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With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether for 2h;
With lithium aluminium tetrahydride In tetrahydrofuran
With potassium hydroxide; sodium hydroxide; LiAlH4 In tetrahydrofuran; hydrogenchloride
6 9-Amino-1,2,3,4-tetrahydroacridin-1-ol
EXAMPLE 6 9-Amino-1,2,3,4-tetrahydroacridin-1-ol In 100 ml of dry tetrahydrofuran was added 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. The mechanically stirred suspension was cooled to -5° C. and 21.4 ml (1.0 eq) of 1.1M LiAlH4 solution in ether was added dropwise. After completion of the addition, the reaction mixture was stirred further for 2 hours, whereupon the reaction appeared complete based on thin layer chromatography analysis. The LiAlH4 was neutralized with 2 ml of saturated NH4 Cl and the salts were dissolved with 30% potassium hydroxide. The insoluble product was filtered off and rinsed with water. The precipitate was then dissolved in 3N HCl and the residual insoluble salts filtered off. The acid solution was washed with EtOAc and made basic (pH 9) with 10% NaOH. The precipitated product was filtered and washed with water. After drying at 80° C. under vacuum overnight, 4.15 g (82%) of a powder was obtained, melting point 245° C. ANALYSIS: Calculated for C13 H14 N2 O: 72.87% C; 6.58% H; 13.07% N. Found: 72.57% C; 6.71% H; 13.00% N.
With potassium hydroxide; sodium hydroxide; LiAlH4 In tetrahydrofuran; hydrogenchloride
6 9-Amino-1,2,3,4-tetrahydroacridin-1-ol
EXAMPLE 6 9-Amino-1,2,3,4-tetrahydroacridin-1-ol In 100 ml of dry tetrahydrofuran was added 5.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one. The mechanically stirred suspension was cooled to -5° C. and 21.4 ml (1.0 eq) of 1.1M LiAlH4 solution in ether was added dropwise. After completion of the addition, the reaction mixture was stirred further for 2 hours, whereupon the reaction appeared complete based on thin layer chromatography analysis. The LiAlH4 was neutralized with 2 ml of saturated NH4 Cl and the salts were dissolved with 30% potassium hydroxide. The insoluble product was filtered off and rinsed with water. The precipitate was then dissolved in 3N HCl and the residual insoluble salts filtered off. The acid solution was washed with EtOAc and made basic (pH 9) with 10% NaOH. The precipitated product was filtered and washed with water. After drying at 80° C. under vacuum overnight, 4.15 g (82%) of a powder was obtained, melting point 245° C. ANALYSIS: Calculated for C13 H14 N2 O: 72.87% C, 6.58% H, 13.07% N. Found: 72.57% C, 6.71% H, 13.00% N.
3 2-Phenyl-1,2,3a,4,5,6-hexahydro[1,3]oxazino[6,5,4-kl]acridine
EXAMPLE 3 2-Phenyl-1,2,3a,4,5,6-hexahydro[1,3]oxazino[6,5,4-kl]acridine 9-Amino-1,2,3,4-tetrahydroacridine-1-ol (15.0 g) was refluxed in 1 liter of toluene that contained 12.28 g of morpholine and 9.29 g of benzaldehyde that had been freshly washed with K2 CO3. The reaction mixture was refluxed overnight and allowed to cool. The crude product was then filtered off and purified by flash chromatography (20% isopropanol/ethyl acetate) to give 8.07 g of a 80:20 mixture of diastereomers after recrystallization from methanol/water. Recrystallization from dimethylformamide/water gave a 60:40 mixture of diastereomers, m.p. 225°-235° C.
