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[ CAS No. 123536-15-2 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 123536-15-2
Chemical Structure| 123536-15-2
Chemical Structure| 123536-15-2
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Product Details of [ 123536-15-2 ]

CAS No. :123536-15-2 MDL No. :MFCD08669630
Formula : C7H14N2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 126.20 Pubchem ID :-
Synonyms :

Safety of [ 123536-15-2 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:3259
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 123536-15-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 123536-15-2 ]

[ 123536-15-2 ] Synthesis Path-Downstream   1~57

  • 1
  • [ 35700-40-4 ]
  • [ 123536-15-2 ]
  • C16H20N2O2 [ No CAS ]
  • 2
  • [ 123536-15-2 ]
  • [ 123654-26-2 ]
  • C16H20ClN3O2 [ No CAS ]
  • 3
  • [ 2438-05-3 ]
  • [ 123536-15-2 ]
  • <i>N</i>-(1-aza-bicyclo[2.2.2]oct-3-yl)-4-propyl-benzamide [ No CAS ]
  • 4
  • [ 22855-95-4 ]
  • [ 123536-15-2 ]
  • <i>N</i>-(1-aza-bicyclo[2.2.2]oct-3-yl)-4-benzylsulfanyl-benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-benzylsulfanylbenzoic acid With diphenylphosphoranyl azide; triethylamine In dichloromethane for 0.5h; Stage #2: (R)-3-aminoquinuclinine In dichloromethane
  • 5
  • [ 525-47-3 ]
  • [ 123536-15-2 ]
  • [ 590369-85-0 ]
YieldReaction ConditionsOperation in experiment
64% Stage #1: 5-nitroquinoline-2-carboxylic acid; (R)-3-aminoquinuclinine With N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide); water for 48h; Stage #2: With (2E)-but-2-enedioic acid In isopropyl alcohol at 60℃; 12 EXAMPLE 12; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitroquinoline-2-carboxamide DIEA (156 μL, 0.9 mmol), DMF (25 mL), 5-nitroquinoline-2-carboxylic acid (0.098 g, 0.45 mmol), and HATU (0.171 g, 0.45 mmol) are added to a solution of (R)-3-aminoquinuclidine (0.090 g, 0.45 mmol) in water (2.5 mL). The resulting solution is stirred for 48 hours under N2. The solution is diluted with 1 volume of MeOH and loaded onto a column of AG50W-X2 resin (H+ form). The resin is washed with MeOH and the product is eluted with a solution of 5% TEA in MeOH. This solution is evaporated to dryness, concentrated from MeCN, and dried in vacuo. The resulting material is dissolved in i-PrOH and heated to 60° C. 1 equivalent of fumaric acid (0.0516 g, 0.44 mmol) is added and a brown solid precipitates immediately. The solution is cooled to rt and the solid is filtered. The resulting salt is dissolved in MEOH and passed through a plug of Amberjet 4400 resin (OH- form). The resulting material is concentrated from MeOH three times and then dried in vacuo to yield Example 12 as a brown solid (0.094 g, 64%). HRMS (FAB) calculated for C17H18N4O3+H+: 327.1457, found 327.1439.
  • 6
  • [ 188904-08-7 ]
  • [ 123536-15-2 ]
  • [ 590369-73-6 ]
YieldReaction ConditionsOperation in experiment
69% Stage #1: 7-benzyloxy-2-naphthoic acid; (R)-3-aminoquinuclinine With triethylamine; HATU In DMF (N,N-dimethyl-formamide); water for 24h; Stage #2: With hydrogenchloride In methanol 5 Coupling: (R)-3-aminoquinuclidine (80 mg, 0.4 mmol) is dissolved in water (200 μL). Triethylamine (165 μL, 1.2 mmol), DMF (2 mL), 7-benzyloxy-2-naphthoic acid (111 mg, 0.4 mmol), and HATU (152 mg, 0.4 mmol) are added in order. The resulting mixture is allowed to stir for 24 hours, diluted with methanol, and poured onto a column of AG50W×2 resin (H+ form). The column is washed with methanol then the product is eluted with 5% TEA in methanol. The resulting material is evaporated to dryness. The material is dissolved in 1M HCl in methanol, evaporated to dryness then crystallized from MeOH/IPA to give Example 5 as an off-white solid (116 mg, 69%). HRMS (FAB) calculated for C25H26N2O2+H+387.2072, found 387.2073.
  • 7
  • [ 588720-90-5 ]
  • [ 123536-15-2 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]imidazo[1,2-c]pyrimidine-7-carboxamide dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% Stage #1: ethyl imidazo[1,2-c]pyrimidine-7-carboxylate; (R)-3-aminoquinuclinine In ethanol for 36h; Heating / reflux; Stage #2: With hydrogenchloride 29 [1221] Ethyl imidazo[1,2-c]pyrimidine-7-carboxylate (0.50 g, 2.6 mmol) and (3R)-1-azabicyclo[2.2.2]octan-3-amine are heated under reflux in 5 mL EtOH. After 36 h, the solvent is removed. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3/MeOH/NH4OH), the hydrochloride salt is prepared and recrystallized from MeOH/EtOAc to provide 0.377 g (42%) of the product. HRMS (FAB) calcd for C14H17N5O+H 271.1433, found 271.1428.
  • 8
  • [ 677304-64-2 ]
  • [ 123536-15-2 ]
  • CH2O2*C16H19N3O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With HATU; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20℃; B Procedure B To a solution of 6-methoxybenzisothiazole-3-carboxylic acid (61 mg, 0.30 mmol) in a 5/1] mixture of terahydrofuran/N,N-dimethylformamide (12 mL) was added diisopropylethylamine (0.2 ml, 1.1 mmol) and (115 mg, 0.6 mmol) 3-(R)-aminoquinuclidine dihydrochloride. The mixture was cooled to 0 C, and HATU (115 mg, 0.3 mmol) was added in one portion. The reaction mixture was allowed to warm to rt and was maintained overnight. The mixture was partitioned between saturated aqueous potassium carbonate solution and a 95/5 mixture of dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane/methanol (2X), and the combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) to provide 72 mg (75%) of the amide as a colorless solid.
  • 9
  • [ 541-41-3 ]
  • [ 123536-15-2 ]
  • (3R)-N-methylquinuclidin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: chloroformic acid ethyl ester; (R)-3-aminoquinuclinine With triethylamine In dichloromethane at 0 - 20℃; for 15h; Stage #2: With potassium carbonate In chloroform; water Stage #3: With sodium hydroxide; lithium aluminium tetrahydride; water more than 3 stages; I-4 Preparation of (3R)-N-methylquinuclidin-3-amine (Intermediate I-4) [1G] (0.0079 mol) of (3R)-aminoquinuclidine was dissolved in 20 ml of [CH2CI2] and 1.22 ml (0.0087 mol) of triethylamine were added. The obtained solution was cooled to 0C, ClCO2Et (0.835 [ML,] 0.0087 mol) was added and the mixture was stirred 15 h at room temperature. After this time, solvents were evaporated in vacuo, the obtained residue was dissolved in CHCI3 and the solution washed with [K2CO3] (saturated solution) and water. The organic phase was dried over [NA2SO4,] filtered and concentrated to dryness. The obtained residue was used without further purification as is described as follows. The obtained residue was dissolved in 15 [ML] of THF, the solution was cooled to [0C] and 0. [6019] (0.016 mol) of LiAIH4 were added in several portions. The reaction mixture was heated under reflux for 4h. After this time, was cooled to [0C] and the excess of hydride was decomposed by the consecutive addition, under stirring, dropwise and cautiously of 0. 6 ml of [H2O,] 0. 6 ml of [NAOH] (10% solution) and 1. 8 [ML] of [H20. WHEN] the decomposition was finished, the reaction mixture was filtered and the sludge was washed with THF and CHCI3, the organic solutions were combined and concentrated to dryness to obtain 830 mg (75%) of the title product, structure confirmed by'H-RMN and ['3C-RMN.] '3C-RMN (CDCl3) : [8] 57.0 (CH), 56.5 [(CH2),] 47.5 [(CH2),] 46.9 (CH2), 34.3 (CH3), 26.1 [(CH2),] 24.6 (CH), 19.9 (CH2).
  • 10
  • [ 4023-34-1 ]
  • [ 123536-15-2 ]
  • C11H18N2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h; 28 Cyclopropanecarbonyl chloride (12 mmol) was added dropwise to a solution of (R)-3- aminoquinuclidine (10 mmol) and N, N diisopropylethylamine (30 mmol) in dichloromethane (100 mL). The resulting solution was maintained at rt for 4 h and was evaporated to dryness. The crude amide was dissolved in tetrahydrofuran (150 mL) and was treated with lithium aluminum hydride (66 mmol) in small portions. The reaction mixture was quenched with sodium sulfate decahydrate and the resulting slurry was diluted with tetrahydrofuran and filtered through Celite. The filtrate was concentrated and the residue was then diluted with freshly prepared methanolic hydrogen chloride (generated by the dropwise addition of 3 mL of acetyl chloride into 30 mL of methanol) and maintained at rt for 15 min. The residue obtained by the removal of the volatiles was recrystallized (2-propanol/methanol) to provide the secondary amine in 41% yield as a colorless solid.
