cyclopropylmethanamine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 59.8 mg 3-{1-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-piperidin-4-yl}-benzoic acid are placed in 2.3 ml dimethylformamide, then 91 l diisopropylethylamine and 60 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min a mixture of 15.5 mg cyclopropylmethylamine hydrochloride in 300 l dimethylformamide is added. The reaction mixture is stirred at ambient temperature until there is no further reaction, and the product is purified directly by preparative HPLC (method B). 50 mg Example 249 are obtained as a solid. Analytical HPLC-MS (method D): RT=1.05 min. is added no further reaction the product is purified directly by preparative HPLC (method B)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 55 mg of Example 184 (see 40.) are placed in 2 ml dimethylformamide, then 81 l diisopropylethylamine and 53.1 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min 13.8 mg cyclopropylmethylamine hydrochloride are added. The reaction mixture is stirred at ambient temperature until there is no further reaction and the product is purified directly by preparative HPLC (method B). 30 mg of Example 242 are obtained as a solid. no further reaction the product is purified directly by preparative HPLC (method B)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 mg tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate are placed in 28 ml dimethylformamide, then 1.14 ml diisopropylethylamine and 747 mg HATU are added. The reaction mixture is stirred for 15 min at ambient temperature, then 194 mg cyclopropylmethylamin hydrochloride are added. The reaction mixture is stirred overnight at ambient temperature. Then the product is purified by preparative HPLC (method A). 480 mg product are obtained as an oil. Analytical HPLC-MS (method B): RT=1.64 min. The reaction mixture is stirred overnight at ambient temperature Then the product is purified by preparative HPLC (method A)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-2-carboxypyridine (2.0 g), (aminomethyl)cyclopropane hydrochloride (1.7 g), 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (WSC) (2.9 g), 1-hydroxybenzotriazole (HOBt) (2.3 g), triethylamine (2.1 ml) and tetrahydrofuran (30 ml) were stirred together at room temperature for 2 hours. Water was added, extraction was performed with ethyl acetate, and then silica gel was added to the extract and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil. extraction silica gel was added to the extract the solvent was distilled off under reduced pressure The silica gel was charged into a dry column purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM), 0.026 cm3 of triethylamine and 21 mg of aminomethylcyclopropane hydrochloride. 68 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 (s, 3H), 3.15 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64 (t, J=6 Hz, 1H)].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM), 0.026 cm3 of triethylamine and 21 mg of aminomethylcyclopropane hydrochloride. 68 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 (s, 3H), 3.15 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64 (t, J=6 Hz, 1H)].

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of acetic acid 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (3.5 g, 0.011 mol), cyclopropylmethylamine hydrochloride (2.5 g, 0.023 mol) and triethylamine (4.6 g, 0.046 mol) in acetonitrile (15 ml) was stirred at room temperature for 12 h. The solvent was removed by distillation, and the residue was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over anhydrous sodium sulphate, concentrated to give acetic acid 4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (3.5 g, 89%) as brown solid. 1H NMR (400 MHz, CDCl3): δ 0.43-0.47 (m, 2H), 0.69-0.77 (m, 2H), 1.71-1.77 (m, 2H), 1.87-1.93 (m, 2H), 2.18 (s, 3H), 2.82-2.92 (m, 5H), 3.03 (s, 3H), 5.19 (s, 2H); LC-MS: [M+H]=331.8 m/z. The solvent was removed by distillation the residue was diluted with water extracted with ethyl acetate (3×25 ml) The combined organic layers were dried over anhydrous sodium sulphate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of acetic acid 4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (3.5 g, 0.011 mol), cyclopropylmethylamine hydrochloride (2.5 g, 0.023 mol) and triethylamine (4.6 g, 0.046 mol) in acetonitrile (15 ml) was stirred at room temperature for 12 h. The solvent was removed by distillation, and the residue was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over anhydrous sodium sulphate, concentrated to give acetic acid 4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethyl ester (3.5 g, 89%) as brown solid. 