1-azabicyclo[2.2.2]octan-8-ol (3-Quinuclidinol; Quinuclidin-3-ol) [CAS 1619-34-7; InChIKey IV

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Date

43 reactions in Reaxys

2016-04-25 15h:26m:09s (EST)

43 reactions in Reaxys

2016-04-25 15h:44m:33s (EST)

HO

1. Query N

Search as: As drawn 2. Query

(1. Query) AND itemno in (1,2,3)

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O

HO

N

N

Rx-ID: 22210754 View in Reaxys 1/43 Yield 97 %

Conditions & References With RuCl[(S)-daipena][(S)-3,5-xylyl-BINAP], potassium tert-butylate, hydrogen in isopropyl alcohol, Time= 6h, T= 10 °C , p= 22801.5Torr , optical yield given as percent ee, enantioselective reaction Matsumura, Kazuhiko; Arai, Noriyoshi; Hori, Kiyoto; Saito, Takao; Sayo, Noboru; Ohkuma, Takeshi; Journal of the American Chemical Society; vol. 133; nb. 28; (2011); p. 10696 - 10699 View in Reaxys

95 %

27 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 25 except that ethanol:t-butanol=3:1 was used as the solvent in place of ethanol, and (S)-3-quinuclidinol with 86percent ee was formed with a yield of 95percent.

With potassium tert-butylate, hydrogen, RuCl2[(R,R)-xylskewphos][(S)-ampy] in ethanol, tert-butyl alcohol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys

89 - 96 %

25; 28 :RuCl2[(R,R)-xylskewphos][(S)-ampy] (1.6 mg, 0.002 mmol), 3-quinuclidinone (0.25 g, 2 mmol), KOC(CH3)3 (9 mg, 0.08 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with ethanol (4 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (S)-3-quinuclidinol with 86percent ee was formed with a yield of 96percent; RuCl2[(R,R)-xylskewphos][(S)-ampy] (3.3 mg, 0.004 mmol), 3-quinuclidinone (0.25 g, 2 mmol), KOC(CH3)3 (18 mg, 0.16 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with ethanol (4 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 0° C, and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (S)-3-quinuclidinol with 88percent ee was formed with a yield of 89percent With potassium tert-butylate, hydrogen, RuCl2[(R,R)-xylskewphos][(S)-ampy] in ethanol, Time= 19h, T= 0 - 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys Reaction Steps: 2 1: lithium alanate; diethyl ether 2: (1S)-2-oxo-bornane-10-sulfonic acid With lithium aluminium tetrahydride, diethyl ether, camphor-10-sulfonic acid Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys 8 :The same reaction as Example 1 was carried out with the exception of using (R)-1,1'-binaphthyl-2,2'-bis(di-p-tolyl) phosphine ruthenium (II) dichloride (S,S)-1,4-diphenylbutane-1,4-diamine complex for the ruthenium compound (II) to obtain (S)-3-quinuclidinol (3-S). S/C, conversion rate and enantiomeric excess are indicated below.

With potassium tert-butylate, hydrogen, (R)-1,1'-binaphthyl-2,2'-bis(di-p-tolyl)phosphine ruthenium(II) dichloride (S,S)-1,4-diphenylbutane-1,4-diamine in isopropyl alcohol, T= 20 - 25 °C , p= 1500.15 - 15001.5Torr , Inert atmosphere, Avtoclave, Product distribution / selectivity Patent; National University Corporation Hokkaido University; Nippon Soda Co., Ltd.; EP2186812; (2010); (A1) English

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View in Reaxys With trans-RuCl2((R)-BINAP)((S)-ipban), potassium tert-butylate, hydrogen in isopropyl alcohol, Time= 5h, T= 25 °C , p= 15201Torr , optical yield given as percent ee, enantioselective reaction Arai, Noriyoshi; Akashi, Masaya; Sugizaki, Satoshi; Ooka, Hirohito; Inoue, Tsutomu; Ohkuma, Takeshi; Organic Letters; vol. 12; nb. 15; (2010); p. 3380 - 3383 View in Reaxys 14 :To a 100 mL autoclave with a stirrer, 3-quinuclidinone (2.5 g, 20.0 mmol) and RuCl[(S)-xylbinap][(S)-daipen] (0.5 mg, 0.40 umol, 1/50,000 molar fold of 3-quinuclidinone) obtained from the Example 1 above were added. After the autoclave was purged with nitrogen, 2-propanol (15 mL) and 2-propanol solution of potassium t-butoxide (0.1 mol/L, 1.0 mL, 0.1 mmol) were added. Subsequently, the autoclave was purged with hydrogen, the mixture was stirred at 30°C for 6 hours under hydrogen pressure of 3 MPa As a result of analysis of the reaction solution, it was found that the conversion rate is 99percent or more and the optical purity is 912 percent ee.