  • 11
  • [ 123536-15-2 ]
  • [ 93777-26-5 ]
  • [ 906004-01-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (R)-3-aminoquinuclinine; 5-bromo-2-fluorobenzaldehyde With sodium triacetoxyborohydride; acetic acid; triethylamine In 1,2-dichloro-ethane at 20℃; for 4.5h; Stage #2: With sodium hydroxide In water; 1,2-dichloro-ethane 77.1 Sodium triacetoxyborohydride (1.6 g, 7.53 mmol) and enough acetic acid to bring the pH to 5 were added to a solution of 5-bromo-2-fluorobenzaldehyde (510 mg, 2.51 mmol), (R)-(-)-l-aza- bicyclo[2.2.2]oct-3i?-ylamine (1.0 g, 5.02 mmol) and triethylamine (508 mg, 5.02 mmol) in 8 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 4.5 h, and then it was quenched by the careful addition of 1 M sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave 816 mg of product.
  • 12
  • [ 478148-53-7 ]
  • [ 123536-15-2 ]
  • [ 478148-57-1 ]
YieldReaction ConditionsOperation in experiment
56% With hydrogenchloride; ammonium hydroxide; triethanolamine; diphenylphosphoranyl azide In methanol; dichloromethane; isopropyl alcohol 3.B Method B Method B Acid C7 (435 mg, 2.2 mmol) and TEA (307 μL, 2.2 mmol) in CH2Cl2 (10 mL) are stirred until dissolved, diphenylphosphoryl azide (431 mL, 2.0 mmol) is added, and the reaction is stirred for 20 min at rt. R-(+)-3-aminoquinuclidine (252 mg, 2.0 mmol) in CH2Cl2 (3 mL) is added, and the reaction is stirred for 18 h at rt. The solution is diluted with MeOH and loaded onto a column of AG 50W-X2 resin (hydrogen form). The column is rinsed with MeOH, and the product eluted with a 5% TEA/MeOH solution onto a column of AMBERJET 4400 OH resin. The eluted material is concentrated to an oil. The crude material is chromatographed over 25 g slurry-packed silica gel, eluding with 0.3% ammonium hydroxide/4% MeOH/CH2Cl2 followed by 0.5% ammonium hydroxide/5% MeOH/CH2Cl2, and finally 0.5% ammonium hydroxide/8% MeOH/CH2Cl2. The fractions with the desired compound are collected and concentrated to an oil. The oil is dissolved in a minimum amount of MeOH and 1N HCl in MeOH (5 mL) is added. The material is concentrated to dryness, dissolved in MeOH (1 mL) and isopropanol is added until a solid began to form. The resulting solid is collected under N2 and dried in vacuo at 50° C. overnight to afford Example 3 as a white solid (56% yield). HRMS (FAB) calculated for C15H16ClN3O2+H: 306.1009, found 306.1020 (M+H)+.
  • 13
  • [ 39177-38-3 ]
  • [ 123536-15-2 ]
  • [ 2524-64-3 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With triethanolamine In methanol; dichloromethane; N,N-dimethyl-formamide 1.B EXAMPLE 1 Step B. Preparation of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxy-phenoxy)benzamide. TEA (830 μL, 6.0 mmol) is added to a suspension of the product of Step A (1.5 g, 5.7 mmol) in CH2Cl2 (5 mL). Diphenylchlorophosphate (1.2 mL, 5.7 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. This solution is added to a solution of (R)-3-aminoquinuclidine (680 mg, 5.4 mmol) in DMF (6 mL). The resulting solution is stirred overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W*2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness. The hydrochloride salt is formed and triturated with hot CH3CN to yield the desired product (1.2 g, 60%). MS for C20H22N2O3 (ESI) (M+H)+ m/z 339.
  • 14
  • [ 123536-15-2 ]
  • [ 2524-64-3 ]
  • [ 129623-61-6 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-fluorophenoxy)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With triethanolamine; In methanol; dichloromethane; acetonitrile; Step G. Preparation of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-fluoro-phenoxy)benzamide. TEA (50 muL, 0.35 mmol) is added to a suspension of the acid from Step F (81 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 muL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1.0M in CH3CN, 0.2 mL, 0.2 mmol) is added and the resulting solution is shaken overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W*2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (58 mg, 85%). MS for C20H21FN2O2 (ESI) (M+H)+ m/z 341.
  • 15
  • [ 123536-15-2 ]
  • [ 141358-10-3 ]
  • [ 2524-64-3 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenyl-sulfanyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With triethanolamine In methanol; dichloromethane; N,N-dimethyl-formamide 17.J EXAMPLE 17 Step J. Preparation of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenyl-sulfanyl)benzamide. TEA (50 μL, 0.35 mmol) is added to a suspension of the acid from Step I (93 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1.0 M in DMF, 0.2 mL, 0.2 mmol) is added and the resulting solution is allowed to sit overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50 W*2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (59 mg, 75%). MS for C20H21ClN2OS (ESI) (M+H)+ m/z 373.
  • 16
  • [ 16205-47-3 ]
  • [ 123536-15-2 ]
YieldReaction ConditionsOperation in experiment
In thionyl chloride; dichloromethane; EXAMPLE 11 Synthesis of (R)-(+)-N-(1-azabicyclo[2.2.2]oct-3-yl)-7-methylpyrazolo[1,5-a]pyridine-3-carboxamide A solution of 166 mg (0.945 mmol) of <strong>[16205-47-3]7-methyl-3-pyrazolo[1,5-a]pyridinecarboxylic acid</strong> in 3 ml of thionyl chloride was heated under reflux for 30 minutes. Thionyl chloride was distilled off under reduced pressure and the residue was dissolved in 5 ml of methylene chloride. The resultant solution was added dropwise under ice cooling to a solution of 200 mg (1 mmol) of (R)-(+)-1-azabicyclo[2.2.2]octan-3-amine, which had been prepared in accordance with the procedure disclosed in Japanese Patent Application Laid-Open No. 196583/1988, in 5 ml of methylene chloride.
  • 17
  • [ 123536-15-2 ]
  • [ 4023-02-3 ]
  • (R)-N-1-azabicyclo[2.2.2]oct-3-ylguanidine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60 - 70℃; for 6 - 40h; 3.3a; 34.34c Example 3: Preparation of the alkylguanidine hydrochloride; 3(a) Preparation of ( R)-N-1-azabicyclo[2.2.2]oct-3-ylguanidine hydrochloride; To a mixture of ( R)-3-aminoquinuclidine (5.85g, 46.4 mmol) and pyrazole carbox-amidine hydrochloride ( 6.8Og, 46.4 mmol) is added Hunig's base (8.07 ml, 46.4 mmol) and DMF (30 ml). The reaction is heated at 70° C for 40 hours. The reaction is then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirring at room temperature for 2 hours. Product separates out as a white solid, which is filtered, washed and dried (8.94g, 94%).300 MHz 1H NMR (DMSOd6) δ: 8.33 (d, J= 7.9 Hz, 1H), 7.21 (br.s, 4H), 3.19 (ddd, J = 12.0 11.4 1.8 Hz, 1H), 2.7 (m, 5H), 2.44 (dd, J= 13.8 2.3 Hz, 1H), 1.8 (m, 2H), 1.57 (m, 2H), 1.37 (m, 1H); LCMS: 169 [M+H]. CaIc. for C8H16N4 1 HCl 0.5 H2O: C 44.92, H 8.49, N 26.21; found C 44.74, H 8.19, N 26.62.; 34(c) Preparation of (i?)-N-1-azabicyclo[2.2.2]oct-3-ylguanidine hydrochloride; To a mixture of 3-aminoquinuclidine (5.85g, 46.4 mmol) and pyrazole carboxamidine ( 6.8Og, 46.4 mmol) is added Hunig's base (8.07 ml, 46.4 mmol) and DMF (30 ml). The reaction is heated at 70° C for 40 hours. The reaction is then cooled to room temperature and quenched by adding 400 ml of diethyl ether and stirred at room temperature for 2 hours. Product separated out as a white solid, which is filtered, washed and dried to produce a 94% yield (8.94g).300 MHz 1H NMR (DMSO-d6) δ: 8.33 (d, J= 7.9 Hz, 1H), 7.21 (br.s, 4H), 3.19 (ddd, J= 12.0 11.4 1.8 Hz, 1H), 2.7 (m, 5H), 2.44 (dd, J= 13.8 2.3 Hz, 1H), 1.8 (m, 2H), 1.57 (m, 2H), 1.37 (m, 1H); LCMS: 169 [M+H]. CaIc. for C8Hi6N4 1 HCl 0.5 H2O: C 44.92, H 8.49, N 26.21; found C 44.74, H 8.19, N 26.62.
