N-methylcyclopropanamine;hydrochloride

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

Procedure: To a solution of 2.64 g (15 mmol) 8-methoxy tetralone, 6 g (60 mmol) methylcyclopropylamine HCl and 4.92 g (60 mmol) NaOAc in 30 mL MeOH/THF (1:1) was added HOAc dropwise to adjust the pH to 4-5. The reaction mixture stirred for 15 minutes under N2, then 1.26 g (20 mmol) NaCNBH3 was added. When the reaction was complete by TLC (24 h), 1N NaOH (20 mL) and H2O (200mL) was added to quench the reaction. The solution was extracted with CH2Cl2 (2×500 mL) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 400 g of silica gel 60 (230-400m), eluting with hexane/acetone (3:1). Fractions homogeneous by TLC were combined and concentrated in vacuo to give pure compound as an oil. The HCl salt was formed by using a MeOH/HCl solution. The title compound was recovered by recrystallization as a white solid using EtOAc/MeOH (1.77 g, 44%); m.p. 216°-218° C. was added to quench the reaction The solution was extracted with CH2Cl2 (2×500 mL) the combined organic layers were washed with brine dried (MgSO4) filtered concentrated in vacuo The resulting oil was purified by liquid chromatography on 400 g of silica gel 60 (230-400m) eluting with hexane/acetone (3:1) concentrated in vacuo to give pure compound as an oil

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

Procedure: Cyclopropyl-methyl amine HCl (1.32 g, 0.0123 mol) and Et3N (2.4 g, 0.0246 mol) were added to a solution of (4-chloro-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl)-acetic acid ethyl ester (2 g, 0.00615 mol) in 20 ml of methanol and the mixture was stirred for 18 h at ambient temperature. The methanol was removed under vacuum and the crude was purified by chromatography on silica gel using 10% ethyl acetate in hexanes to give [4-(cyclopropyl-methyl-amino)-6,7,8,9-tetrahydro-5H-10-thia-1,3-diaza-benz[a]azulen-2-yl]-acetic acid ethyl ester (1.8 g, 81%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 4.18 (q, 2H), 3.89 (s, 2H), 2.92-3.00 (m, 5H), 2.78-2.90 (m, 3H), 1.85-1.92 (m, 2H), 1.68-1.77 (m, 2H), 1.60-1.67 (m, 2H), 1.25 (t, 3H), 0.68-0.75 (m, 2H), 0.40-0.47 (m, 2H); LC-MS: [M+H]: =359.9 m/z. The methanol was removed under vacuum the crude was purified by chromatography on silica gel using 10% ethyl acetate in hexanes

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

Procedure: The TEA (0.6 g, 0.0064 mol) was added dropwise at 10° C. to a mixture of 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester (1 g, 0.0032 mol) and cyclopropyl methyl amine hydrochloride (0.35 g, 0.0032 mol) in methanol (20 ml). The resulting mixture was stirred at R.T for 10 hrs. Methanol was removed and the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4, concentrated and subjected to column purification on 60-120 silica using ethyl acetate (50%) in hexane to give 0.5 g (43%) of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=0.35 (m, 2H), 0.72 (m, 2H), 1.69 (m, 2H), 1.85 (m, 2H), 2.77 (q, 4H), 2.86 (q, 2H), 2.9 (m, 1H), 2.97 (s, 3H) 3.02 (t, 2H), 3.56 (s, 3H). LC-MS: [M+H]=345.8. Methanol was removed the reaction mixture was diluted with water extracted with ethyl acetate (3×25 ml) The combined organic layers were dried over Na2SO4 concentrated subjected to column purification on 60-120 silica

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

Procedure: The TEA (0.6 g, 0.0064 mol) was added dropwise at 10° C. to a mixture of 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl)-propionic acid methyl ester (1 g, 0.0032 mol) and cyclopropyl methyl amine hydrochloride (0.35 g, 0.0032 mol) in methanol (20 ml). The resulting mixture was stirred at R.T for 10 hrs. Methanol was removed and the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4, concentrated and subjected to column purification on 60-120 silica using ethyl acetate (50%) in hexane to give 0.5 g (43%) of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=0.35 (m, 2H), 0.72 (m, 2H), 1.69 (m, 2H), 1.85 (m, 2H), 2.77 (q, 4H), 2.86 (q, 2H), 2.9 (m, 1H), 2.97 (s, 3H) 3.02 (t, 2H), 3.56 (s, 3H). LC-MS: [M+H]=345.8. Methanol was removed the reaction mixture was diluted with water extracted with ethyl acetate (3×25 ml) The combined organic layers were dried over Na2SO4 concentrated subjected to column purification on 60-120 silica

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

Procedure: To a stirring suspension of compound 4-Chloro-2-methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (1.0 g, 0.0037 mol) and cyclopropyl methylamine hydrochloride (1.18 g, 0.111 mol) in methanol (100 ml) was added TEA (3.1 ml, 0.022 mol) at 0-5° C. Reaction mixture was then warmed to room temperature and stirred for about 20 h. After completion of the reaction (monitored by TLC) volatilities were removed under vacuum and solid residue obtained was diluted with ice-water solution (200 ml). Aqueous phase was extracted with DCM (2×250 ml). Combined organic layer was washed with brine solution, dried and concentrated on rotary evaporator to get crude material which was purified by prep HPLC to get the desired title compound cyclopropyl-(2-methoxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-methyl-amine(N-cyclopropyl-2-(methoxymethyl)-N-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine) as a yellow solid. Yield: (600 mg, 54.5%); 1H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 1.88-1.82 (m, 2H), 1.72-1.68 (m, 2H), 0.76 1H NMR (400 MHz, DMSO) δ ppm=4.41 (s, 2H), 3.36 (s, 3H), 3.30 (s, 3H), 2.97-2.92 (m, −0.70 (m, 2H), 0.40-0.36 (m, 2H); LCMS: [M+H]=304.40; HPLC (purity): 99.61% at 236 nm, 99.45% at 220 nm, 99.32% at 254 nm. Reaction mixture After completion of the reaction (monitored by TLC) volatilities were removed under vacuum and solid residue obtained Aqueous phase was extracted with DCM (2×250 ml) Combined organic layer was washed with brine solution dried concentrated on rotary evaporator to get crude material which was purified by prep HPLC