With potassium tert-butylate, hydrogen, RuCl[(S)-xylbinap][(S)-daipen] in isopropyl alcohol, Time= 6h, T= 30 °C , p= 22502.3Torr , Autoclave, Inert atmosphere, Product distribution / selectivity Patent; TAKASAGO INTERNATIONAL CORPORATION; NARA, Hideki; YOKOZAWA, Tohru; WO2011/135753; (2011); (A1) English View in Reaxys

O

HO

N

N

Rx-ID: 22210755 View in Reaxys 2/43 Yield 100 %

Conditions & References 30 :RuCl2[(S,S)-xylskewphos] (dmf)n (0.002 mmol) prepared from (S,S)-XylSKEWPHOS and [RuCl2(p-cymene)]2, 2picolylamine (0.2 mg, 0.002 mmol), 3-quinuclidinone (0.250 g, 2 mmol), and KOC(CH3)3 (9 mg, 0.08 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with ethanol (4 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 90percent ee was formed with a yield of 100percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-xylskewphos] (dmf)n in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys

99 %

With trans-RuCl2((S)-BINAP)((R)-iphan), potassium tert-butylate, hydrogen in isopropyl alcohol, Time= 24h, T= 25 °C , p= 38002.6Torr , optical yield given as percent ee, enantioselective reaction Arai, Noriyoshi; Akashi, Masaya; Sugizaki, Satoshi; Ooka, Hirohito; Inoue, Tsutomu; Ohkuma, Takeshi; Organic Letters; vol. 12; nb. 15; (2010); p. 3380 - 3383 View in Reaxys

95 %

15 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that RuBr2[(S,S)-xylskewphos](6-Me-pica) was used as the catalyst in place of RuBr2[(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 82percent ee was formed with a yield of 95percent.

With potassium tert-butylate, hydrogen, RuBr2[(S,S)-xylskewphos](6-Me-pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys

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94 %

11 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that RuCl2[(S,S)-3,S-diEtskewphos](pica) was used as the catalyst in place of RuBr2[(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 81percent ee was formed with a yield of 94percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-3,5-dietskewphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys

59 - 98 %

9; 17 :RuBr2[(S,S)-xylskewphos](pica) (1.8 mg, 0.002 mmol), 3-quinuclidinone (0.25 g, 2 mmol), KOC(CH3)3 (9 mg, 0.08 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with ethanol (4 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 84percent ee was formed with a yield of 92percent; RuBr2[(S,S)-xylskewphos](pica) (0.5 mg, 0.54 μmol), 3-quinuclidinone (20.37 g, 162.7 mmol), KOC(CH3)3 (219 mg, 1.9 mmol) were placed in a 500-mL glass autoclave, replaced with argon, subsequently added with ethanol (65 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 89percent ee was formed with a yield of 98percent; Hydrogenation of 3-quinuclidinone was carried out similar to the Example 17 except that the amount of KOC(CH3)3 was reduced from 219 mg (1.9 mmol) to 146 mg (1.3 mmol), and (R)-3-quinuclidinol with 89percent ee was formed with a yield of 59percent.

With potassium tert-butylate, hydrogen, RuBr2[(S,S)-xylskewphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys Reaction Steps: 2 1: lithium alanate; diethyl ether 2: (1S)-2-oxo-bornane-10-sulfonic acid With lithium aluminium tetrahydride, diethyl ether, camphor-10-sulfonic acid Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys 1 :To a 100-mL autoclave were added 3-quinuclidinone (500 mg, 4.0 mmol), [RuCl(p-cymene)((R)-DM-SEGPHOS)]Cl (4.1 mg, 0.004 mmol), and (R)-DAIPEN (5.0 mg, 0.016 mmol). Under a nitrogen atmosphere, IPA (4 mL) and potassium t-butoxide/IPA solution (1.0 mol/L, 0.4 mL) were added thereto. Then, the mixture was stirred under a hydrogen pressure of 3 MPa at 30° C. for 15 hours. After analysis of the reaction solution, (R)-3-quinuclidinol was obtained at an optical purity of 90.8percent ee and a conversion ratio of 99percent or more.