  • 18
  • [ 123536-15-2 ]
  • [ 75-36-5 ]
  • [ 134869-61-7 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h; 30 Procedure 30 Procedure 30 provides a method for the preparation of N-alkylated 3-aminoquinuclidines from 3-aminoquinuclidine. Acetyl chloride (12 mmol) was added dropwise to a solution of (R)-3-aminoquinuclidine (10 mmol) and N,N-diisopropylethylamine (30 mmol) in dichloromethane (100 mL). The resulting solution was maintained at rt for 4 h and was evaporated to dryness. The crude amide was dissolved in tetrahydrofuran (150 mL) and was treated with lithium aluminum hydride (66 mmol) in small portions. The reaction mixture was quenched with sodium sulfate decahydrate and the resulting slurry was diluted with tetrahydrofuran and filtered through Celite. The filtrate was concentrated and the residue was then diluted with freshly prepared methanolic hydrogen chloride (generated by the dropwise addition of 3 mL of acetyl chloride into 30 mL of methanol) and maintained at rt for 15 min. The residue obtained by the removal of the volatiles was recrystallized (2-propanol/methanol) to provide the secondary amine in 41% yield as a colorless solid.
  • 19
  • [ 467-69-6 ]
  • [ 123536-15-2 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-9-hydroxy-9H-fluorene-9-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
4% Stage #1: 9-hydroxy-9-fluorene carboxylic acid With 1,1'-carbonyldiimidazole In DMF (N,N-dimethyl-formamide) at 20℃; for 1h; Stage #2: (R)-3-aminoquinuclinine With dmap In DMF (N,N-dimethyl-formamide) at 20℃; for 14h; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate 44 Preparation of N-[(3R)-1-Azabicyclo [2.2. 2] oct-3-yl]-9-hydroxy-9H-fluorene-9- carboxamide (Example 44) 5 [G] (0.022 mol) of 9-hydroxy-9H-fluorene-9-carboxylic acid were dissolved in 50 ml of dry DMF and 4.2 [G] (0.026 mol) of 1, 1'-carbonyldiimidazole were added. The mixture was stirred during 1 h at room temperature. After this time 3.26 [G] (0.026 mol) of (3R)- aminoquinuclidine and 0.324 [G] (0.0027 mol) of [DMAP (4- (DIMETHYLAMINO)] pyridine) were added. The reaction mixture was stirred at room temperature during 14 hours, then was concentrated in vacuo to eliminate the DMF and the obtained residue was dissolved in AcOEt. The organic solution was washed with NaHC03 (saturated solution) and water. The organic layer was separated, dried over [NA2SO4] and solvent was evaporated. The obtained product was purified by column chromatography [(SILICA GEL, CHCI3] : NH40H 100: 1 [E CHCI3] : MeOH: [NH40H] 80: 20: 1 as eluent). Appropriate fractions were combined and evaporated to yield 304 mg of the title product (4%). MS [M+1]+ : 335 'H-RMN (CDCI3) : [8] 7.67-7. 62 (m, 2H), 7.42-7. 36 (m, 4H), 7.32-7. 25 (m, 2H), 6.08- 5.93 (m, NH, 1H), 3.74 (m, [1 H),] 3.00-2. 87 (m, [1H),] 2.52-2. 27 (m, 4H), 2.02-1. 92 (m, [1H),] 1.80-1. 76 (m, 1H), 1.51-1. 44 (m, 2H), 1.26-1. 17 (m, 2H).
  • 20
  • [ 4075-59-6 ]
  • [ 123536-15-2 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-oxo-2-thien-2-ylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-thiopheneglyoxylic acid With oxalyl dichloride In chloroform at 0 - 20℃; for 2h; Stage #2: (R)-3-aminoquinuclinine In chloroform at 0 - 20℃; for 18h; Stage #3: With potassium carbonate In chloroform; water I-1 Method (c); Preparation of [N- [ (3R)-1-AZABICYCLO [2.] 2. [2] OCT-3-YL]-2-OXO-2-THIEN-2-YLACETAMIDE] (Intermediate 1-1) Oxalyl chloride (4.5 [ML,] 0.0516 mol) was added to a solution of 6.68 [G] (0.0428 mol) of [2-] oxo-2-thien-2-ylacetic acid and DMF (several drops) in 100 mi of CHCI3 (ethanol free) at [0C.] The mixture was stirred and allowed to warm to room temperature.. After two hours at this temperature, the solvents were evaporated and the residue was dissolved in CHCI3 and evaporated again. This procedure was repeated two times. The oil obtained was dissolved in [CHC13] and the solution obtained cooled at [0C.] A solution of (3R)- [AMINOQUINUCLIDINE] (5. [91G,] 0.0468 mol) in 50 ml of CHCI3 was added. The mixture was stirred and allowed to warm to room temperature. After 18 hours at this temperature, the reaction mixture was washed with an aqueous [K2CO3] solution. The basic aqueous solution was extracted again with CHCI3. The organic phases were combined, washed with water, dried over [NA2SO4] and evaporated to give 11.34 g of the title product. MS [[M+1] +] : 265 'H-NMR [(CDC13)] : [# ] 1.40-1. 85 (m, 4H), 2.0 (m, 1H), 2.60 (m, [1H),] 2.70-3. 0 (m, 4H), 3.4 (m, 1H), 4.0 (m, 1H), 7.20 (m, [1 H),] 7.50 (d, 1H, NH), 7.85 (m, 1H), 8.40 (m, 1H).
  • 21
  • [ 1467-70-5 ]
  • [ 123536-15-2 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(2-furyl)-2-oxoacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: furan-2-yl-oxo-acetic acid With oxalyl dichloride In chloroform at 0 - 20℃; for 1h; Stage #2: (R)-3-aminoquinuclinine In chloroform at 0 - 20℃; for 16h; Stage #3: With potassium carbonate In chloroform; water 45 Preparation of [N- [ (3R)-1-AZABICYCLO] [2.2. 2] [OCT-3-YL]-2-FUR-2-YL-2-HYDROXYPENT-3-] ynamide (Example 45) To a suspension [COOLED TO 0C OF] 1. 72 g (0. [012] mol) of 2-fur-2-yl-2-oxoacetic acid and two drops of DMF in 40 ml of CHCI3 (ethanol free), 1.17 ml (0.013 mol) of oxalyl chloride were added. The resulting mixture was allowed to warm to room temperature under stirring and continued stirring during 1 hour. After this time, the mixture was concentrated to dryness in vacuo and the obtained residue was dissolved in [CHC13] (20 [MT)] and concentrated again. This procedure was repeated two times. The obtained product was dissolved in CHCI3 (50 ml), the solution was cooled to [0C] and 1.7 g (0.013 mol) of (3R)-aminoquinuclidine were added. The mixture was allowed to warm to room temperature and continued stirring during 16 hours. After this time the reaction mixture was treated with [K2CO3] (saturated solution) and the aqueous layer was extracted with CH2CI2. The organic layers were combined, washed with water, dried over [NA2SO4,] filtered and evaporated. The obtained product (N- [ (3R)-1-azabicyclo [2.2. 2] [OCT-3-YL]-2-(2-] furyl)-2-oxoacetamide) was used without further purification as is described as follows. This product was dissolved in dry THF (50 [ML).] The solution obtained was [COOLED TO-80C] and 28 ml of a 0. 5 M solution in THF of 1-propynylmagnesium bromide (0.014 mol) were added. The mixture was allowed to warm to room temperature during 3 hours. After this time, the reaction mixture was treated with [NH4CI] (saturated solution) and extracted with AcOEt and [CH2CI2.] The organic layers were combined, dried over [NA2SO4,] filtered and solvents were evaporated. The obtained product was purified by column chromatography (silica [GEL, CHC13] : MeOH : NH40H 97: 3: [1 # CHCL3 ]: MeOH:NH4OH 94: 6: 1 as eluent) to yield 1.38 [G] of the title compound (39% from the starting acid) as a mixture of diastereomers. [MS [M+1] + :] 289 ['H-RMN] [(CDCI3)] : (mixture of diastereomers) [5] 7.36-7. 35 (m, 1 H), 6.87-6. 76 (m, NH, [1H),] 6.54-6. 52 (m, 1H), 6.34-6. 32 (m, [1H),] 3.92 (m, 1H), 3.29-3. 17 (m, [1H),] 2.78-2. 64 (m, 4H), 2.47-2. 35 (m, 1 H), 2.00-1. 90 (m, [1 H),] 1.92 (s, 3H), 1.70-1. 39 (m, 4H).
