cyclopropanamine;hydrochloride

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

Procedure: Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.

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

Procedure: Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.

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

Procedure: Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.

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

Procedure: 9.36 g (0.1 mole) of cyclopropylamine hydrochloride and 8.9 g (0.1 mole) of the sodium salt of cyanoguanidine are suspended in 100 ml of n-butanol and 8 ml of water. The mixture is heated under reflux for 2 hours. The suspension is filtered and the filter cake is washed with 100 ml of n-butanol. The filtrate is evaporated under reduced pressure. The residual oil is taken up in 300 ml of acetonitrile. The mixture is heated to reflux, filtered hot and the filter cake is washed with acetonitrile. The filtrate is evaporated off and the oil obtained crystallizes slowly. 7.7 g of N-cyano-N'-cyclopropylguanidine are obtained. Yield: 62%. M.P.: 106° C. (isopropyl alcohol/diethyl ether). The mixture is heated under reflux for 2 hours The suspension is filtered the filter cake is washed with 100 ml of n-butanol The filtrate is evaporated under reduced pressure The mixture is heated to reflux filtered hot the filter cake is washed with acetonitrile The filtrate is evaporated off the oil obtained crystallizes slowly

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

Procedure: 9.36 g (0.1 mole) of cyclopropylamine hydrochloride and 8.9 g (0.1 mole) of the sodium salt of cyanoguanidine are suspended in 100 ml of n-butanol and 8 ml of water. The mixture is heated under reflux for 2 hours. The suspension is filtered and the filter cake is washed with 100 ml of n-butanol. The filtrate is evaporated under reduced pressure. The residual oil is taken up in 300 ml of acetonitrile. The mixture is heated to reflux, filtered hot and the filter cake is washed with acetonitrile. The filtrate is evaporated off and the oil obtained crystallizes slowly. 7.7 g of N-cyano-N'-cyclopropylguanidine are obtained. Yield: 62%. M.P.: 106° C. (isopropyl alcohol/diethyl ether). The mixture is heated under reflux for 2 hours The suspension is filtered the filter cake is washed with 100 ml of n-butanol The filtrate is evaporated under reduced pressure The mixture is heated to reflux filtered hot the filter cake is washed with acetonitrile The filtrate is evaporated off the oil obtained crystallizes slowly

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

Procedure: To a mixture of N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucine from Example 8 (0.83 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.78 g), cyclopropylamine hydrochloride (0.466 g) in DMF (18 mL) at 0° C. was added triethylamine (0.9 mL). The mixture was kept at room temperature for 48 hours and then poured into dilute aqueous ammonium chloride and diethyl ether. The ether layer was separated and the aqueous further extracted with diethylether. The combined ether extracts were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo. The residue was purified in SiO2 using ethyl acetate and hexanes (1:1) as eluant, followed by a swish in diethyl ether to yield the title compound. The ether layer was separated the aqueous further extracted with diethylether The combined ether extracts were washed with brine dried with magnesium sulfate the solvent was removed in vacuo The residue was purified in SiO2

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

Procedure: To a mixture of N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-leucine from Example 8 (0.83 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.78 g), cyclopropylamine hydrochloride (0.466 g) in DMF (18 mL) at 0° C. was added triethylamine (0.9 mL). The mixture was kept at room temperature for 48 hours and then poured into dilute aqueous ammonium chloride and diethyl ether. The ether layer was separated and the aqueous further extracted with diethylether. The combined ether extracts were washed with brine, dried with magnesium sulfate and the solvent was removed in vacuo. The residue was purified in SiO2 using ethyl acetate and hexanes (1:1) as eluant, followed by a swish in diethyl ether to yield the title compound. The ether layer was separated the aqueous further extracted with diethylether The combined ether extracts were washed with brine dried with magnesium sulfate the solvent was removed in vacuo The residue was purified in SiO2

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

Procedure: 6-Chloro-9-vinylpurine (0.54 g, 3 mmol) was mixed with cyclopropylamine (1.71 g, 30 mmol) in THF (10 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (cyclopropylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then recrystallized from EtOAc/hexanes yielding the desired product. The aqueous layer was extracted with ethyl acetate the combined organic layers were dried over sodium sulfate concentrated on a rotavap recrystallized from EtOAc/hexanes yielding the desired product

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

Procedure: 6-Chloro-9-vinylpurine (0.54 g, 3 mmol) was mixed with cyclopropylamine (1.71 g, 30 mmol) in THF (10 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (cyclopropylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then recrystallized from EtOAc/hexanes yielding the desired product. The aqueous layer was extracted with ethyl acetate the combined organic layers were dried over sodium sulfate concentrated on a rotavap recrystallized from EtOAc/hexanes yielding the desired product

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

Procedure: In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.78 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclopropylamine hydrochloride (405 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.59 g) as a colorless powder.

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

Procedure: In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.78 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclopropylamine hydrochloride (405 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.59 g) as a colorless powder.

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

Procedure: Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 414 mg cyclopropylamine hydrochloride, 134 mg of the title compound was obtained in the same manner as in Production Example 4.