With R-DAIPEN, potassium tert-butylate, hydrogen, [RuCl(p-cymene)((R)-DM-SEGPHOS)]Cl in isopropyl alcohol, Time= 15h, T= 30 °C , p= 22502.3Torr , Conversion of starting material Patent; Takasago International Corporation; US2006/47122; (2006); (A1) English View in Reaxys 30 :RuCl2-[(S,S)-xylskewphos](dmf)n (0.002 mmol) prepared from (S,S)-XylSKEWPHOS and [RuCl2(p-cymene)]2, 2picolylamine (0.2 mg, 0.002 mmol), 3-quinuclidinone (0.250 g, 2 mmol), and KOC(CH3)3 (9 mg, 0.08 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with ethanol (4 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C., and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 90percent ee was formed with a yield of 100percent.

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With potassium tert-butylate, hydrogen, RuCl2[(S,S)-2,4-bis(di-3,5-xylylphosphino)pentane](dmf)n in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Inert atmosphere, Autoclave Patent; Kanto Kagaku Kabushiki Kaisha; US2009/216019; (2009); (A1) English View in Reaxys 100 1 :1.63 g (13 mmol) of the 3-quinuclidinone (I) were added to a 50 ml Schlenk tube and after reducing pressure in%Chromat. side the vessel with a vacuum pump, argon was sealed inside. This procedure was repeated three times to replace the inside of the vessel with argon. 12.7 ml of 2-propanol and 0.26 ml (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0M) were respectively added to the vessel with a glass syringe. After completely dissolving the 3-quinuclidinone using an ultrasonic device, the solution was frozen at the temperature of liquid nitrogen. After reducing the pressure inside the vessel with a vacuum pump, the solution was thawed using a heat gun. This freezingdegassing procedure was repeated three times to obtain a substrate solution. A polytetrafluoroethylene-coated stirrer bar and 1.4 mg of the ruthenium compound (II) in the form of (S)-1,1'-binapthyl-2,2'- bis(di-p-tolyl)phosphine ruthenium (II) dichloride (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine complex (1.3 μmol, S/C = (substrate: 13 mmol)/(ruthenium compound (II): 1.3 μmol) = 10,000) were added to a 100 ml stainless steel autoclave (provided with a glass inner tube) followed by replacing the inside of the vessel with argon. Next, the substrate solution was transferred to the autoclave using a polytetrafluoroethylene tube. The autoclave was connected to a hydrogen tank using a hydrogen feed tube and hydrogen at 0.2 MPa was released 10 times to replace air inside the feed tube with hydrogen. Subsequently, hydrogen at 1.0 MPa was sealed in the autoclave vessel followed immediately by releasing hydrogen until the pressure reached 0.2 MPa, and this procedure was repeated 10 times to replace the inside of the vessel with hydrogen. Finally, hydrogen was filled to a pressure of 2. 0 MPa followed by stirring for 5 hours at 20 to 25°C. Following completion of the reaction, 146.1ml (1.105 mmol) of distillation purified tetralin were added to the reaction solution as an internal standard followed by stirring to achieve uniformity. When the reaction mixture was analyzed by gas chromatography, 13 mmol of (R)-3-quinuclidinol (3-R) were determined to have been formed at a enantiomeric excess of 97percent ee(R) (yield: 100percent).

With potassium tert-butylate, hydrogen, (S)-1,1'-binapthyl-2,2'-bis(di-p-tolyl)phosphine ruthenium(II) dichloride (2R, 3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine in isopropyl alcohol, T= 20 - 25 °C , p= 1500.15 - 15001.5Torr , Inert atmosphere, Autoclave, Product distribution / selectivity Patent; National University Corporation Hokkaido University; Nippon Soda Co., Ltd.; EP2186812; (2010); (A1) English View in Reaxys 16 :To a 100 mL autoclave with a stirrer, 3-quinuclidinone (2.5 g, 20.0 mmol) and RuCl[(R)-dm-segphos][(R)-daipen] obtained from Example 3 above (0.5 mg, 0.40 umol, 1/50,000 molar equivalent fold of 3-quinuclidinone) were added.