  • 22
  • [ 24716-09-4 ]
  • [ 123536-15-2 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-phenylhexanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
63.1% Stage #1: 2-phenylhexanoic acid With oxalyl dichloride In chloroform at 0 - 20℃; for 1h; Stage #2: (R)-3-aminoquinuclinine In chloroform at 0 - 20℃; for 1h; Stage #3: With potassium carbonate In chloroform; water 27 Method (a); Preparation of [N-[(3R)-1-AZABICYCLOL2.] 2. [2] OCT-3-YL]-2-PHENYLHEXANAMIDE] (Example 27) 2-phenylhexanoic acid was prepared by [ALKYLATION] of [PHENYLACETIC] acid with 1- [CHLOROBUTANE] following a standard method. Oxalyl chloride (0.88 ml, 0.0101 mol) was then added to a solution of 1.62 [G] of [2-PHENYLHEXANOIC] acid (0.0084 mol) and [DIMETHYLFORMAMIDE] (DMF, one drop) in 25 ml of CHCI3 (ethanol free) at [0C.] The mixture was stirred and allowed to warm at room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCI3 and evaporated again. This procedure was repeated two times. The oil obtained was dissolved in [CHC13] and the solution obtained cooled at [0C.] A solution of (3R)-aminoquinuclidine (1.28 g, 0.0101 mol) in [CHC13] was added. The mixture was stirred and allowed to warm at room temperature. After 1 hour at this temperature, the reaction mixture was diluted with [CHC13] and washed with a 10% solution of aqueous potassium.. carbonate, then washed with water, dried over [NA2SO4] and evaporated to give 3.57 [G] of an oil which was purified by column chromatography (silica gel, CHCI3 : MeOH : [NH40H] 90: 10: 1 as eluent). Appropriate fractions were combined and evaporated to give 2.42 [G] of a solid that after treatment with isopropyl ether yielded 1.59 [G] (63. [1%)] of the title product as a mixture of diastereomers. mp: [136C.] MS [[M+1] +] : 301 ['H-NMR] [(DMSO-D6)] : (mixture of diastereomers 50: 50) 8 0.84 (t, 3H), 1.10-1. 60 (m, 9H), 1.70 (m, 1 H), 1.90 (m, 1 H), 2.25-2. 50 (m, 1 H), 2.50-2. 80 (m, 4H), 2.94 & 3.05 (m, [1H),] 3.50 (m, [1H),] 3.65 (m, [1 H),] 7.15-7. 40 (m, 5H), 8.04 (m, 1H, NH).
  • 23
  • [ 123536-15-2 ]
  • [ 22098-18-6 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(5-bromothien-2-yl)-2-oxoacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-(5-bromothiophen-2-yl)-2-oxoacetic acid With oxalyl dichloride In chloroform at 0 - 20℃; for 1.5h; Stage #2: (R)-3-aminoquinuclinine In chloroform at 0 - 20℃; for 3h; Stage #3: With potassium carbonate In chloroform; water 48 Preparation of N-[(3R)-1-Azabicyclo[2. 2. [2] OCT-3-Y !]-2- (5-BROMOTHIEN-2-Y))-2- (4-F) UORO-] 3-methylphenyl)-2-hydroxyacetamide (Example 48) Oxalyl chloride (1.16 ml, 0.013 mol) was added to a suspension of [2- (5-BROMOTHIEN-2-YL)-] 2-oxoacetic acid (2.6 g, 0.011 mol) and two drops of DMF in 30 ml of [CHC13] (ethanol free) cooled to [0C.] The mixture was allowed to warm to room temperature under stirring. After 1.5 hours the reaction mixture was concentrated to dryness in vacuo and the obtained residue was dissolved in CHCI3 (15 [ML)] and concentrated again. This procedure was repeated two times. The obtained residue was dissolved in CHCI3 (30 ml), the solution was cooled to [0C] and 1.67 g (0.013 mol) of (3R)-aminoquinuclidine were added. The mixture was allowed to warm to room temperature and continued stirring during 3 hours. After this time the reaction mixture was treated with [K2CO3] (saturated solution) and the aqueous layer was extracted with [CH2CI2.] The organic layers were combined, washed with water, dried over [NA2SO4,] filtered and evaporated. The obtained product [(N- [ (3R)-1-AZABICYCLO [2.] 2.2] [OCT-3-YL]-2- (5-BROMOTHIEN-2-YL)-2-OXOACETAMIDE)] was used without further purification as is described as follows. The obtained product was dissolved in dry THF (45 [ML).] The solution obtained was cooled [TO-80C] and 14.4 ml of a 1 M solution in THF of 4-fluoro-3-methylphenylmagnesium bromide (0.014 mol) were added. The mixture was stirred during 3 hours at low temperature. After this time, the reaction mixture was treated with NH4CI (saturated solution) and extracted with AcOEt. The organic layer was dried over [NA2SO4,] filtered and solvents were evaporated. The obtained product was purified by column chromatography (silica gel, CHCI3 : MeOH : NH40H 99: 1: [1 G CHCI3 : MEOH] : [NH40H] 96: 4: 1) to yield 2. [1G] of the title compound (42% from the starting acid) as a mixture of diastereomers. MS [[M+L] +] : 453,455 'H-RMN [(CDCI3)] : (mixture of diastereomers) 8 7.35-7. 20 (m, 2H), 7.08-6. 89 (m, 3H), 6.80 (dd, [1 H),] 3.93-3. 84 (m, 1H), 3.18-3. 07 (m, 1H), 2.69-2. 58 (m, 4H), 2.33-2. 22 (m, 4H), 1.92-1. 87 (m, [1 H),] 1.63-1. 42 (m, 4H)
  • 24
  • [ 123536-15-2 ]
  • [ 60249-09-4 ]
  • N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-6-carboxamide dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
31% Stage #1: thieno[3,2-c]pyridine-6-carboxylic acid With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: (R)-3-aminoquinuclinine In DMF (N,N-dimethyl-formamide); dichloromethane for 4h; Stage #3: With hydrogenchloride In methanol 1 Example 1; N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]thieno[3,2-c]pyridine-6- carboxamide dihydrochloride Thieno [3,2-c] pyridine-6-carboxylic acid (185 mg, 1.03 mmol) is combined with TEA (0.167 ml, 1.20 mmol) in CH2C12 (4 ml). Bis (2-oxo-3-oxazolidinyl)- phosphinic chloride (308 mg, 1.20 mmol) is added portionwise and the solution is stirred at rt for 30 min. 0. 5M free-based (R)- (3)-AMINOQUINUCLIDINE solution in DMF (3 ml, 1.5 mmol) is added drop-wise and the reaction stirred for 4 h. The reaction mixture is poured through pre-washed AMBERJET 4400 OH Strongly Basic Anion Exchanger resin directly into pre-washed AG 50W-X2 Hydrogen Form resin. The acid resin is washed with MEOH (100 ml), and the product eluted with 10% TEA/MeOH solution (100 ml). The solution is concentrated in vacuo to a glass. The crude material is chromatographed over 10 g slurry-packed silica, eluting with 1 % NH40H/10% MEOH/CH2CI2 into 100 mm fractions. The appropriate fractions arecollected and concentrated in vacuo to yield 0.115 g (39%) of glass. The glass is dissolved in 1M HC1 in MEOH (1.6 ml) and stirred for 2 h. IPA (2 ml) and Et20 (4 ml) are added to enhance precipitation. The precipitate is isolated via filtration and dried to afford 116 mg (31 %) of as a white salt. HRMS (FAB) calcd for CL5HL7N3OS+H : 288.1170, found 288.1174 (M+H) +.
