September 17, 2020 - Heterocyclic Building Blocks-Quinuclidine

The origin of a common compound about 22766-68-3

This compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route,22766-68-3,Ethyl quinuclidine-4-carboxylate,its application will become more common.

A common heterocyclic compound, 22766-68-3,Ethyl quinuclidine-4-carboxylate, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc., below Introduce a new synthetic route. 22766-68-3

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol A solution of phenyllithium (1.5-1.7 M in 70 cyclohexane/30 ether, 20.0 mL, 32 mmol) was chilled down to -30 C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (1.51 g, 8.23 mmol) in THF (20 mL) was slowly added to the reaction mixture at -30 C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with H2O and then evaporated to dryness under vacuum. H2O and EtOAc were added, causing a white solid to crash out. This solid was filtered off, to give the title compound (0.79 g). The aqueous phase was further extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The crude product was treated with EtOAc and hexane and filtered to yield more of the title compound (0.67 g). Total yield (1.46 g, 60.7%). EI-MS m/z 294(M+H+) Rt (1.37 min).

Reference£º
Patent; Laine, Damane I.; Palovich, Michael R.; McCleland, Brent W.; Neipp, Christopher E.; Thomas, Sonia M.; US2007/185155; (2007); A1;,
Quinuclidine – Wikipedia
Quinuclidine | C7H13N | ChemSpider

Some scientific research about Ethyl quinuclidine-4-carboxylate

22766-68-3 A common heterocyclic compound, 22766-68-3,Ethyl quinuclidine-4-carboxylate, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc., below Introduce a new synthetic route.

Ethyl quinuclidine-4-carboxylate (900 mg, 4.91 mmol) was hydrolyzed in a mixture of ethanol (2 mL) and sodium hydroxide (aq) (2M, 7.5 mL) at 50 C. The reaction was followed by TLC (methanol/diethylamine 20/1). After 3 hours the mixture was neutralized with HC1 (2 M) to pH=5 and evaporated. The residue was extracted with methanol which however also extracted NaCl. The extract was evaporated and the solid was extracted with ethanol which was not very effective in extracting the desired zwitterionic amino acid. All extracts and solids were combined and HC1 (2 M) was added to pH< 1 and the mixture was evaporated until it was completely dry. The solid residue was suspended in dichioromethane (10 mL) and oxalyl chloride (25 mmol, 2.3 mL) was added followed by two drops of N,N-dimethylformamide. The mixture was refluxed for 6 hours and then evaporated to dryness. To the residue was added N,N-dimethylformamide (10 mL) and sodium azide (10.4 mmol, 680 mg) and the mixture was stirred at 50 C for 20 h, then partitioned between saturated sodium carbonate and toluene. A three phase liquid system was formed. The toluene phase (on top) was collected, dried, and heated at reflux for 1 hours (visible gas formation occurred before reaching the reflux temperature), then cooled and extracted three times with HC1 (SM, 3 x 20 mL). The aqueous phases were combined and heated at reflux for 1 h, then evaporated to almost dryness and triturated with abs. ethanol. The precipitate was collected and gave the desired 4-aminoquinuclidine as the dihydrochloride (173 mg, 0.87 mmol, 18% yield). ?H NMR (400 MHz, deuterium oxide) 3.68- 3.52 (m, 4H), 2.37-2.23 (m, 4H). This compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route,22766-68-3,Ethyl quinuclidine-4-carboxylate,its application will become more common. Reference£º
Patent; ACADIA PHARMACEUTICALS INC.; BURSTEIN, Ethan, S.; OLSSON, Roger; JANSSON, Karl, Erik; SKOeLD, Niklas, Patrik; WAHLSTROeM, Larisa, Yudina; VON WACHENFELDT, Henrik; BERGNER, Magnus, Gustav Wilhelm; DREISCH, Klaus; POPOV, Kyrylo; KOVALENKO, Oleksnadr; KLINGSTEDT, Per Tomas; (357 pag.)WO2019/40106; (2019); A2;,
Quinuclidine – Wikipedia
Quinuclidine | C7H13N | ChemSpider

The origin of a common compound about 40117-63-3

This compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route,40117-63-3,Quinuclidine-4-carboxylic acid hydrochloride,its application will become more common.

A common heterocyclic compound, 40117-63-3,Quinuclidine-4-carboxylic acid hydrochloride, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc., below Introduce a new synthetic route. 40117-63-3

(Quinuclidin-4-yl)carboxylic acid was prepared from 4-cyanoquinuclidine (Oakwood Products) following the procedure of Grob and Renk, Helv. Chim. Acta, 37, 1681 (1954). To a stirred suspension of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.523 mmol) in 3 mL of anhydrous tetrahydrofuran at 0 C. was added borane methylsulfide complex (42 mg, 0.553 mmol). The mixture was stirred at room temperature for 1 hr and heated to reflux overnight. The reaction was cooled to 0 C. and carefully treated with 1 mL of methanol. The solvent was then removed under reduced pressure to leave the desired alcohol. Yield 36 mg. MS (m/e): 141.

Reference£º
Patent; CoMentis, Inc.; BILCER, Geoffrey M.; NG, Raymond; (104 pag.)US2016/9706; (2016); A1;,
Quinuclidine – Wikipedia
Quinuclidine | C7H13N | ChemSpider

Some scientific research about Quinuclidine-4-carboxylic acid hydrochloride

40117-63-3 A common heterocyclic compound, 40117-63-3,Quinuclidine-4-carboxylic acid hydrochloride, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc., below Introduce a new synthetic route.