After purging with nitrogen, 2-propanol (15 mL) and 2-propanol solution of t-BuOK (0.1 mol/L, 1.0 mL, 0.1 mmol) were added. Subsequently, purging with hydrogen, the mixture was stirred at 30°C for 6 hours under hydrogen pressure of 3 MPa. As a result of analysis of the reaction solution, it was found that the conversion rate is 99percent or more and the optical purity is 91.1 percent ee.

With potassium tert-butylate, hydrogen, RuCl[(R)-dm-segphos][(R)-daipen] in isopropyl alcohol, Time= 6h, T= 30 °C , p= 22502.3Torr , Inert atmosphere, Autoclave, Product distribution / selectivity Patent; TAKASAGO INTERNATIONAL CORPORATION; NARA, Hideki; YOKOZAWA, Tohru; WO2011/135753; (2011); (A1) English View in Reaxys With D-glucose, Reduced nicotinamide-adenine dinucleotide, Time= 4.5h, T= 30 °C , pH= 7, Enzymatic reaction, Kinetics Zhang, Wen-Xia; Xu, Guo-Chao; Huang, Lei; Pan, Jiang; Yu, Hui-Lei; Xu, Jian-He; Organic Letters; vol. 15; nb.

19; (2013); p. 4917 - 4919 View in Reaxys

O

HO

Cl N

H N

Rx-ID: 22228698 View in Reaxys 3/43

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Yield

Conditions & References

92 %

2.7. Preparation of 3-quinuclidinol General procedure: For Nocardia sp. WY1202, 3-quinuclidinone hydrochloride (1.6 g, 9.9 mmol) and glucose (2.7 g) were added into suspension of resting cells (8 g, wet weight) in 100 ml of phosphate buffer (100 mM, pH 8.0). The resulting mixture was incubated at 30 °C and 200 rpm for 48 h. For R. erythropolis WY1406, 3-quinuclidinone hydrochloride (1.0 g, 6.2 mmol) and glucose (3.3 g) were added into suspension of resting cells (8.5 g, wet weight) in 125 ml of phosphate buffer (100 mM, pH 8.0). The resulting mixture was incubated at 37 °C and 200 rpm for 30 h. After centrifugation at 7875×g for 20 min, the bacterial cells were washed with water and centrifuged again. The supernatantswere combined and alkalified by addition of K2CO3 (pH 12). The mixture was evaporated under vacuum, then CH2Cl2 was added to the residue. The mixture was stirred and filtrated. The filtrate was concentrated under vacuum to give crude product. Then acetone was added to the crude product, stirred and concentrated under vacuum to yield 3-quinuclidinol as white powder. 1.17 g(9.20 mmol) (R)-3-quinuclidinol (93percent yield) and 0.73 g (5.74 mmol) (S)-3-quinuclidinol (92percent yield) were obtained. The ee value were all >99percent. 1H NMR: (600 MHz, CDCl3) δppm: 1.33 (m, 1H), 1.43 (m, 1H),1.65 (m, 1H), 1.80 (m, 1H), 1.90 (m, 1H), 2.25 (br, 1H), 2.60 (m, 1H),2.65 (m, 1H), 2.74 (m, 2H), 2.89 (m, 1H), 3.12 (m, 1H), 3.85 (m, 1H).

With D-glucose in aq. phosphate buffer, Time= 48h, T= 30 °C , pH= 8, Concentration, Temperature, pH-value, Time Wang, Yu; Li, Jianjiong; Wu, Qiaqing; Zhu, Dunming; Journal of Molecular Catalysis B: Enzymatic; vol. 88; (2013); p. 14 - 19 View in Reaxys Reaction Steps: 2 1: sodium; ethanol 2: (1S)-2-oxo-bornane-10-sulfonic acid With ethanol, camphor-10-sulfonic acid, sodium Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys

OH O

O

O

HO N

HO

OH O

O

O

N

Rx-ID: 37568954 View in Reaxys 4/43 Yield 91 %

Conditions & References Preparation of (R)-3-Quinuclidinol (2a) A mixture of dibenzoyl-D(+)-tartaric acid monohydrate (150.0 g, 0.4 mol), methanol(300 ml) and 3-quinuclidinol (100.0 g, 0.79 mol) was stirred for 30 min and then heatedto 60–65C and maintained at reflux for 3 h. The suspension containing the precipitatedsolid was cooled to 0–5C and stirred for 1 h. The (R)-3-quinuclidinol dibenzoyl-D(+)tartrate salt was collected and washed with 100 ml of chilled methanol to yield 130.0 gof a white crystalline solid. It was dissolved in methanol (600 ml) at 55–60C and stirredfor 30 min. The clear solution was cooled to 0–5C and stirred for 1 h. The resultingsolid was collected, washed with chilled methanol (100 ml), dried under vacuum to affordpure (R)-3-quinuclidinol dibenzoyl-D(+)-tartrate salt (100.0 g, 83percent) as a white solid, mp.174–178C, [α]D25= +550 (c = 2, MeOH).The salt was dissolved in water (100 ml) and ethyl acetate was then added (250 ml),and the mixture was stirred for 10 min. It was then treated with conc. HCl (42 ml) to adjustthe pH to 1–2 and stirred for 1 h at 25–30C. The aqueous and organic layers were separatedand then the organic layer was saved to recover dibenzoylD(+)-tartaric acid. The aqueouslayer was treated with aqueous NaOH (23.0 g in 50 ml of water) to adjust the pH 12– 13and extracted with chloroform (4 × 200 ml). The combined chloroform extracts were driedover sodium sulfate and the solvent was evaporated completely under vacuum below 50Cto give a white solid (40.0 g). It was treated with mixture of methanol (10 ml) and acetone(90 ml) and stirred at 55–60C for 30 min. The suspension containing the solid was cooledto 0–5C and stirred for 1 h. The product was collected, washed with chilled acetone (30ml)to yield 38.0 g (91percent) of a white crystalline solid, mp. 221–224C., lit.9 220–222C. [α]D25=−43.6 (c = 3, 1N HCl)., lit.9

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[α]D25=−43.8 (c = 3, 1N HCl). 99.9percent chiral purity byHPLC. IR (cm−1): 3400, 3095, 2940, 1445, 1340; 1HNMR: δ 1.25–2.0 (5H, m), 2.50–2.90(5H, m), 3.05 (1H, m), 3.75 (1H, m, CH-OH); MS (ESI): m/z 128 (M +H).

With hydrogenchloride in water, ethyl acetate, Time= 1h, T= 25 - 30 °C , pH= 1 - 2, Resolution of racemate Chavakula, Ramadas; Mutyala, Narayana Rao; Chennupati, Srinivasa Rao; Organic Preparations and Procedures International; vol. 45; nb. 6; (2013); p. 507 - 509 View in Reaxys

HO

HO

Cl N

H N

Rx-ID: 23311127 View in Reaxys 5/43 Yield 99 %

Conditions & References 4.A : (3R)-3-Quinuclidinol Example 4A (3R)-3-Quinuclidinol (3R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution (20percent, 50 mL) at ambient temperature for 10 min.

It was then extracted with CHCl3/iPrOH (v. 10:1, 3*200 mL).

The extracts were combine, washed with brine (50 mL) and dried over MgSO4.

The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15.5 g, yield, 99percent).

1H NMR (300 MHz, CD OD) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 3 2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCl/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C Patent; Ji, Jianguo; Li, Tao; US2005/137184; (2005); (A1) English View in Reaxys

99 %

9.9A :(R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution (20percent, 50 mL) at ambient temperature for 10 minutes and extracted with CHCl3/isopropyl alcohol (10:1, 3.x.200 mL).