  • 25
  • [ 590369-80-5 ]
  • [ 201230-82-2 ]
  • [ 104-15-4 ]
  • [ 123536-15-2 ]
  • [ 590369-78-1 ]
YieldReaction ConditionsOperation in experiment
22% Stage #1: 5-[(tert-butoxycarbonyl)amino]-2-naphthyl trifluoromethanesulfonate; carbon monoxide; (R)-3-aminoquinuclinine In dimethyl sulfoxide at 70℃; for 18h; Stage #2: toluene-4-sulfonic acid 7 (R)-3-aminoquinuclidine dihydrochloride is free-based by dissolving the salt in minimal water and MeOH and passing it through a plug of Amberjet resin (OH- form). This material is repeatedly concentrated from MeCN until a white solid is obtained. This white solid (1.00 g, 7.94 mmol) is combined with 5-[(tert-butoxycarbonyl)amino]-2-naphthyl trifluoromethanesulfonate (0.932 g, 2.38 mmol), palladium (II) acetate (0.178 g, 0.79 mmol), and 1,3-bis(diphenylphosphino)ferrocene (0.484 g, 0.87 mmol). DMSO (10 mL) is added and the reaction is stirred vigorously. The flask is evacuated and flushed six times with CO, and the reaction is stirred under a CO balloon at 70° C. for 18 hours. The reaction is cooled to rt and 50 mL of water is added. The water layer is washed with 5×50 mL of methyl-tert-butyl ether, and then 5×200 mL of EtOAc. The methyl-tert-butyl ether layers are discarded, and the EtOAc layers are dried (MgSO4), filtered, and concentrated. The crude product is dissolved in MeOH and loaded onto a column of AGW-×2 resin (H+ form). The resin is washed with MeOH, and the product is eluted with a solution of 5%TEA in MeOH. This solution is then evaporated to dryness. This material is converted to the tosylate salt and the resulting solid is dried in vacuo at 80° C. for 1 hour, then at 60° C. overnight to yield Example 7 as a brown solid (0.373 g, 22% in two steps). HRMS (ESI) calculated for C18H21N3O+H+: 296.1763, found 296.1767
  • 26
  • methyl 2-[(aminocarbonyl)amino]-5-phenylthiophene-3-carboxylate [ No CAS ]
  • [ 123536-15-2 ]
  • 2-[(aminocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-phenylthiophene-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% Stage #1: (R)-3-aminoquinuclinine With trimethylaluminum In tetrahydrofuran; hexane at 0℃; for 0.166667h; Stage #2: methyl 2-[(aminocarbonyl)amino]-5-phenylthiophene-3-carboxylate In tetrahydrofuran at 18 - 25℃; for 10h; 178 2-f (aminocarbonv aminol-N-1 (3R)-l-azabicyclof2. 2. 21 oct-3-yll-5-phenvlthiophene-3- carboxamide. ; To a solution of methyl 2-[(aminocarbonyl) amino] -5-phenylthiophene-3- carboxylate (1. 37 g, 5 mmol) in anhydrous THF (15 mL) was added via cannula a solution of [Me3Al and (3R)-quinuclidin-3-amine] in THF (preformed by the careful addition of Me3Al (2. 0M in hexanes, 5 mL, 10 mmol) to a solution of (3R)-quinuclidin-3-amine (1.0 g, 5 mmol) in 10 mL of THF at 0°C and subsequently stirring at rt for 10 mins). The resulting yellow solution was stirred at rt for 10 h. The reaction mixture was cooled to 0°C and a 10% aqueous solution of Rochelle's salt was added slowly to quench the reaction. The mixture was partitioned between EtOAc and H2O, the aqueous layer was extracted with EtOAc (3x) and the combined organic extracts were washed with H2O, brine and dried (MgS04). Evaporation gave a pale yellow solid. Purification by Gilson (5%-95% MeCN-H2O) gave 1.2 g (70%) of the title compound as white solid. 1H NMR (300 MHz, DMSO-d6) 8 ppm 1.60-1. 74 (m, 1 H) 1.75-1. 94 (m, 2 H) 1.96- 2.11 (m, 1 H) 2.11-2. 25 (m, 1 H) 2.90-3. 35 (m, 4 H) 3.61 (t,. J=11. 49 Hz, 1 H) 4.10-4. 45 (m, 1 H) 6.96 (s, 1 H) 7.19 (t, J=7. 35 Hz, 1 H) 7.33 (t, J=7. 63 Hz, 2 H) 7.50 (d, J=7. 35 Hz, 2 H) 7.79 (s, 1 H) 8.19 (d, J=5. 65 Hz, 1 H); LC/MS (ES, M+H=371).
  • 27
  • [ 1262419-75-9 ]
  • [ 123536-15-2 ]
  • [ 1262419-76-0 ]
YieldReaction ConditionsOperation in experiment
86% Stage #1: (R)-3-aminoquinuclinine With sodium hydride In dichloromethane for 1h; Stage #2: methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate With acetic acid In dichloromethane at 20℃; for 2h; Stage #3: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; 1.C Step C: To a stirred suspension of (R)-(+)-3-aminoquinuclidine (1.4 g, 7.0 mmol) in methylene chloride (50 mL) was added sodium hydride (562 mg, 14.0 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise, followed by methyl l-(2-oxoethyl)-lH-indole-7-carboxylate (1.3g, 5.9 mmol) from Step B above and the mixture continued to stir at room temperature for 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90: 10: 1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (R)- methyl l-(2-(quinuclidin-3-ylamino)ethyl)-lH-indole-7-carboxylate (1.64 g, 86%) as a brown solid: 1H NMR ( 500 MHz, CD3OD) δ 7.77 (d, J = 4.0 Hz, I H), 7.62 (d, J= 3.8 Hz I H), 7.30 (d, J = 1.5 Hz, I H), 7.08 (., /= 7.5 Hz, I H), 6.58 (d, J= 1.5 Hz, I H), 4.50 (t, J = 6.5 Hz, 2H), 3.96 (s, 3H), 3.35 (s, 2H), 3.00-2.97 (m, I H), 2.85-2.58 (m, 7H), 2.21-2.17 (m, IH), 1.70-1.56 (m, 3H), 1.44-1.42 (m, I H), 1.27-1.25 (m, I H); MS (ESI+) m/z 328 (M+H).
  • 28
  • [ 33263-43-3 ]
  • [ 123536-15-2 ]
  • C12H18N4O2S [ No CAS ]
  • 29
  • [ 33263-43-3 ]
  • [ 123536-15-2 ]
  • [ 1297487-86-5 ]
  • 30
  • 4-chloro-3-cyano-2-fluoro-N-hydroxybenzimidoyl chloride [ No CAS ]
  • [ 123536-15-2 ]
  • C15H16ClFN4O [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.2 g With triethylamine In methanol at 20℃; for 2h; 34 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (i?)-34 was prepared from compound A-77: [00623] Compound (i?)-A-77-l was prepared as follows: A solution of (i?)-quinuclidin-3 -amine (0.27 g, 2.2 mmol) in methanol (5 mL) was added dropwise to a solution of 4-chloro-3-cyano-2- fluoro-N-hydroxybenzimidoyl chloride compound A-77 (0.50 g, 2.2 mmol) in methanol (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC[Instrument: GX-B; Column: Atlantis Hilic Silica C18 150x 19 mm, particle size: 5 μπι; Mobile phase: 11-41% acetonitrile in H20 (add 0.1% TFA-ACN, v/v)] to give compound (R)-A-77-l (0.20 g, 28% yield over two steps) as a yellow solid. LCMS (M): tR=0.540 min., 323.1 m/z (M+1).
  • 31
  • 2-fluoro-N-hydroxy-3-methoxy-4-methylbenzimidoyl chloride [ No CAS ]
  • [ 123536-15-2 ]
  • C16H22FN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.13 g With triethylamine In methanol at 20℃; for 4h; 38 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (i?)-38 was prepared from compound A-92: [00643] Compound (i?)-A-92-l (0.13 g, yellow solid, 13% yield over two steps) was prepared from compound A-92 (0.50 g, 2.3 mmol) and (i?)-quinuclidin-3 -amine (0.4 g, 3.2 mmol) with a reaction time of 4 hours. The product was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Gemini C18 250x50mm, particle size: 10 μπι; Mobile phase: 21-51% acetonitrile in H20 (add 0.05% ammonia, v/v)]. LCMS (J): (ES+) m/z (M+H)+ = 308.2, tR=1.092 min.
  • 32
  • [ 123536-15-2 ]
  • [ 57848-46-1 ]
  • (R)-6-bromo-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
91 mg Stage #1: 4-bromo-2-fluorobenzaldehyde With hydroxylamine hydrochloride; sodium acetate In ethanol; water at 20℃; for 2h; Stage #2: With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 72h; Stage #3: (R)-3-aminoquinuclinine Further stages; 43 (R)-6-bromo-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine ((R)-43) To a solution of aldehyde in ethanol/water (8/1, v/v) at room temperature was added hydroxylamine hydrochloride (2 eq.) and sodium acetate (3 eq.). The reaction was stirred for 1-2 hour until TLC showed the reaction was complete. The mixture was concentrated in vacuo, and the residue was triturated from water, collected by filtration, washed with water and dried in vacuo to afford the oxime product, which was used as such in the next step. [00191] To a solution of oxime in N,N-dimethylformamide at room temperature was added N- chlorosuccinimide (1 eq.). The reaction was stirred for 1 or more hours until TLC showed the reaction was complete. The solution was diluted with ethyl acetate and water and filtered through Celite to remove particles. The layers were separated, and the organic layer was washed with water and brine (2x), dried with sodium sulfate, filtered, and concentrated in vacuo to afford the N- hydroxybenzimidoyl chloride product, which was used as such in the next step; Following general procedure A2, compound A-105 was prepared from 4-bromo-2- fluorobenzaldehyde : [00400] Compound A-104 (2.5 g, 93% yield, 9: 1 mixture of (E)/(Z) isomers) was prepared as a white solid from 4-bromo-2-fluorobenzaldehyde (2.5 g, 12.3 mmol) using 45 mL of ethanol/water and a reaction time of 2 hours. 1H NMR (300 MHz, DMSO-d6, major isomer) δ 11.69 (s, IH), 8.15 (s, 1H), 7.69 - 7.60 (m, 2H), 7.48 - 7.42 (m, IH). [00401] Compound A-105 (2.3 g, 82% yield) was prepared as a white solid from compound A- 104 (2.4 g, 11.0 mmol) using 20 mL of N,N-dimethylformamide and a reaction time of 3 days. IH NMR (300 MHz, DMSO-d6) δ 12.73 (s, IH), 7.73 (dd, J= 10.4, 1.8 Hz, IH), 7.66 - 7.52 (m, 2H); Following general procedure C2, compound (i?)-43 was prepared from compound A-105: [00686] Compound (i?)-A-105-l: To a solution of (i?)-quinuclidin-3 -amine (634 mg, 5.0 mmol) and triethylamine (533 mg, 5.3 mmol) in methanol (12 mL) at room temperatue was added a solution of compound A-105 (1.3 g, 5.3 mmol) in methanol (25 mL) over 4 hours using a syringe pump. The mixture was stirred for an additional 12 hours, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography [chloroform: 7M NH3 in methanol = 99: 1 to 9: 1] to afford (i?)-A-105-l (1.2 g, 70% yield) as a white solid. LCMS (1): tR=2.753 min., (ES+) m/z (M+H)+ = 342.0/344.0. To a solution of compound (i?)-A-105-l (320 mg, 0.9 mmol) in dimethylsulfoxide (5 mL) was added potassium tertbutoxide (131 mg, 1.2 mmol). The mixture was stirred at room temperature for 1.5 hours. Additional potassium tertbutoxide (60 mg, 0.5 mmol) was added, and the mixture was stirred for an additional hour. Additional potassium tertbutoxide (40 mg, 0.4 mmol) was added, and the mixture was stirred for 30 min. The solution was put on an SCX column and eluted with methanol. The product was eluted from the column using 3.5 M ammonia in methanol, concentrated and purified by silica gel column chromatography [chloroform: 7M NH3 in methanol = 1/0 to 9/1]. The resulting product was further purified by preparative HPLC [Instrument: AT; Column: Phenomenex Gemini-NX C18 100x21.2 mm, particle size: 10 μπι; Mobile phase A: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water pH=9.0, Mobile phase B: lOmM ammonium bicarbonate in water pH=9.0] and lyophilized to afford: [00688] Compound (i?)-43 (91 mg, 21% yield) as a white solid: LCMS (1): tR=3.222 min., (ES+) m/z (M+H)+ = 322.0/324.0; iNMR ^OO MHz, CDC13) δ 7.61 (dd, J= 1.3, 0.8 Hz, 1H), 7.41 - 7.32 (m, 2H), 4.29 (d, J= 5.0 Hz, 1H), 3.88 - 3.84 (m, 1H), 3.54 - 3.42 (m, 1H), 2.98 - 2.80 (m, 4H), 2.70 - 2.59 (m, 1H), 2.29 - 2.21 (m, 1H), 1.88 - 1.64 (m, 3H), 1.56 - 1.45 (m, 1H).