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

Procedure: To a stirring suspension of compound 4-Chloro-2-methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (1.0 g, 0.0037 mol) and cyclopropyl methylamine hydrochloride (1.18 g, 0.111 mol) in methanol (100 ml) was added TEA (3.1 ml, 0.022 mol) at 0-5° C. Reaction mixture was then warmed to room temperature and stirred for about 20 h. After completion of the reaction (monitored by TLC) volatilities were removed under vacuum and solid residue obtained was diluted with ice-water solution (200 ml). Aqueous phase was extracted with DCM (2×250 ml). Combined organic layer was washed with brine solution, dried and concentrated on rotary evaporator to get crude material which was purified by prep HPLC to get the desired title compound cyclopropyl-(2-methoxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-methyl-amine(N-cyclopropyl-2-(methoxymethyl)-N-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine) as a yellow solid. Yield: (600 mg, 54.5%); 1H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 1.88-1.82 (m, 2H), 1.72-1.68 (m, 2H), 0.76 1H NMR (400 MHz, DMSO) δ ppm=4.41 (s, 2H), 3.36 (s, 3H), 3.30 (s, 3H), 2.97-2.92 (m, −0.70 (m, 2H), 0.40-0.36 (m, 2H); LCMS: [M+H]=304.40; HPLC (purity): 99.61% at 236 nm, 99.45% at 220 nm, 99.32% at 254 nm. Reaction mixture After completion of the reaction (monitored by TLC) volatilities were removed under vacuum and solid residue obtained Aqueous phase was extracted with DCM (2×250 ml) Combined organic layer was washed with brine solution dried concentrated on rotary evaporator to get crude material which was purified by prep HPLC

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2 H) 0.48-0.56 (m, 2 H) 1.43 (s, 9 H) 1.64 (tt, J=6.7, 3.9 Hz, 1 H) 2.28 (s, 3 H) 3.50 (tt, J=7.5, 5.7 Hz, 1 H) 3.84-4.01 (m, 4 H). The solution was concentrated in vacuo to give white solid which washed with saturated sodium bicarbonate (50 mL) and brine dried with magnesium sulfate concentrated in vacuo purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2 H) 0.48-0.56 (m, 2 H) 1.43 (s, 9 H) 1.64 (tt, J=6.7, 3.9 Hz, 1 H) 2.28 (s, 3 H) 3.50 (tt, J=7.5, 5.7 Hz, 1 H) 3.84-4.01 (m, 4 H). The solution was concentrated in vacuo to give white solid which washed with saturated sodium bicarbonate (50 mL) and brine dried with magnesium sulfate concentrated in vacuo purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 4-bromo-3-fluorobenzoic acid, N-methylcyclopropanamine hydrochloride (J&W PharmLab: Cat. #20-0433S) and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=471.2. 1H NMR (400 MHz, DMSO-D6): δ 12.83 (s, 1H), 9.17 (s, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 7.85 (s, 1H), 7.33 (m, 3H), 6.71 (t, J=9.0 Hz, 1H), 4.66 (d, J=8.0 Hz, 2H), 4.41 (d, J=8.0 Hz, 2H), 3.79 (s, 2H), 2.97 (m, 1H), 2.93 (s, 3H), 0.59 (m, 2H), 0.42 (m, 2H). This compound was prepared

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2H) 0.48-0.56 (m, 2H) 1.43 (s, 9H) 1.64 (tt, J=6.7, 3.9 Hz, 1H) 2.28 (s, 3H) 3.50 (tt, J=7.5, 5.7 Hz, 1H) 3.84-4.01 (m, 4H). The solution was concentrated in vacuo to give white solid which washed with saturated sodium bicarbonate (50 mL) and brine dried with magnesium sulfate concentrated in vacuo purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined a solution of tert-butyl 3-oxoazetidine-1-carboxylate (175 mg, 1.022 mmol) and N-methylcyclopropanamine hydrochloride (121 mg, 1.124 mmol) in methylene chloride (5 mL) and added sodium triacetoxyborohydride (325 mg, 1.533 mmol) and the solution stirred at 20° C. for 30 min. The solution was concentrated in vacuo to give white solid which was taken up in ethyl acetate (50 mL), washed with saturated sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo, and then purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes to give the title compound (128 mg, 0.566 mmol, 55.3%) as a clear, colorless oil. MS: 227 (M+H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.41-0.47 (m, 2H) 0.48-0.56 (m, 2H) 1.43 (s, 9H) 1.64 (tt, J=6.7, 3.9 Hz, 1H) 2.28 (s, 3H) 3.50 (tt, J=7.5, 5.7 Hz, 1H) 3.84-4.01 (m, 4H). The solution was concentrated in vacuo to give white solid which washed with saturated sodium bicarbonate (50 mL) and brine dried with magnesium sulfate concentrated in vacuo purified on a 40 g silica gel column eluted with 0 to 50% ethyl acetate in hexanes

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

Procedure: The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A1) (3.40 g, 10 mmol) and cyclopropyl-methyl-amine hydrochloride (3.22 g, 30 mmol) and Et3N (6.97 mL, 50 mmol) in DMSO (50 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (3.74 g).