The extracts were combine, washed with brine (50 mL), dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (15. 5 g, yield, 99percent). 1H NMR (300 MHz, MeOH-d4) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 2.50-2.95 (m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCl/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C Patent; Ji, Jianguo; Li, Tao; US2005/137203; (2005); (A1) English View in Reaxys

99 %

4A : (3R)-3-Quinuclidinol (3R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution (20percent, 50 mL) at ambient temperature for 10 min. It was then extracted with CHCl3/PrOH (v. 10:1, 3.x.200 mL). The extracts were combine, washed with brine (50 mL) and dried over MgSO4. The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15.5 g, yield, 99percent). 1H NMR (300 MHz, CD3OD) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCl/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C Patent; Abbott Laboratories; US2005/137204; (2005); (A1) English View in Reaxys

99 %

R.1 : REFERENCE EXAMPLES; Reference Example 1; (R)-3-quinuclidinol Reference Example 1 (R)-3-quinuclidinol

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(R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution(20percent, 50 mL) at ambient temperature for 10 min.

It was then extracted with CHCl3/PrOH (v. 10:1, 3*200 mL).

The extracts were combine, washed with brine (50 mL) and dried over MgSO4.

The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15.5 g, yield, 99percent).

1H NMR (300 MHz, MeOH-d ) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 4 2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCl/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C Patent; Abbott Laboratories; US2005/137226; (2005); (A1) English View in Reaxys 99 %

R.1 : (R)-3-quinuclidinol Reference Example 1 (R)-3-quinuclidinol (R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution (20percent, 50 mL) at ambient temperature for 10 min.

It was then extracted with CHCl3/iPrOH (v. 10:1, 3*200 mL).

The extracts were combine, washed with brine (50 mL) and dried over MgSO4.

The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15.5 g, yield, 99percent).

1H NMR (300 MHz, MeOH-d ) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 4 2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (Cl/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C , Product distribution / selectivity Patent; Ji, Jianguo; Li, Tao; US2005/137398; (2005); (A1) English View in Reaxys

99 %

9A : (R)-3-Quinuclidinol Example 9A (R)-3-Quinuclidinol (R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution (20percent, 50 mL) at ambient temperature for 10 minutes and extracted with CHCO3/isopropyl alcohol (10:1, 3*200 mL).

The extracts were combine, washed with brine (50 mL), dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (15. 5 g, yield, 99percent).

1H NMR (300 MHz, MeOH-d ) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 4 2.50-2.95 (m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCl/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C , Product distribution / selectivity Patent; Abbott Laboratories; US2005/159597; (2005); (A1) English View in Reaxys

99 %

21.21A :(R)-3-Quinuclidinol hydrochloride (20 g, 12.2 mmol; Aldrich) was treated with aq. NaOH (20percent, 50 mL) at ambient temperature for 10 min, then extracted with CHCl3/iPrOH (10:1, 3.x.200 mL). The extracts were combined, washed with brine (50 mL) and dried over MgSO4. After removal of the drying agents by filtration, the filtrate was concentrated under reduced pressure to afford the title compound as white solid (15.5 g, 122 mmol, 99percent yield).

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C Patent; Schrimpf, Michael R.; Sippy, Kevin B.; Ji, Jianguo; Li, Tao; Pace, Jennifer M.; Briggs, Clark A.; US2005/171079; (2005); (A1) English View in Reaxys

99 %

4.4A :(3R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated withNaOH aqueous solution(20percent, 50 ml_) at ambient temperature for 10 min. It was then extracted with CHCI3ZPrOH (v. 10 : 1 , 3 x 200 ml_).

The extracts were combine, washed with brine (50 ml_) and dried over MgSO4. The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15. 5 g,

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yield, 99percent). 1H NMR (300 MHz, CD3OD) δ 1.36-1.50 (m, 1 H), 1.52-1.60 (m, 1 H), 1 .76-1.85 (m, 2H), 1.90-2.05 (m, 1 H), 2.50- 2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1 H), 3.82-3.88 (m, 1 H) ppm. MS (DCI/NH3): m/z 128 (M+H)+.