  • 33
  • [ 123536-15-2 ]
  • [ 159693-01-3 ]
  • C14H17ClFN3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In methanol at 20℃; for 1h; 3 To a solution of amine A-NH2 (1 eq.) and triethylamine (1 eq.) in methanol (3-5 mL/mmol amine A-NH2) at room temperature was added dropwise a solution of -N- hydroxybenzimidoyl chloride (1 eq) in methanol (3-5 mL/mmol N-hydroxybenzimidoyl chloride). The mixture was stirred for 1 or more hours, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the Ν-hydroxyimidamide intermediate; Following general procedure C2, compound (i?)-3 was prepared from compound A-107: [00436] Compound (i?)-A-107-l (144 mg, 61% yield) was prepared as a white solid from A-107 (165 mg, 0.8 mmol) and (i?)-quinuclidin-3 -amine (100 mg, 0.8 mmol) using 5 mL of methanol and a reaction time of 1 hour. The product was purified by silica gel column chromatography [chloroform: methanol = 1:0 to 17:3]. LCMS (1): tR=2.965 min., (ES+) m/z (M+H)+ = 298.1.
  • 34
  • [ 51088-25-6 ]
  • [ 123536-15-2 ]
  • C14H17ClFN3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.1 g With triethylamine In methanol at 20℃; for 1h; 10 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Compound (R)-A-10-l (0.1 g, white solid, 42% yield over two steps) was prepared from compound A-10 (0.3 g, 1.46 mmol) and (i?)-quinuclidin-3 -amine (0.25 g, 2.0 mmol). The product was purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C18 250x50 mm, particle size: 10 μιη; Mobile phase: 22-52% acetonitrile in H20 (add 0.5% NH3 H20, v/v)]. LCMS (J): (ES+) m/z (M+H)+ = 298, tR=0.866 min.
  • 35
  • [ 123536-15-2 ]
  • [ 247091-95-8 ]
  • C14H17F2N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.1 g With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; 11 (R)-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine hydochloride ((R)-ll) General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (i?)-ll was prepared from compound A-12: [00482] Compound (i?)-A-12-l (0.10 g, white solid, 31% yield over two steps) was prepared from compound A-12 (0.20 g, 1.0 mmol) and (i?)-quinuclidin-3 -amine (0.25 g, 2.0 mmol), using N, N- dimethylformamide as the solvent instead of methanol. The product was purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C18 250x50 mm, particle size: 10 μπι; Mobile phase: 19-49% acetonitrile in H20 (add 0.5% NH3 H20, v/v)]. LCMS (B): (ES+) m/z (M+H)+ = 282.1, tR=2.387 min.
  • 36
  • 2-fluoro-N-hydroxy-4-(trifluoromethoxy)benzimidoyl chloride [ No CAS ]
  • [ 123536-15-2 ]
  • C15H17F4N3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.22 g With triethylamine In N,N-dimethyl-formamide at 20℃; for 10h; 16 (R)-6-fluoro-N-(quinuclidin-3-yl)benzo[d]isoxazol-3-amine hydochloride ((R)-ll) General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (i?)-ll was prepared from compound A-12: [00482] Compound (i?)-A-12-l (0.10 g, white solid, 31% yield over two steps) was prepared from compound A-12 (0.20 g, 1.0 mmol) and (i?)-quinuclidin-3 -amine (0.25 g, 2.0 mmol), using N, N- dimethylformamide as the solvent instead of methanol. The product was purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C18 250x50 mm, particle size: 10 μπι; Mobile phase: 19-49% acetonitrile in H20 (add 0.5% NH3 H20, v/v)]. LCMS (B): (ES+) m/z (M+H)+ = 282.1, tR=2.387 min.
  • 37
  • [ 118591-69-8 ]
  • [ 123536-15-2 ]
  • C14H17F2N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In methanol at 20℃; for 2h; 19 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (i?)-19 was prepared from compound A-32: [00539] Compound (i?)-A-32-l (0.60 g, white solid, crude) was prepared from compound A-32 (0.40 g, 2.1 mmol) and (i?)-quinuclidin-3 -amine (0.26 g, 2.1 mmol). The reaction time was 2 hours. LCMS (Q): (ES+) m/z (M+H)+ = 282.1, tR= 2.310 min.
  • 38
  • 2,3,4-trifluoro-N-hydroxybenzimidoyl chloride [ No CAS ]
  • [ 123536-15-2 ]
  • C14H16F3N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.11 g With triethylamine In methanol at 20℃; for 3h; 21 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Compound (R)-A-36-l (0.11 g, white solid, 77% yield over two steps) was prepared from compound A-36 (0.10 g, 0.48 mmol) and (i?)-quinuclidin-3 -amine (0.12 g, 1.0 mmol) with a reaction time of 3 hours. The product was purified by prep-HPLC [Instrument: GX-H; Column: Waters Xbridge 150x25 mm, particle size: 5 μπι; Mobile phase: 20-5% acetonitrile in H20 (add 0.05%ammonia-ACN, v/v)]. LCMS (J): (ES+) m/z (M+H)+ = 300.1, tR=l.lmin
  • 39
  • 4-chloro-2-fluoro-N-hydroxy-3-methylbenzimidoyl chloride [ No CAS ]
  • [ 123536-15-2 ]
  • C15H19ClFN3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.14 g With triethylamine In methanol at 18℃; for 2h; 23 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (i?)-23 was prepared from compound A-43: [00559] Compound (i?)-A-43-l (0.14 g, white solid, 20% yield over four steps) was prepared from compound A-43 (0.45 g, 2.3 mmol) and (i?)-quinuclidin-3 -amine (0.29 g, 2.3 mmol). The reaction was stirred at 18 °C for 2 hours. The product was purified by prep-HPLC [Instrument: GX-C; Column: Phenomenex Synergi C18 250x50 mm, particle size: 10 μπι; Mobile phase: 27-58% acetonitrile in H20 (add 0.05%ammonia-ACN, v/v)]. LCMS (J): (ES+) m/z (M+H)+ = 312.2, tR=1.172 min.
  • 40
  • 4-chloro-2-fluoro-N-hydroxy-3-methoxybenzimidoyl chloride [ No CAS ]
  • [ 123536-15-2 ]
  • C15H19ClFN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.15 g With triethylamine In methanol at 20℃; for 0.5h; 24 Synthesis of Aminobenzoisoxazole General procedure: N-hydroxybenzimidoyl chloride intermediate (1 eq.) in methanol (7 mL/mmol imidoyl chloride intermediate) was added dropwise over 30 min. to a solution of amine A-NH2 (1.2-2 eq.) and triethylamine (2 eq) in methanol (5-10 mL/mmol imidoyl chloride intermediate) at room temperature. The resulting mixture was stirred at room temperature for 30 min. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the N-hydroxyimidamide intermediate; Following general procedure CI, compound (R)-24 was prepared from compound A-45: [00564] Compound (i?)-A-45-l (0.15 g, white solid, 23% yield over three steps) was prepared from compound A-45 (0.45 g, 1.89 mmol) and (i?)-quinuclidin-3 -amine (0.24 g, 2.0 mmol) with a reaction time of 0.5 h. The product was purified by prep-HPLC [Instrument: GX-H; Column: Waters Xbridge 150x25 mm, particle size: 5 μπι; Mobile phase: 20-50% acetonitrile in H20 (add 0.5% NH3 H20, v/v)]. LCMS (J): (ES+) m/z (M+H)+ = 328.1, tR=1.04 min.
