solution was concentrated to a crystalline slurry which was cooled (5° C). 8-chloro-6,11-dihydro-11-(1-ethoxycarbonyl-4-piperidylidene)-5H-benzo[5,6]cyclohepta [1,2-b]pyridine containing the two corresponding fluoro-substituted compounds of the invention as discussed in Examples 1G below was isolated by filtration yielding 42.4 g: m.p. 134.5°-136° C.; NMR (400 MHz, CDCl3)delta1.25 (t,3H,J=8 Hz), 2.3-2.4 (m,3H), 2.4-2.5 (m,1H), 2.7-2.9 (m,2H), 3.1-3.2 (m,2H), 3.3-3.4 (m,2H), 3.81 (br s, 2H), 4.13 (q,2H,J=8 Hz), 7.1-7.3 (m,4H), 7.43 (dd,1H,J=9,2 Hz), 8.40 (d,1H,J=5 Hz); mass spectrum, m/e (relative intensity) 385M+3 (35), 383 M+1 (100). Anal. Calcd. for C22 H23 N2 ClO2: C,69.00; H,6.05; N,7.32; Cl9.26. Found: C,69.37; H,6.09; N,7.35; Cl 9.37.
With 10% Pd/C; hydrogen; acetic acid In ethanol at 60℃; for 20h;
1-4 The loratadine impurity (Formula II) is prepared using the following steps:
To a 100mL three-necked flask, add methylloratadine (3.25g, 10mmol, 1.0eq) and ethanol (25mL), then add acetic acid (1.2g, 20mmol, 2.0eq) and 10% palladium on carbon (1.60g, 1.5mmol) , 0.15eq). Then evacuate, replace with hydrogen three times, and finally raise the temperature to 60 ° C in a hydrogen balloon atmosphere, stir the reaction for 20 hours, drop to room temperature, filter to remove the palladium carbon, concentrate, and the residue is purified by silica gel column chromatography to obtain loratadine impurities 2.54g, yield 87.5%, HPLC purity 99.57%.
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