1H NMR (400 MHz, CDCl3): δ 0.43-0.47 (m, 2H), 0.69-0.77 (m, 2H), 1.71-1.77 (m, 2H), 1.87-1.93 (m, 2H), 2.18 (s, 3H), 2.82-2.92 (m, 5H), 3.03 (s, 3H), 5.19 (s, 2H); LC-MS: [M+H]=331.8 m/z. The solvent was removed by distillation the residue was diluted with water extracted with ethyl acetate (3×25 ml) The combined organic layers were dried over anhydrous sodium sulphate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2.6 g (0.024 mole) of (aminomethyl) cyclopropane hydrochloride in 50 ml of pyridine was stirred under a blanket of nitrogen while 3.9 g (0.024 mole) of 1,1'-carbonyldiimidazole was added. After stirring for 45 minutes, the TLC (5% methanol/methylene chloride on silica gel) showed no reaction; therefore, 2 ml of triethylamine was added. The reaction mixture after 10 minutes became cloudy and the TLC showed a new product. The reaction was treated with 6.2 g (0.02 mole) of 3-(3-(trifluoromethyl)phenoxy]azetidine oxalate. After stirring for 1 hr, a sample was removed, and upon dilution with water, a solid precipitated. The CI mass spectrum indicated it was product. After 2 days, the reaction was diluted with 5 volumes of water and the resulting precipitate collected by filtration to yield 6.5 g of pale yellow crystalline product. Recrystallization from ethanol/water produced white plate-like crystals which were dried at 82° C. for 3 hr in a drying pistol under vacuum; weight of the product was 5.8 g (92%), m.p. 132°-133° C. was added no reaction The reaction mixture after 10 minutes became cloudy After stirring for 1 hr a sample was removed upon dilution with water, a solid precipitated After 2 days the reaction was diluted with 5 volumes of water the resulting precipitate collected by filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-2-carboxypyridine (2.0 g), (aminomethyl)cyclopropane hydrochloride (1.7 g), 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (WSC) (2.9 g), 1-hydroxybenzotriazole (HOBt) (2.3 g), triethylamine (2.1 ml) and tetrahydrofuran (30 ml) were stirred together at room temperature for 2 hours. Water was added, extraction was performed with ethyl acetate, and then silica gel was added to the extract and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil. extraction silica gel was added to the extract the solvent was distilled off under reduced pressure The silica gel was charged into a dry column purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-2-carboxypyridine (2.0 g), (aminomethyl)cyclopropane hydrochloride (1.7 g), 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (WSC) (2.9 g), 1-hydroxybenzotriazole (HOBt) (2.3 g), triethylamine (2.1 ml) and tetrahydrofuran (30 ml) were stirred together at room temperature for 2 hours. Water was added, extraction was performed with ethyl acetate, and then silica gel was added to the extract and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil. extraction silica gel was added to the extract the solvent was distilled off under reduced pressure The silica gel was charged into a dry column purified by column chromatography (hexane:ethyl acetate=4:1, followed by 2:1) to obtain 1.5 mg of the target substance as a yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2.6 g (0.024 mole) of (aminomethyl) cyclopropane hydrochloride in 50 ml of pyridine was stirred under a blanket of nitrogen while 3.9 g (0.024 mole) of 1,1'-carbonyldiimidazole was added. After stirring for 45 minutes, the TLC (5% methanol/methylene chloride on silica gel) showed no reaction; therefore, 2 ml of triethylamine was added. The reaction mixture after 10 minutes became cloudy and the TLC showed a new product. The reaction was treated with 6.2 g (0.02 mole) of 3-(3-(trifluoromethyl)phenoxy]azetidine oxalate. After stirring for 1 hr, a sample was removed, and upon dilution with water, a solid precipitated. The CI mass spectrum indicated it was product. After 2 days, the reaction was diluted with 5 volumes of water and the resulting precipitate collected by filtration to yield 6.5 g of pale yellow crystalline product. Recrystallization from ethanol/water produced white plate-like crystals which were dried at 82° C. for 3 hr in a drying pistol under vacuum; weight of the product was 5.8 g (92%), m.p. 132°-133° C. was added no reaction The reaction mixture after 10 minutes became cloudy After stirring for 1 hr a sample was removed upon dilution with water, a solid precipitated After 2 days the reaction was diluted with 5 volumes of water the resulting precipitate collected by filtration