  • 41
  • [ 123536-15-2 ]
  • [ 110-17-8 ]
  • (R)-3-aminoquinuclidine monofumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% In methanol at 20℃; 9 Example 9: Synthesis of (R)-3-aminoquinuclidine.monofumarate Methanol solution (29.92 g) containing (R)-3-aminoquinuclidine (4.98 g: 39.5 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and methanol suspension (14.61 g) containing fumaric acid (4.60 g: 39.6 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.monofumarate (9.01 g (37.2 mmol, yield=94%) as a white crystal. (0112) 1H-NMR (D2O, ppm): 1.83-2.02 (4H, m), 2.28-2.30 (1H, m), 3.10-3.29 (5H, m), 3.63-3.69 (1H, m), 3.76-3.81 (1H, m), 6.36 (2H, s) (0113) Endothermic peak top temperature in DSC: 202° C. (0114) Elemental analysis: C7H14N2.C4H4O4 (0115) Theoretical value: C, 54.53%, H, 7.49%, N, 11.56% (0116) Actual measured value: C, 54.4%, H, 7.5%, N, 11.7%
  • 42
  • [ 100-21-0 ]
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine monoterephthalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% In methanol at 20℃; 10 Example 10: Synthesis of (R)-3-aminoquinuclidine.monoterephthalate Methanol suspension (35.21 g) containing terephthalic acid (5.26 g: 31.7 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and methanol solution (12.08 g) containing (R)-3-aminoquinuclidine (4.05 g: 32.1 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.monoterephthalate (8.12 g: 27.7 mmol, yield=87%) as a white crystal. (0118) 1H-NMR (D2O, ppm): 1.77-1.98 (4H, m), 2.22-2.27 (1H, m), 3.05-3.26 (5H, m), 3.59-3.65 (1H, m), 3.72-3.76 (1H, m), 7.72 (4H, s) (0119) Endothermic peak top temperature in DSC: 250° C. (0120) Elemental analysis: C7H14N2.C8H6O4 (0121) Theoretical value: C, 61.63%, H, 6.90%, N, 9.58% (0122) Actual measured value: C, 61.6%, H, 6.7%, N, 9.2%
  • 43
  • [ 123536-15-2 ]
  • [ 110-16-7 ]
  • (R)-3-aminoquinuclidine monomaleate [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% In methanol at 20℃; 15 Comparative Example 15: Synthesis of (R)-3-aminoquinuclidine.monomaleate Methanol solution (14.08 g) containing (R)-3-aminoquinuclidine (4.04 g: 32.0 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and methanol solution (13.70 g) containing maleic acid (3.69 g: 31.8 mmol) was added thereto while stirring at room temperature. Further, isopropanol (16.02 g) was added thereto, and precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine-monomaleate (5.90 g: 24.4 mmol, yield=76%) as a white crystal. (0157) 1H-NMR (D2O, ppm): 1.83-2.02 (4H, m), 2.24-2.28 (1H, m), 3.08-3.29 (5H, m), 3.60-3.66 (1H, m), 3.71-3.75 (1H, m) 5.91 (2H, s) (0158) Endothermic peak top temperature in DSC: 159° C., 188° C.
  • 44
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine dinitrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With nitric acid In isopropyl alcohol at 20℃; 11 Comparative Example 11: Synthesis of (R)-3-aminoquinuclidine.dinitrate Isopropanol solution (39.10 g) containing (R)-3-aminoquinuclidine (3.98 g: 31.5 mmol) was charged into a 100 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and 70% nitric acid (5.91 g: 64.7 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.dinitrate (7.40 g: 29.3 mmol, yield=93%) as a white crystal. (0145) 1H-NMR (D2O, ppm): 1.88-2.05 (4H, m), 2.31-2.34 (1H, m), 3.13-3.31 (5H, m), 3.67-3.73 (1H, m), 3.80-3.83 (1H, m) (0146) Endothermic peak top temperature in DSC: 141° C.
  • 45
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine monosulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With sulfuric acid In toluene Cooling with ice; 8 Example 8: Synthesis of (R)-3-aminoquinuclidine.monosulfate Toluene solution (22.84 g) containing (R)-3-aminoquinuclidine (3.50 g:27.7 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and 95% sulfuric acid (2.87 g: 27.8 mmol) was added thereto while stirring on ice. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.monosulfate (4.85 g: 21.6 mmol, yield=78%) as a white crystal. (0106) 1H-NMR (D2O, ppm): 1.83-2.01 (4H, m) 2.29-2.33 (1H, m), 3.10-3.33 (5H, m), 3.64-3.70 (1H, m), 3.78-3.81 (1H, m) (0107) Endothermic peak top temperature in DSC: 108° C., 175° C., 286° C. (0108) Elemental analysis: C7H14N2.H2SO4 (0109) Theoretical value: C, 37.49%, H, 7.19%, N, 12.49%, S 14.29% (0110) Actual measured value: C, 36.5%, H, 7.1%, N, 12.3%, S 14.4%
  • 46
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine dihydrobromide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With hydrogen bromide In water; isopropyl alcohol at 20℃; 10 Comparative Example 10: Synthesis of (R)-3-aminoquinuclidine-dihydrobromide Isopropanol solution (30.11 g) containing (R)-3-aminoquinuclidine (4.94 g: 39.1 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and 47% hydrobromic acid (13.64 g: 79.2 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine-dihydrobromide (6.73 g: 23.4 mmol, yield=60%) as a white crystal. (0142) 1H-NMR (D2O, ppm): 1.88-2.06 (4H, m), 2.32-2.35 (1H, m), 3.14-3.33 (5H, m), 3.68-3.74 (1H, m), 3.82-3.85 (1H, m) (0143) Endothermic peak top temperature in DSC: 274° C.
  • 47
  • [ 144-62-7 ]
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine monooxalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% In ethanol at 20℃; 11 Example 11: Synthesis of (R)-3-aminoquinuclidine.monooxalate Ethanol solution (14.86 g) containing oxalic acid (2.86 g: 31.8 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and ethanol solution (12 g) containing (R)-3-aminoquinuclidine (4.00 g: 31.7 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.monooxalate (3.14 g: 14.5 mmol, yield=46%) as a white crystal. (0124) 1H-NMR (D2O, ppm): 1.84-2.02 (4H, m), 2.28-2.31 (1H, m), 3.10-3.27 (5H, m), 3.63-3.69 (1H, m), 3.77-3.81 (1H, m) (0125) Endothermic peak top temperature in DSC: 282° C. (0126) Elemental analysis: C7H14N2.C2H2O4 (0127) Theoretical value: C, 49.99%, H, 7.46%, N, 12.96% (0128) Actual measured value: C, 50.1%, H, 7.4%, N, 13.1%
  • 48
  • [ 104-15-4 ]
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine mono-p-toluenesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% In isopropyl alcohol at 20℃; 12 Example 12: Synthesis of (R)-3-aminoquinuclidine.mono-p-toluenesulfonate Isopropanol solution (31.02 g) containing p-toluenesulfonic acid monohydrate (6.02 g: 31.6 mmol) was charged into a 100 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and isopropanol solution (12.02 g) containing (R)-3-aminoquinuclidine (4.01 g: 31.8 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.mono-p-toluenesulfonate (9.02 g: 30.2 mmol, yield=95%) as a white crystal. (0130) 1H-NMR (D2O, ppm): 1.62-1.99 (5H, m), 2.25 (3H, s), 2.65-2.70 (1H, m), 2.94-3.13 (4H, m), 3.21-3.26 (1H, m), 3.35-3.41 (1H, m), 7.22 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz) (0131) Endothermic peak top temperature in DSC: 221° C. (0132) Elemental analysis: C7H14N2.C7H8O3S (0133) Theoretical value: C, 56.35%, H, 7.43%, N, 9.39%, S 10.74% (0134) Actual measured value: C, 56.3%, H, 7.4%, N, 9.5%, S 10.3%
  • 49
  • [ 123536-15-2 ]
  • [ 64-19-7 ]
  • (R)-3-aminoquinuclidine diacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% In isopropyl alcohol at 20℃; 12 Comparative Example 12: Synthesis of (R)-3-aminoquinuclidine.diacetate Isopropanol solution (30.16 g) containing (R)-3-aminoquinuclidine (5.03 g: 39.9 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and acetic acid (4.75 g: 79.1 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine-diacetate (4.41 g: 17.9 mmol, yield=45%) as a white crystal. (0148) 1H-NMR (D2O, ppm): 1.75 (6H, s), 1.82-2.01 (4H, m), 2.23-2.27 (1H, m), 3.06-3.26 (5H, m), 3.60-3.66 (1H, m), 3.70-3.75 (1H, m) (0149) Endothermic peak top temperature in DSC: 105° C., 135° C.