With sodium hydroxide in water, Time= 0.166667h, T= 20 °C , Product distribution / selectivity Patent; ABBOTT LABORATORIES; WO2006/65233; (2006); (A1) English View in Reaxys 14.1 : Step 1) Synthesis of 3-(quinuclidin-3-yloxy)benzoic acid Step 1) Synthesis of 3-(quinuclidin-3-yloxy)benzoic acid [0331][0332](R)-quinuclidin-3-ol as the HCl salt (1 g, 6.11 mmol) was dissolved in 5 mL of H2O and neutralized with NaHCO3 (0.51 g, 6.11 mmol) and the mixture was lyophilized. The residue was extracted with EtOH and the EtOH layer concentrated to afford (R)-quinuclidin-3-ol as the free base which was subsequently taken up in 30 mL of THF along with DIAD (2.4 mL, 12.22 mmol), PPh3 (1.6 g, 12.22 mmol) and methyl 3-hydroxybenzoate (0.93 g, 7.33 mmol). Reaction mixture was stirred at rt for 24 hours. It was then concentrated and partitioned between CH2Cl2 and 2N HCl. The aqueous layer was separated and washed (1×CH2Cl2). The aqueous layer was neutralized with NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated to afford methyl 3-(quinuclidin-3-yloxy)benzoate (0.85 g, 53.2percent) as crude material. The crude material was subjected to standard base hydrolysis conditions in ethanol with aqueous LiOH solution and brought to reflux. Upon completion, the reaction was cooled to rt and neutralized with 5N HCl to afford 3(quinuclidin-3-yloxy)benzoic acid.

With sodium hydrogencarbonate in water Patent; Dai, Han; Riera, Thomas V.; Stein, Ross L.; Szczepankiewicz, Bruce; US2013/102009; (2013); (A1) English View in Reaxys

O

OH

O OH

HO OH

O

O

HO

N N

Rx-ID: 23336117 View in Reaxys 6/43 Yield 90 %

Conditions & References 6.6B :The product of Example 6A (4.5 g, 11.8 mmol) in methanol (40 mL) was treated with NaOH (15percent, 40 mL) at 50° C. for 10 hours. The methanol was removed under reduced pressure and the residue was extracted with chloroform (4.x.80 mL). The extracts were combined, dried over MgSO4, dried, filtered, and the filtrate was concentrated to give the title product as a white solid (1.35 g, yield, 90percent). MS (DCl/NH3) m/z 128 (M+H)+.

With sodium hydroxide, water in methanol, Time= 10h, T= 50 °C Patent; Ji, Jianguo; Li, Tao; US2005/137203; (2005); (A1) English View in Reaxys

90 %

13B : (3R)-Quinuclidin-3-ol The product of the Example 13A (4.5 g, 11.8 mmol) was treated with Hydrolysis was NaOH (15percent, 40 mL) MeOH (40 mL)at 50° C. for 10 h. The methanol was removed under reduced pressure and the residue was extracted with chloroform (4.x.80 mL). The extracts were combined and dried over MgSO4 (anhydrous). The drying agents were filtered off and the filtrate was concentrated to give the title product as white solid (1.35 g, yield, 90percent). MS (DCl/NH3) m/z 128 (M+H)+.

With sodium hydroxide, water in methanol, Time= 10h, T= 50 °C Patent; Abbott Laboratories; US2005/137204; (2005); (A1) English View in Reaxys

90 %

R.2.B : Reference Example 2B; (R)-quinuclidin-3-ol Reference Example 2B (R)-quinuclidin-3-ol The product of Reference Example 2A (4.5 g, 11.8 mmol) in MeOH (40 mL) was treated with 15percent aqueous NaOH (40 mL) and heated at 50 ° C. for 10 hours.

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The mixture was allowed to cool to room temperature, the MeOH was removed under reduced pressure, and the residue was extracted with chloroform (4*80 mL).

The extracts were combined, dried over MgSO4 (anhydrous), filtered, and the filtrate was concentrated to give the title product as a white solid (1.35 g, yield, 90percent). MS (DCl/NH3) m/z 128 (M+H)+.

With sodium hydroxide in methanol, water, Time= 10h, T= 50 °C Patent; Abbott Laboratories; US2005/137226; (2005); (A1) English View in Reaxys 90 %

R.2.B : (R)-quinuclidin-3-ol Reference Example 2B (R)-quinuclidin-3-ol The product of Reference Example 2A (4.5 g, 11.8 mmol) in methanol (40 mL) was treated with 15percent aqueous NaOH (40 mL) and heated at 50° C. for 10 hours.

The mixture was allowed to cool to room temperature, the methanol was removed under reduced pressure, and the residue was extracted with chloroform (4*80 mL).

The extracts were combined, dried over MgSO4 (anhydrous), filtered, and the filtrate was concentrated to give the title product as a white solid (1.35 g, yield, 90percent). MS (DCl/NH3) m/z 128 (M+H)+.