4 2-(4-Fluorophenyl)-1,2,3a,4,5,6-hexahydro[1,3]oxazino[6,5,4-kl]acridine
EXAMPLE 4 2-(4-Fluorophenyl)-1,2,3a,4,5,6-hexahydro[1,3]oxazino[6,5,4-kl]acridine A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.77 g), 4-fluorobenzaldehyde (5.9 g) and morpholine (6.3 ml) in 400 ml of xylenes was refluxed with removal of water for sixteen hours. The solvent was then removed and the desired compound was purified via flash chromatography (20% isopropanol/ethyl acetate) to give 3.5 g of a yellow solid, m.p. 220°-234° C. (dec.). This was recrystallized from methanol/water to give 2.3 g of a yellow solid, m.p. 238°-241° C. (dec.).
With p-toluenesulfonic acid monohydrate In toluene
2 1-(1-Piperidinyl)-1,2,3,4-tetrahydro-9-acridinamine
EXAMPLE 2 1-(1-Piperidinyl)-1,2,3,4-tetrahydro-9-acridinamine 9-Amino-1,2,3,4-tetrahydroacridin-1-ol (10.32 g) was refluxed in 500 ml of toluene containing 8.5 g of piperidine and 19.0 g of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed overnight and thereafter concentrated and triturated with aqueous NH3. The crude product obtained in this manner was filtered off, triturated with Et2O, and then recrystallized from benzene to give 7.02 g of analytically pureproduct, m.p. 215°-217° (d). ANALYSIS: Calculated for C18 H23 N3: 76.82%C, 8.24%H, 14.94%N. Found: 76.99%C, 8.20%H, 14.81%N.
11 1-(4-Phenyl-1-piperazinyl)-1,2,3,4-tetrahydro-9-acridinamine, maleate
EXAMPLE 11 1-(4-Phenyl-1-piperazinyl)-1,2,3,4-tetrahydro-9-acridinamine, maleate 9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 24 h in 300 ml of toluene that contained 1-phenylpiperazine (8.10 g) and p-toluensulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was distributed between EtOAc and aqueous K2 CO3 and then the combined organic phase was concentrated and the residue purified by flash chromatography (5% Et3 N/toluene) to give, after concentration of the product-containing fractions and recrystallization from CH2 Cl2 -pentane, a product that contained a high mass weight impurity by mass spectrometry. The maleate was formed in isopropanol, filtered off and recrystallized from MeOH/Et2 O to give 3.03 g of analytically pure product, m.p. 205°-207°. ANALYSIS: Calculated for C23 H26 N4 C4 H4 O4: 68.34%C, 6.37%H, 11.81%N. Found: 68.25%C, 6.36%H, 11.71%N.
3 1-(4-Morpholinyl)-1,2,3,4-tetrahydro-9-acridinamine
EXAMPLE 3 1-(4-Morpholinyl)-1,2,3,4-tetrahydro-9-acridinamine 9-Amino-1,2,3,4-tetrahydroacridin-1-ol (15.0 g) was refluxed in 1000 ml of toluene that contained 12.18 g of morpholine and 9.285 g of benzaldehyde that had been freshly washed in K2 CO3. The reaction mixture wasrefluxed overnight and allowed to cool. It was then filtered off and the crude product was purified by flash chromatography (20% PrOH/EtOAc) to give 2.20 g of analytically pure product after recrystallization from benzene/pentane, m.p. 215°-217°. ANALYSIS: Calculated for C17 H21 N3 O: 72.05%C, 7.47%H, 14.83%N. Found: 71.92%C, 7.44%H, 14.70%N.
With p-toluenesulfonic acid monohydrate In toluene
1 1-(1-Pyrrolidinyl)-1,2,3,4-tetrahydro-9-acridinamine
EXAMPLE 1 1-(1-Pyrrolidinyl)-1,2,3,4-tetrahydro-9-acridinamine 9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed overnight in 250 ml of toluene that contained pyrrolidine (7.10 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was washed with an aqueous K2 CO3 solution and then the organic phase was concentrated. The residue obtained in this manner was purified by flash chromatography (5% Et3 N, toluene) to give, after recrystallization from benzene/pentane, 2.91 g, m.p. 201°-203°. ANALYSIS: Calculated for C17 H21 N3: 76.37%C, 7.92%H, 15.72%N. Found: 76.13%C, 8.01%H, 15.33%N.