  • 50
  • [ 75-75-2 ]
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine monomesylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% In isopropyl alcohol at 20℃; 17 Comparative Example 17: Synthesis of (R)-3-aminoquinuclidine.monomesylate Isopropanol solution (36.25 g) containing (R)-3-aminoquinuclidine (4.19 g: 33.2 mmol) was charged into a 100 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and mesylic acid (3.19 g: 33.2 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.monomesylate (7.06 g: 31.7 mmol, yield=96%) as a white crystal. (0163) 1H-NMR (D2O, ppm): 1.64-2.00 (5H, m), 2.66 (3H, s), 2.67-2.71 (1H, m), 2.95-3.14 (4H, m), 3.24-3.28 (1H, m), 3.37-3.43 (1H, m) (0164) Endothermic peak top temperature in DSC: 181° C.
  • 51
  • [ 123536-15-2 ]
  • [ 802294-64-0 ]
  • (R)-3-aminoquinuclidine monopropionate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% In toluene at 20℃; 13 Comparative Example 13: Synthesis of (R)-3-aminoquinuclidine.monopropionate Toluene solution (24.03 g) containing (R)-3-aminoquinuclidine (3.99 g: 31.6 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and propionic acid (2.36 g: 31.9 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine-monopropionate (3.30 g: 16.5 mmol, yield=52%) as a white crystal. (0151) 1H-NMR (D2O, ppm): 0.89 (3H, t, J=7.8 Hz), 1.63-1.99 (4H, m), 2.01 (2H, q, J=7.8 Hz), 2.65-2.69 (1H, m), 2.93-3.08 (5H, m), 3.22-3.26 (1H, m), 3.35-3.41 (1H, m) (0152) Endothermic peak top temperature in DSC: 116° C., 149° C.
  • 52
  • [ 123536-15-2 ]
  • [ 65-85-0 ]
  • (R)-3-aminoquinuclidine dibenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
64% In isopropyl alcohol at 20℃; 14 Comparative Example 14: Synthesis of (R)-3-aminoquinuclidine.dibenzoate Isopropanol solution (20.03 g) containing (R)-3-aminoquinuclidine (5.05 g: 40.0 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and isopropanol solution (24.87 g) containing benzoic acid (9.70 g: 79.4 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.dibenzoate (9.54 g: 25.8 mmol, yield=64%) as a white crystal. (0154) 1H-NMR (D2O, ppm): 1.79-1.98 (4H, m), 2.23-2.27 (1H, m), 3.06-3.26 (5H, m), 3.59-3.66 (1H, m), 3.71-3.76 (1H, m), 7.29-7.34 (4H, m), 7.37-7.41 (2H, m), 7.70-7.72 (4H, m) (0155) Endothermic peak top temperature in DSC: 126° C., 218° C.
  • 53
  • [ 123536-15-2 ]
  • [ 77-92-9 ]
  • (R)-3-aminoquinuclidine 2/3 citrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% In isopropyl alcohol at 20℃; 16 Comparative Example 16: Synthesis of (R)-3-aminoquinuclidine.2/3citrate Isopropanol solution (25.00 g) containing (R)-3-aminoquinuclidine (5.01 g: 39.7 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and isopropanol solution (15.54 g) containing citric acid monohydrate (5.57 g: 26.5 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.2/3citrate (8.56 g: 33.7 mmol, yield=85%) as a white crystal. (0160) 1H-NMR (D2O, ppm): 1.01-2.03 (4H, m), 2.27-2.31 (1H, m), 2.41 (4/3H, d, J=15.3 Hz), 2.53 (4/3H, d, J=15.3 Hz), 3.10-3.31 (5H, m), 3.61-3.68 (1H, m), 3.76-3.80 (1H, m) (0161) Endothermic peak top temperature in DSC: 195° C.
  • 54
  • [ 123536-15-2 ]
  • (R)-3-aminoquinuclidine sesquiphosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid In methanol at 20℃; 7 Example 7: Synthesis of (R)-3-aminoquinuclidine.sesquiphosphate Methanol solution (27.04 g) containing (R)-3-aminoquinuclidine (3.04 g: 24.1 mmol) was charged into a 50 mL-flask equipped with a magnetic stirrer, a thermometer, and a cooling line, and phosphoric acid (85% in water) (4.15 g: 36.0 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 65° C., to obtain (R)-3-aminoquinuclidine.sesquiphosphate (6.67 g: 24.4 mmol, yield=101%) as a white crystal. (0100) 1H-NMR (D2O, ppm): 1.82-2.02 (4H, m), 2.24-2.28 (1H, m), 3.08-3.29 (5H, m), 3.60-3.66 (1H, m), 3.71-3.75 (1H, m) (0101) Endothermic peak top temperature in DSC: 190° C., 230° C., 279° C. (0102) Elemental analysis: C7H14N2.1.5H3PO4 (0103) Theoretical value: P, 17.01% (0104) Actual measured value: P, 17.0%
  • 55
  • [ 123536-15-2 ]
  • [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid [ No CAS ]
  • (R)-3-aminoquinuclidine mono-(-)-10-camphorsulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% In isopropyl alcohol at 20℃; 13 Example 13: Synthesis of (R)-3-aminoquinuclidine.mono-(-)-10-camphorsulfonate Isopropanol solution (25.73 g) containing (-)-10-camphorsulfonic acid (5.51 g: 23.7 mmol) was charged into a 50 mL-flask equipped with a mechanical stirrer, a thermometer, and a cooling line, and isopropanol solution (9.01 g) containing (R)-3-aminoquinuclidine (2.99 g: 23.7 mmol) was added thereto while stirring at room temperature. Precipitated crystals were filtered, and then dried under reduced pressure at 60° C., to obtain (R)-3-aminoquinuclidine.mono-(-)-10-camphorsulfonate (7.85 g: 21.9 mmol, yield=92%) as a white crystal. (0136) 1H-NMR (D2O, ppm): 0.68 (3H, s), 0.89 (3H, s), 1.27-1.34 (1H, m), 1.46-1.53 (1H, m), 1.64-2.02 (8H, m), 2.22-2.31 (2H, m), 2.65-2.72 (1H, m), 2.72 (1H, d, J=15.3 Hz), 2.95-3.13 (4H, m), 3.13 (1H, d, J=15.3 Hz), 3.22-3.29 (1H, m), 3.37-3.43 (1H, m) (0137) Endothermic peak top temperature in DSC: 201° C. (0138) Elemental analysis: C7H14N2C10H16O4S (0139) Theoretical value: C, 56.96%, H, 8.44%, N, 7.81%, S 8.94% (0140) Actual measured value: C, 56.9%, H, 8.3%, N, 7.8%, S 8.6%
  • 56
  • [ 29835-36-7 ]
  • [ 123536-15-2 ]
  • rac-N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-3-methyl-5-phenyladamantane-1-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: rac-3-methyl-5-phenyladamantane-1-carboxylic acid With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Stage #2: (R)-3-aminoquinuclinine In dichloromethane at 20℃; for 12h; A58 General procedure 1 for preparation of examples Al to A69. General procedure: To a solution of 3-phenyl-5-methyl adamantane-l-carboxylic acid (11 mg, 0.041 mmol) in 1 mL of anhydrous CH2CI2 was added N,N-diisopropylethylamine (9uL, 0.049 mmol), EDC hydrochloride (10 mg, 0.049 mmol), and l-hydroxy-7-azabenzotriazole (HOAt, 6.5 mg, 0.O49mmol) sequentially. The resulting reaction mixture was stirred at room temperature for 0.5 h, then mono Boc protected diamine NH2-W- NHBOC (0.05 mmol) was added. The reaction mixture was stirred at room temperature for 12 h, dilutedwith CH2CI2 and washed with saturated aq. NaHCO3 solution. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. It was dissolved in 1 mL of CH2CI2, and trifluoroacetic acid (0.1 mL) was added and stirred for 2 h at r.t. The solvent was evaporated, the residuewas treated with saturated aq. NaHCO3 solution and extracted with ethylacetate. The organic phase was dried over Na2SO4, filtered, and evaporation of solvent gave a residue which was purified either by flash Si02 column chromatography or preparative HPLC.
  • 57
  • 5-chloro-N-(4-morpholino-2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
  • [ 123536-15-2 ]
  • (R)-N-(4-morpholino-2-(trifluoromethyl)phenyl)-5-(quinuclidin-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With potassium fluoride In dimethyl sulfoxide at 40℃; for 2h; 4.1.28. 5-(cyclohexylamino)-N-(4-morpholino-2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28) General procedure: A mixture of 5-chloro-N-(4-morpholino-2- (trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 38b (50 mg, 0.12 mmol),cyclohexylamine (18 mg, 0.18 mmol), and potassium fluoride (68 mg,1.17 mmol) in DMSO (5 mL) was stirred at 40 °C for 2 h. The reaction mixture was extracted with ethyl acetate (15 mL*2), and the organic layer was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM 1: 20) to give the title compound a light-yellow solid (29 mg, 51%).
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