(2,6-dimethoxyphenyl)methanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 6-Chloro-4-(2-methylphenyl)-2-oxo-2H -1-benzopyran-3-acetic acid was reacted with 2,6-dimethoxybenzylamine by a method similar to Example 1(A) to yield the title compound.

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

Procedure: 2,6-Dimethoxybenzylamine was treated with 48% hydrobromic acid to obtain 2,6-dihydroxybenzylamine hydrobromide. F: 140.

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

Procedure: 2,6-Dimethoxybenzylamine was treated with 48% hydrobromic acid to obtain 2,6-dihydroxybenzylamine hydrobromide. F: 140.

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

Procedure: 2-Chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,6-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.

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

Procedure: 0.37 mL (5.89 mmol) methyl iodide diluted in 2 mL methanol was added dropwise to 1.032 g (4.46 mmol) N-(6-bromopyridin-2-yl)thiourea suspended in 30 mL methanol, and the mixture was heated for 2 hr under reflux. The reaction mixture was in solution. The methylated intermediate product, consisting of methyl N-(6-bromopyridin-2-yl)imidothiocarbamate hydroiodide (ESI-MS [M+H+]=247.85 calculated for C7H8BrN3S=246), was freed of solvent under vacuum. The intermediate product was then suspended in 30 mL ethanol, and 1.122 g (6.442 mmol) 2,6-dimethoxybenzylamine was added, whereupon the solid completely dissolved. The mixture was then heated for 2.25 hr under reflux. The colorless solid which precipitated was suctioned off and washed with ethanol. 1.197 g N-(6-bromopyridin-2-yl)-N′-(2,6-dimethoxybenzyl)guanidine was obtained as crude product. Repeated crystallization from acetonitrile/water resulted in the isolation of 1.311 g (3.589 mmol, 81%) N-(6-bromopyridin-2-yl)-N-(2,6-dimethoxybenzyl)guanidine, which was also used for the subsequent reaction and derivatizations. the mixture was heated for 2 hr under reflux completely dissolved The mixture was then heated for 2.25 hr under reflux The colorless solid which precipitated washed with ethanol

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

Procedure: 0.800 g (5.117 mmol) N-pyridin-2-yl-thiourea was dissolved in 20 mL methanol and combined with 0.45 mL (10.235 mmol) methyl iodide. The mixture was heated under reflux for 15 min and subsequently stirred at room temperature. After reaction was complete the solvent was removed under vacuum, and the residue was used for the subsequent reaction without further purification. For this purpose the solid was dissolved in 20 mL ethanol, and 0.946 g (5.658 mmol) 2,6-dimethoxybenzylamine was added. After addition of 1.80 mL (10.235 mmol) diisopropylethylamine the mixture was heated under reflux for a total of 7 hr. After reaction was complete the solvent was removed under vacuum. The residue was taken up in dichloromethane and extracted with water (2×30 mL). The organic phase was dried over magnesium sulfate, and the solvent was evaporated under vacuum. 0.402 g of the desired product N-(2,6-dimethoxybenzyl)-N′-pyridin-2-yl-guanidine crystallized from acetonitrile/water (1:1), and by use of ion exchanger (Fluka, acetate on 1.5 mmol CH3COO/g/resign polymer substrate) was converted to the acetate salt. The residual mother liquor of the crystallizate was separated from impurities via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid), resulting in isolation of a total of 0.516 g (1.489 mmol) N-(2,6-dimethoxybenzyl)-N′-pyridin-2-yl-guanidine acetate as a pure substance. The mixture was heated under reflux for 15 min After reaction was removed under vacuum the residue was used for the subsequent reaction without further purification was heated under reflux for a total of 7 hr After reaction was removed under vacuum extracted with water (2×30 mL) The organic phase was dried over magnesium sulfate the solvent was evaporated under vacuum 0.402 g of the desired product N-(2,6-dimethoxybenzyl)-N′-pyridin-2-yl-guanidine crystallized from acetonitrile/water (1:1) The residual mother liquor of the crystallizate was separated from impurities via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.019 g (7.233 mmol) N-(5-iodopyridin-2-yl)thiourea was dissolved in 50 mL methanol, 0.60 mL (9.553 mmol) methyl iodide in 2 mL methanol was added dropwise, and the mixture was heated for 2.7 hr at 75° C. (oil bath temperature). The solvent was removed under vacuum, and the intermediate product was redissolved in 50 mL ethanol. 1.870 g (0.736 mmol) 2,6-dimethoxybenzylamine was added to the reaction mixture and heated for 2.25 hr at 90° C. (oil bath temperature). The solvent was then evaporated under vacuum. The crude product was dissolved in acetonitrile, and the product crystallized out with addition of water. The solid was suctioned off and washed with water. 2.698 g (6.152 mmol, 85%) N-(2,6-dimethoxybenzyl)-N′-(5-iodopyridin-2-yl)guanidine was isolated and used for further reaction. The solvent was removed under vacuum the intermediate product was redissolved in 50 mL ethanol heated for 2.25 hr at 90° C. (oil bath temperature) The solvent was then evaporated under vacuum The crude product was dissolved in acetonitrile the product crystallized out with addition of water washed with water

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

Procedure: A solution of (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 36) (150 mg, 0.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol), hydroxybenzotriazole monohydrate (47 mg, 0.35 mmol) in N,N-dimethylformamide (3 ml) was treated with triethylamine (0.09 ml, 0.63 mmol) and 2,6-dimethoxybenzylamine (58 mg, 0.35 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate (10 ml). The organic phase was separated, and the aqueous phase extracted with further ethyl acetate (2×10 ml). The combined organic extracts were washed with water (5 ml), brine (5 ml), dried (sodium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give the title compound as a pale yellow oil (128 mg). the resulting suspension left The solvent was removed in vacuo the residue partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate (10 ml) The organic phase was separated the aqueous phase extracted with further ethyl acetate (2×10 ml) The combined organic extracts were washed with water (5 ml), brine (5 ml) dried (sodium sulphate) the solvent removed in vacuo The residue was purified by flash column chromatography on silica gel eluting with dichloromethane