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Thursday, 9 February 2017

(l,4-bis((3-(l-propylpiperidin-4' yl)phenyI)sulfonyl)butane)

Example 3 - Preparation Of Compound 3 (l,4-bis((3-(l-propylpiperidin-4' yl)phenyI)sulfonyl)butane)
Preparation of 1.4-bis((3-bromophenyl)thio')butane (Compound 3. 1st int.)
1 ,4-bis((3-bromophenyl)thio)butane
KOH (56.2g) was added into methanol (1200mL) in 15min. The clear solution was cooled on water bath to 0°C. A solution of 3-bromo thiophenol (150.2g, 0.79mol) in methanol (200mL) was added in 50min keeping the temperature at 1-3°C. A solution of 1,4-dibromobutane (86.5g; 0.40 mol) in methanol (150 ml) was added in 40min to give a yellow turbid mixture. After additional 4 hours stirring the reaction mixture became white turbid and it was stirred for additional 20h at 25°C. The suspension was filtered and washed with water (3xl00mL) and methanol (2xl00mL) to give 239g wet white solid that was dried to 163.6g (94.6% yield, HPLC: 97.9%).
Preparation of l ,4-bis((3-bromophenyl)sulfonyl)butane ("Compound 3, 2nd intermediate)
1 ,4-bis((3-bromophenyl)sulfonyl)butane
To a solution of l,4-bis-(3-bromophenylthio)-butane (155.0g, 0.358mol) in acetic acid (1500mL) was added sodium tungstate dihydrate (2.5 g, 0.0075mol) and the suspension was heated on water-bath to 45°C. 50%¾θ2 (300 mL, 5.28 mol) was added drop-wise into the reaction mixture during 3.5h keeping the temperature at 45-55°C. The reaction mixture was kept under stirring for additional 3h at 45°C and 16h at 23°C. The off white slurry was filtered, washed with water (3x200mL) and dried on air to give 179.6g (99% crude yield, HPLC: 92.2% product, 7.1% by product). The crude product (175g) was added to toluene (1400mL) and heated to >85°C for distillation. Distillation stopped when no more water was distilled (180mL toluene and lOmL water). The clear reaction mixture was allowed to cool down and was filtered after overnight stirring at ambient temperature. The bright colorless crystals were washed (150mL toluene) and dried to give 156. lg product (86.7% yield, HPLC: product 96.0%, main by-product 3.5%).
Preparation of 1 -bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane (Compound 3 3rd intermediate)
1 ,4-bis((3-(pyridin-4-yl)phenyl)sulfonyl)butane
To a solution of l,4-Bis-((3-bromophenyl)-sulfonyl)-butane (92.0g, 185mmol) and butanol (1.0L) was added 4-pyridinylboronic acid (75.0g, 610mmol), potassium carbonate (172g, 1.24mol) and the catalyst trans-dichlorobis-(triphenylphosphine) palladium (2.0g; 2.8mmol). The violet suspension was heated at stirring under nitrogen to 90-95°C within lh. The reaction mixture became brown and heating continued for more 4h. Additional 4-pyridinylboronic acid (3.5g, 28mmol) was added and the reaction mixture heated up to 100°C for lh. Heating stopped, water (600mL) was added and the temperature dropped to 60°C. The resulting dark gray suspension was stirred overnight at ambient temperature and filtered (slowly). The filter cake was washed with water (lOOmL) to give 153g wet solid which was suspended in hot acetone (2xlL, 50°C). The solid was then suspended with 0.5L water at 65°C followed by 2xlL acetone suspension. The acetone solution were combined and concentrated on a rotavapor to give 90.3g pale yellow solid (yield: 91%, HPLC: 91.8% area).