With p-toluenesulfonic acid monohydrate In toluene
10 1-(4-Methyl-1-piperazinyl)-1,2,3,4-tetrahydro-9-acridinamine
EXAMPLE 10 1-(4-Methyl-1-piperazinyl)-1,2,3,4-tetrahydro-9-acridinamine 9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 h in 300 ml of toluene that contained 1-methylpiperazine (5.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was distributed between EtOAc and aqueous K2 CO3 and then the combined organic phase was concentrated and the residue purified by flash chromatography (5% Et3 N/EtOAc) to give, after concentration of the product-containing fractions and recrystallization from EtOAc, 2.30 g of analytically pure product, m.p. 200°-202°. ANALYSIS: Calculated for C18 H24 N4: 72.94%C, 8.16%H, 18.90%N. Found: 72.92%C, 8.27%H, 18.80%N.
5 N1 -Propyl-1,2,3,4-tetrahydro-1,9-acridinediamine
EXAMPLE 5 N1 -Propyl-1,2,3,4-tetrahydro-1,9-acridinediamine A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.66 g), p-toluensulfonic acid (8.5 g) and propylamine (19.9 ml) in 250 ml of toluene was refluxed with removal of water for twenty hours. An additional4 ml of the amine was then added and reflux was continued for thirty hours. The mixture was treated with a dilute NaOH solution and extracted with ethyl acetate (3x). The organics were then washed with water and dried (saturated NaCl solution, MgSO4). The desired amine was purified via flash chromatography (7.5% Et3 N/C6 H5 CH3) to give 7.8 g of a yellow solid, m.p. 171°-177° C. A 3.85 g portion was recrystallized from methanol/water to give 2.79 g of yellow crystals, m.p. 175°-177° C. ANALYSIS: Calculated for C16 H21 N3: 75.26%C, 8.29%H, 16.45%N. Found: 75.40%C, 8.39%H, 16.52%N.
7 N1 -Benzyl-1,2,3,4-tetrahydro-1,9-acridinediamine
EXAMPLE 7 N1 -Benzyl-1,2,3,4-tetrahydro-1,9-acridinediamine A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.19 g), benzylamine (14.7 ml) and p-toluensulfonic acid (7.6 g) in 250 ml of xylenes were refluxed with removal of water for eighteen hours. The reaction mixture was quenched into a dilute K2 CO3 solution and extracted with ethyl acetate (2X). The organics were washed with waterand dried (saturated NaCl, MgSO4). The amine was purified via flash chromatography (5% Et3 N/C6 H5 CH3) to give 6.1 g of an off-white solid m.p. 161°-167° C. A 4.0 g portion was recrystallized from ethyl acetate/hexane to give 3.24 g of a white powder, m.p.: 166°-168° C. ANALYSIS: Calculated for C20 H21 N3: 79.17%C, 6.98%H, 13.85%N. Found: 79.15%C, 7.10%H, 13.75%N.
9 N1 -(2-Phenylethyl)-1,2,3,4-tetrahydro-1,9-acridinediamine
EXAMPLE 9 N1 -(2-Phenylethyl)-1,2,3,4-tetrahydro-1,9-acridinediamine A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g), phenylethylamine (15.6 ml) and p-toluensulfonic acid (8.7 g) in 250 ml of toluene was refluxed with removal of water for twenty hours. The mixture was then treated with a dilute NaOH solution, and extracted with ethyl acetate (3x). The combined organics were washed with water and dried (saturated NaCl solution, MgSO4). The amine was purified via flash chromatography (7.5% Et3 N/C6 H5 CH3) to give 10.6 g (81%) of a yellowish solid, m.p. 124°-128° C. A 4.02 g portion was recrystallized from ethyl acetate/hexane to give 3.05 g (61%) of a white powder, m.p. 120°-122° C. ANALYSIS: Calculated for C21 H23 N3: 79.46%C, 7.30%H, 13.24%N. Found: 79.63%C, 7.26%H, 13.37%N.
