(1-methyl-3,6-dihydro-2H-pyridin-4-yl)methanol

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

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

Procedure: The title compound was prepared from 4-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D9) and 2-iodophenol, using a procedure similar to that of Description 1 in 74% yield.

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

Procedure: To a solution of ethyl 1-methyl-1,2,3,6tetrahydro-4-pyridinecarboxylate (10.0 ml, 0.061 mole) in THF (200 ml) was added, maintaining temperature below 25° C., lithium aluminium hydride (2.76 g, 0.073 mole). After stirring for a further 15 min, water (2.75 ml), 10% NaOH (4 ml) and water (4 ml) were successively added, and the mixture was filtered. The filtrate was dried (Na2SO4) and evaporated in vacuo to give the title compound as an amber oil (6.30 g, 81%), which solidified on standing. the mixture was filtered The filtrate was dried (Na2SO4) evaporated in vacuo

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

Procedure: To a solution of ethyl 1-methyl-1,2,3,6tetrahydro-4-pyridinecarboxylate (10.0 ml, 0.061 mole) in THF (200 ml) was added, maintaining temperature below 25° C., lithium aluminium hydride (2.76 g, 0.073 mole). After stirring for a further 15 min, water (2.75 ml), 10% NaOH (4 ml) and water (4 ml) were successively added, and the mixture was filtered. The filtrate was dried (Na2SO4) and evaporated in vacuo to give the title compound as an amber oil (6.30 g, 81%), which solidified on standing. the mixture was filtered The filtrate was dried (Na2SO4) evaporated in vacuo

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

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

Procedure: 4-(Hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1, 5.63 g, 0.044 mol), 2-iodophenol (7.80 g, 0.035 mol) and triphenylphosphine (11.61 g, 0.044 mol) were stirred in dry THF (200 ml) under Ar as diethyl azodicarboxylate (7.0 ml, 0.044 mol) was added portionwise. The solution was stirred for 1h, concentrated, diluted with ethyl acetate, and extracted with dil. HCl. The extract was basified (sat. K2CO3 solution) and extracted with ethyl acetate. This organic extract was dried (Na2SO4) and evaporated to give a brown oil. Purification by chromatography on silica gel, eluting with 0-10% methanol/chloroform (gradient) gave the title compound (7.65 g, 65%) as an amber oil. was added portionwise concentrated diluted with ethyl acetate extracted with dil. HCl extracted with ethyl acetate This organic extract was dried (Na2SO4) evaporated to give a brown oil Purification by chromatography on silica gel eluting with 0-10% methanol/chloroform (gradient)

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

Procedure: To a solution of ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate (10.0 ml, 0.061 mole) in THF (200 ml) was added, maintaining temperature below 25° C., lithium aluminum hydride 2.76 g, 0.073 mole). After stirring for a further 15 min, water (2.75 ml), 10% NaOH (4 ml) and water (4 ml) were successively added, and the mixture was filtered. The filtrate was dried (Na2SO4) and evaporated in vacuo to give the title compound as an amber oil (6.30 g, 81%), which solidified on standing. the mixture was filtered The filtrate was dried (Na2SO4) evaporated in vacuo

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

Procedure: The title compound was prepared from 1-acetyl-5-bromo-6-hydroxyindoline (D64) and 1-methyl-1,2,5,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) using the procedure of Description 8a in WO96/19477. The product was purified by acid/base extraction, then used in the next step. The product was purified by acid/base extraction

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

Procedure: The title compound was prepared from 1-acetyl-8-bromo-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine (D25) and 4-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1) following the procedure of Description 2.

Conditions: temp:32.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of powdered 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron, 1973, 29(8), 1115) (19 g, 0.074 mole) in dry THF (1700 ml) at room temp. under argon was treated with triphenylphosphine (19.6 g, 0.075 mole) and 1-methyl-1,2,3,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) (9.5 g, 0.075 mole), followed by the dropwise addition over 15 mins. of a solution of diethyl azodicarboxylate (11.8 ml, 0.075 mole) in THF (40 ml). A mild exotherm occured and the insoluble material dissolved. The solution was warmed at 32° C. for 1 hour, then concentrated in vacuo to approx. 500 ml volume. The solid which had formed was filtered off and dried according 16.1 g of beige solid. The filtrate was concentrated in vacuo and the residue treated with ethyl acetate (700 ml) and 1M HCl acid (500 ml), shaken well and the acid layer separated. This was washed with ethyl acetate, then basified with 40% NaOH and extracted with ethyl acetate, followed by chloroform. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow solid, which was recrystallised from ethyl acetate (3.8 g) giving a total yield of 19.9 g (74%) of 1-acetyl-6-bromo-2,3-dihydro-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-ylmethoxy)-1H-indole. followed by the dropwise addition over 15 mins the insoluble material dissolved concentrated in vacuo to approx. 500 ml volume The solid which had formed was filtered off dried The filtrate was concentrated in vacuo the residue treated with ethyl acetate (700 ml) and 1M HCl acid (500 ml) the acid layer separated This was washed with ethyl acetate extracted with ethyl acetate The combined extracts were dried (Na2SO4) concentrated in vacuo to leave a yellow solid, which was recrystallised from ethyl acetate (3.8 g)

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

Procedure: 4-(Hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1, 5.63 g, 0.044 mol), 2-iodophenol (7.80 g, 0.035 mol) and triphenylphosphine (11.61 g, 0.044 mol) were stirred in dry THF (200 ml) under Ar as diethyl azodicarboxylate (7.0 ml, 0.044 mol) was added portionwise. The solution was stirred for 1 h, concentrated, diluted with ethyl acetate, and extracted with dil. HCl. The extract was basified (sat. K2CO3 solution) and extracted with ethyl acetate. This organic extract was dried (Na2SO4) and evaporated to give a brown oil. Purification by chromatography on silica gel, eluting with 0-10% methanol/chloroform (gradient) gave the title compound (7.65 g, 65%) as an amber oil. was added portionwise concentrated diluted with ethyl acetate extracted with dil. HCl extracted with ethyl acetate This organic extract was dried (Na2SO4) evaporated to give a brown oil Purification by chromatography on silica gel eluting with 0-10% methanol/chloroform (gradient)

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

Procedure: To a solution of ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate (10.0 ml, 0.061 mole) in THF (200 ml) was added, maintaining temperature below 25° C., lithium aluminium hydride (2.76 g, 0.073 mole). After stirring for a further 15 min, water (2.75 ml), 10% NaOH (4 ml) and water (4 ml) were successively added, and the mixture was filtered. The filtrate was dried (Na2SO4) and evaporated in vacuo to give the title compound as an amber oil (6.30 g, 81%), which solidified on standing. the mixture was filtered The filtrate was dried (Na2SO4) evaporated in vacuo