Preparation of 4,4'-((butane- 1 ,4-diyldisulfony l)bis(3 , 1 -phenylene))bis( 1 -propylpyridin- 1 -iurrOiodide (Compound 3 4th intermediate)
To a solution of l,4-Bis-((3-(pyridin-4-yl)-phenyl)-sulfonyl)-butane (85.8g, 160mmol) and butanol (450mL) was added 1-iodopropane (91.7g, 540mmol). The stirring mixture was heated up to 90-95°C in nitrogen atmosphere and kept at this temperature for 6 hours. The dark yellow slurry was then cooled down to room temperature and kept at this temperature for 15h. The yellow clear solution was then decanted and butanol (300mL) was added. The mixture was heated to 70°C where it dissolved. Heating continued to 95°C and light brown slurry appeared. The heating was stopped and the mixture cooled down to 40°C. The yellow cloudy liquid was decanted and a dark yellow solid mass was filtered to give 173.5g (HPLC: 84% area) which was used as is in the next step.
Preparation of l,4-bis((3-(l -propyl- l,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl) butane (Compound 3, 5th intermediate)
1 ,4-bis((3-( 1 -propy 1-1 ,2,3,6-tetrahydropyridin- 4-yl)phenyl)sulfonyl)butane
To the solid crude starting material (173.5g from the previous stage) was added methanol (450mL) and the mixture was heated to reflux to give dark yellowish red clear solution which after cooling gave two phases, the lower one weigh 150g (HPLC: 88.4% area, yield corrected to area%: 13 lg, 157mmol). Methanol (400mL) was added and the mixture was cooled (0°C). Sodium borohydride (23.75g, 624mmol, 4eq) was added and the reaction mixture was allowed to warm to RT and stirred for additional 9h. The workup includes concentrating filtrates and precipitating from butanol and methanol, several slurries in butanol, extraction by hot butanol from water and finally active carbon treatment to the product dissolved in hot butanol to give 63.0g (HPLC: 85% area) which was used as is in the next step.
Preparation of l,4-bis((3-(l-propylpiperidine-4yl)phenyl)sulfonvnbutane (Compound 3)
1 ,4-bis((3-(1-propylpiperidin-4-yl)phenyl)sulfonyl)butane
The product from the previous step (60.Og, 51g as HPLC is 85% area, 87mmol) was added into an autoclave with 350mL acetic acid. A suspension of 10% Pd C catalyst (lOg, 9.4mmol) in water (80mL) was added. Air was exchange to nitrogen and then hydrogen was introduced (150psi) and the reaction was heated to 85°C for 6h. After cooling the catalyst was filtered, washed with acetic acid (2x30mL) and water (2x30mL) and concentrated under vacuum to give 98g of slightly brownish viscous residue. The residue was dissolved with water (200mL), filtered (to remove traces of charcoal) and washed with 50mL water. To the slightly brownish solution was added concentrated NaOH up to pH 13 and the mixture was stirred for 30m. The massive precipitation was filtered to give 78. lg slightly beige wet solid. The wet solid was mixed with water (lOOmL) and toluene (300mL), heated up to 87°C for 30min and the dark yellow water phase was separated. The organic phase was filtered and cooled down to 30°C. After 4h the slurry was filtered, washed with 20mL toluene and dried to give 40.8g off-white solid (HPLC: 74.4% area). The solid was then suspended in toluene (260mL) and water (40mL) and heated up to 85°C. The colorless water phase was separated and the toluene phase was filtered, cooled down to 5°C for 2hr and filtered to give after drying 38.0g off-white solid (HPLC: 81.5% area). The solid was then crystallized twice from toluene (300mL, heating to 90°C, cooled to 3°C, filtered, washed with 30mL toluene, dried) to give 31.2g, HPLC: 96.9% area, 1H-NMR assay: 93.9%.
NMR Identity Analysis of Compound 3
Compound 3:
The following data in Tables 6 and 7 was determined using a sample of 47.82 mg Compound 3, a solvent of 1.0 ml DMSO-D6, 99.9 atom%D, and the instrument was a Bruker Avance ΠΙ 400 MHz.
Table 6: Assignment of ¾ NMRa'c
a The assignment is based on the coupling pattern of the signals, coupling constants and chemical shifts. Due to the low concentration of dissolved material some expected HMBC signals were masked by background noise.
b Weak signal.
c Spectra is calibrated by the solvent residual peak (2.5 ppm).
Table 7: Assignment of 13NMRa 'b
a The assignment is based on the chemical shifts and 1H-13C couplings extracted from HSQC and HMBC experiments.
b Spectra is calibrated by a solvent peak (39.54 ppm).