8 N1 -(3,4-Dimethoxybenzyl)-1,2,3,4-tetrahydro-1,9-acridinediamine
EXAMPLE 8 N1 -(3,4-Dimethoxybenzyl)-1,2,3,4-tetrahydro-1,9-acridinediamine A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.43 g), 3,4-dimethoxybenzylamine (11.9 ml) and p-toluenesulfonic acid (9.0 g) in 250 ml of toluene was refluxed with removal of water overnight. The mixture was then added to iced NaOH solution and extracted with ethyl acetate (3x). The organics were washed with water and dried (MgSO4). The compound was purified via flash chromatography (2.5% Et3 N/EtOAc) to give 6.65 g of an off-white solid. After attempted purification via thefumaric acid addition salt, the free base was twice recrystallized from dichloromethane/hexane to give 2.65 g of a yellowish solid, m.p. 160°-162° C. ANALYSIS: Calculated for C22 H25 N3 O2: 72.70%C, 6.93%H, 11.56%N. Found: 72.66%C, 6.88%H, 11.54%N.
With triphenylphosphine In tetrahydrofuran; isopropyl alcohol
14 1-Azido-1,2,3,4-tetrahydro-9-acridinamine, maleate
EXAMPLE 14 1-Azido-1,2,3,4-tetrahydro-9-acridinamine, maleate A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (17.2 g), triphenylphosphine (23.2 g), diethyl azodicarboxylate (13.9 ml) and diphenylphosphorylazide (19.0 ml) in 500 ml of tetrahydrofuran was heated at 65° C. for 65 hours. The solution was then concentrated off and the desired acid was purified via flash chrometography (EtOAC→2% Et3 N/EtOAC) to give 9.48 g of a yellow solid, m.p. 124°-126° C. (dec.). A 3.13 g portion of the free base was dissolved in isopropanol and 1 equivalent of maleic acid was added. The resulting solid was collected andtwice recrystallized from methanol/ethyl ether to give 1.75 g of a yellow powder, m.p. 163°-165° C. (dec.). ANALYSIS: Calculated for C13 H13 N5.C4 H4 O4: 57.46%C, 4.82%H, 19.71%N. Found: 57.84%C, 4.84%H, 19.27%N.
With sodium hydroxide; toluene-4-sulfonic acid; N-butylamine In toluene
6 N1 -Butyl-1,2,3,4-tetrahydro-1,9-acridinediamine
EXAMPLE 6 N1 -Butyl-1,2,3,4-tetrahydro-1,9-acridinediamine A mixture of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.26 g), n-butylamine (15.2 ml) and p-toluenesulfonic acid (8.8 g) in 250 ml of toluene was refluxed with removal of water for sixteen hours. The mixture was then added to a dilute NaOH solution and extracted with ethyl acetate (3X). The combined organics were washed with water and dried(MgSO4). The amine was purified via flash chromatography (5% Et3 N/C6 H5 CH3) to give 8.0 g of an off-white solid, m.p. 162°-166° C. A 3.9 g portion was recrystallized from methanol/water to give 3.41 g of a white powder, m.p. 164°-166° C. ANALYSIS: Calculated for C17 H23 N3: 75.80%C, 8.61%H, 15.60%N. Found: 75.86%C, 8.61%H, 15.64%N.
With p-toluenesulfonic acid monohydrate In toluene
4 1-(4-Phenyl-1-piperidinyl)-1,2,3,4-tetrahydro-9-acridinamine
EXAMPLE 4 1-(4-Phenyl-1-piperidinyl)-1,2,3,4-tetrahydro-9-acridinamine 9-Amino-1,2,3,4-tetrahydroacridin-1-ol (5.36 g) was refluxed for 48 hours in 300 ml of toluene that contained 4-phenylpiperidine (8.06 g) and p-toluenesulfonic acid monohydrate (9.5 g). At the end of this time the reaction mixture was concentrated and the residue purified by flash chromatography (5% Et3 N/toluene) to give, after concentration of theproduct-containing fractions and recrystallization from EtOAc/pentane, 3.22g of analytically pure product, m.p. 189°-190°. ANALYSIS: Calculated for C24 H27 N3: 80.63%C, 7.61%H, 11.75%N. Found: 80.79%C, 7.72%H, 11.72%N.