Example 1(Quinuclidin-4-yl)methanol (Quinuclidin-4-yl)carboxylic acid was prepared from 4-cyanoquinuclidine (Oakwood Products) following the procedure of Grob and Renk, Helv. Chim. Acta, 37, 1681 (1954).To a stirred suspension of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.523 mmol) in 3 mL of anhydrous tetrahydrofuran at 0 C. was added borane methylsulfide complex (42 mg, 0.553 mmol). The mixture was stirred at room temperature for 1 hr and heated to reflux overnight. The reaction was cooled to 0 C. and carefully treated with 1 mL of methanol. The solvent was then removed under reduced pressure to leave the desired alcohol. Yield 36 mg. MS (m/e): 141.

Reference£º
Patent; CoMentis, Inc.; US2009/88418; (2009); A1;,
Quinuclidine – Wikipedia
Quinuclidine | C7H13N | ChemSpider

A new synthetic route of Ethyl quinuclidine-4-carboxylate

Step 1. A solution of 4-carbethoxyquinuclidine (10.92 g) in THF (155 mL) was treated at-780C with borane-THF (1.0 M, 77.5 mL). The resulting mixture was stirred at -78C for 4 h, then treated with water (50 mL), warmed to room temperature and stirred for an additional hour. The reaction mixture was diluted with ethyl acetate and the aqueous phase was separated and extracted with two further portions of ethyl acetate. The combined organic layers were washed with brine- (twice), dried (MgSO4), filtered and evaporated in vacuo. Purification by silica gel chromatography (eluting with cyclohexane-ethyl acetate [1 :0 to 1 :1]) gave 1-boranyl-1-aza-bicyclo[2.2.2]octane-4- carboxylic acid ethyl ester (7.12 g, 61%) as an off-white solid. 1H NMR (400 MHz, CDCI3) delta 4.16 (2H1 q, J = 6.9), 3.10-3.05 (6H1 m), 1.98-1.93 (6H, m), 1.26 (3H, t, J = 6.9)., 22766-68-3

Reference£º
Patent; ARGENTA DISCOVERY LIMITED; WO2008/99186; (2008); A1;,
Quinuclidine – Wikipedia
Quinuclidine | C7H13N | ChemSpider

A new synthetic route of Ethyl quinuclidine-4-carboxylate

Example 32 Preparation of 1-butyl-4-[hydroxy(di-3-thienyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide A solution of n-Butyl lithium (2.5M in hexanes, 5.0 mL, 12.5 mmol) was chilled to -78 C. under Ar. 3-Bromothiophene (1.15 mL, 12.3 mmol) dissolved in ethyl ether (4.0 mL) was slowly added to the reaction mixture. The reaction was stirred for 30 min and then ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.7640 g, 4.16 mmol) in THF/Et2O (4 mL/4 mL) was added. The reaction was allowed to warm up from -78 C. to room temperature over 16 h then slowly quenched with water. The reaction was concentrated and the resulting brown solid was taken up in water and DCM. The organic phase was separated, dried over MgSO4, filtered and concentrated under vacuum to give a brown solid. The solid was dissolved in DMSO and purified by preparatory HPLC to give the title compound (0.1736 g, 9.4%). EI-MS m/z 362(M+) Rt (1.73 min).

A new synthetic route of Ethyl quinuclidine-4-carboxylate

1-azabicyclo[2.2.2]oct-4-yl[bis(3-fluorophenyl)]methanol A solution of 3-fluorophenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0 C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1756 g, 0.958 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0 C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60 C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.242 g, 76.7%). EI-MS m/z 330(M+H+) Rt (1.45 min).

New downstream synthetic route of 22766-68-3

This compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route,Ethyl quinuclidine-4-carboxylate,22766-68-3,its application will become more common.

22766-68-3, 1-azabicyclo[2.2.2]oct-4-yl(di-2-naphthalenyl)methanol A solution of (2-naphthalenyl)magnesiumbromide (0.5 M in THF, 6.5 mL, 3.25 mmol) was chilled down to 0 C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1597 g, 0.871 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0 C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60 C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.265 g, 77.3%). EI-MS m/z 394(M+H+) Rt (1.90 min).

Some scientific research about Ethyl quinuclidine-4-carboxylate

1-azabicyclo[2.2.2]oct-4-yl]bis(4-fluorophenyl)]methanol A solution of 4-fluorophenylmagnesiumbromide (1.0 M in THF, 4.4 mL, 4.4 mmol) was chilled down to 0 C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1973 g, 1.08 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0 C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60 C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.3152 g, 88.9%). EI-MS m/z 330(M+H+) Rt (1.65 min).

The origin of a common compound about 40117-63-3

1. Preparation of 3-fluorobenzyl quinuclidine-4-carboxylate (Compound 91). A mixture of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.52 mmol) and thionyl chloride (500 mul, 6.85 mmol) was refluxed for 2 hours. The reaction was cooled to room temperature, and the solvent was accurately removed. The residue was suspended in dry DCM and treated with (3-fluorophenyl)methanol (65.8 mg, 0.52 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated, and the residue was dissolved in water (1 ml), basified with NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain 3-fluorobenzyl quinuclidine-4-carboxylate (41 mg, 29.8% yield), which was used in the next step without any further purification.

Reference£º
Patent; Chiesi Farmaceutici S.p.A.; US2012/276018; (2012); A1;,
Quinuclidine – Wikipedia
Quinuclidine | C7H13N | ChemSpider