3 Synthesis of (+-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol via catalytic hydrogenation
The product, (+-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol, is isolated in 90.6% yield following filtration, 80% aqueous n-butanol (15.9 mL) wash, water (50 mL) wash, and drying in a vacuum oven. The following table shows the effect on the yield of 9-amino-1,2,3,4-tetrahydroacridin-1-ol by varying some parameters of Example 3.
6 9-Amino-1,2,3,4-tetrahydroacridin-1-ol
EXAMPLE 6 9-Amino-1,2,3,4-tetrahydroacridin-1-ol In 1&sl0;&sl0;ml of dry tetrahydrofuran was added 5.&sl0;&sl0;g of 9-amino-3,4-dihydroacridin-1(2H)-one. The mechanically stirred suspension was cooled to -5°C and 21.4ml (1.&sl0; eq) of 1.1 M LiAlH4 solution in ether was added dropwise. After completion of the addition, the reaction mixture was stirred further for 2 hours, whereupon the reaction appeared complete based on thin layer chromatography analysis. The LiAlH4 was neutralized with 2ml of saturated NH4Cl and the salts were dissolved with 3&sl0;% potassium hydroxide. The insoluble product was filtered off and rinsed with water. The precipitate was then dissolved in 3N HCl and the residual insoluble salts filtered off. The acid solution was washed with EtOAc and made basic (pH 9) with 1&sl0;% NaOH. The precipitated product was filtered and washed with water. After drying at 8&sl0;°C under vacuum overnight, 4.15g (82%) of a powder was obtained, melting point 245°C.
Examples of compounds of Formula I useful for the method of this invention include: 9-amino-1,2,3,4-tetrahydroacridin-1-ol; 9-benzylamino-1,2,3,4-tetrahydroacridin-1-ol; 9-amino-6-methyl-1,2,3,4-tetrahydroacridin-1-ol; and 9-amino-6-chloro-1,2,3,4-tetrahydroacridin-1-ol.
22
[ 132674-71-6 ]
[ 67-63-0 ]
[ 124027-47-0 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium borohydrid; acetic acid In sodium hydroxide; water
4 Synthesis of (+-)-9-amino-1,2,3,4-tetrahydroacridin-1ol via the sodium borohydride reduction method
EXAMPLE 4 Synthesis of (+-)-9-amino-1,2,3,4-tetrahydroacridin-1ol via the sodium borohydride reduction method To a suspension of 9-amino-3,4-dihydro-1(2H)-acridinone hydrochloride (75 g), in a solvent mixture of 2-propanol (18.8 ml) and water (356 ml) is added portionwise, at room temperature, a solution of sodium borohydride (12.84 g) in 137.5 ml of 0.5% aqueous sodium hydroxide. The pH of the reaction mixture is kept below 8.2 by the intermittent addition of 6N HCl. When the addition of the sodium borohydride solution has been completed, the pH of the reaction mixture is adjusted to 9.5-11 by the addition of 50% aqueous sodium hydroxide. The crude product, as the free base, is filtered and rinsed with water. The wet crude product is suspended in a solvent mixture of 2-propanol and water at room temperature. Aqueous acetic acid (50-60%) is added to adjust the pH of the reaction mixture to 6-7. The mixture is stirred for several minutes until a homogenous solution is attained. The purified free base product, (+-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol can be obtained by rebasification with a 50% NaOH solution, filtration, rinsing with aqueous 2-propanol and water, and drying in a vacuum oven.
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