With methanol, sodium hydroxide, water, Time= 10h, T= 50 °C , Product distribution / selectivity Patent; Ji, Jianguo; Li, Tao; US2005/137398; (2005); (A1) English View in Reaxys

90 %

6B : (3R)-quinuclidin-3-ol Example 6B (3R)-quinuclidin-3-ol The product of Example 6A (4.5 g, 11.8 mmol) in methanol (40 mL) was treated with NaOH (15percent, 40 mL) at 50' C. for 10 hours.

The methanol was removed under reduced pressure and the residue was extracted with chloroform (4*80 mL).

The extracts were combined, dried over MgSO4, dried, filtered, and the filtrate was concentrated to give the title product as a white solid (1.35 g, yield, 90percent). MS (DCl/NH3) m/z 128 (M+H)+.

With sodium hydroxide, water in methanol, Time= 10h, T= 50 °C , Product distribution / selectivity Patent; Abbott Laboratories; US2005/159597; (2005); (A1) English View in Reaxys

90 %

13.13B :The product of the Example 13A (4.5 g, 1 1 .8 mmol) was treated with Hydrolysis was NaOH (15percent, 40 ml_) MeOH (40 ml_)at 500C for 1 Oh. The methanol was removed under reduced pressure and the residue was extracted with chloroform (4 x 80 ml_). The extracts were combined and dried over MgSO4 (anhydrous). The drying agents were filtered off and the filtrate was concentrated to give the title product as white solid (1.35 g, yield, .90percent). MS (DCI/NH3) m/z 128 (M+H)+.

With sodium hydroxide, water in methanol, Time= 10h, T= 50 °C , Product distribution / selectivity Patent; ABBOTT LABORATORIES; WO2006/65233; (2006); (A1) English View in Reaxys

0.90 %

13.B :The product of the Example 13A (4.5 g, 11.8 mmol) was treated with Hydrolysis was NaOH (15percent, 40 mL) MeOH (40 mL) at 50 C. for 10 h. The methanol was removed under reduced pressure and the residue was extracted with chloroform (4x80 mL). The extracts were combined and dried over MgSO4 (anhydrous). The drying agents were filtered off and the filtrate was concentrated to give the title product as white solid (1.35 g, yield, 0.90percent). MS (DCl/NH3) m/z 128 (M+H)+.

With sodium hydroxide in methanol, water, Time= 10h, T= 50 °C Patent; Ji, Jianguo; Li, Tao; US2005/137184; (2005); (A1) English View in Reaxys

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O

HO

N

HO

N

N

Rx-ID: 23315484 View in Reaxys 7/43 Yield

Conditions & References 1 : Example 1 4.9mg chloro (cyclooctadiene) rhodium (I) dimer, 13.2g (S, R) -BPPFOH, AND 4.5MG (1R, 2R) -DPEN WERE DISSOLVED IN 2ML ethanol in a test tube to prepare a catalyst solution. In a separate test tube, 500mg 3-quinuclidinone was dissolved in 8mL ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200mL stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 16 hours at 30 C. Subsequently, the reaction mixture was concentrated under reduced pressure and the solvent was removed. 10mg of the resulting residue was dissolved in 1MZ methanol and the solution was subjected to gas chromatography. The results of the analysis showed 100percent conversion. The reaction residue was then converted to a butyric acid ester of 3-quinuclidinol by reacting with butyric anhydride and the product was subjected to high-performance liquid chromatography. The results of the analysis revealed that R-3-quinuclidinol was generated at an enantiomeric excess of 68. 9percent ee.

With hydrogen, (S)-1-[(R)-1',2- bis (diphenylphosphino) ferrocenyl] ethanol, 1,5-cyclooctadienerhodium (I) chloride dimer, (1R,2R)-(+)-1,2-diphenylethylenediamine in ethanol, Time= 16h, T= 30 °C , p= 26252.6Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys Comparative Example 2 4.9mg chloro (cyclooctadiene) rhodium (I) dimer, 13.9mg (S) -BINAP, AND 4.7MG (1R, 2R) -DPEN WERE DISSOLVED IN 2ML THF IN a test tube to prepare a catalyst solution. In a separate test tube, 250mg 3-quinuclidinone was dissolved in 8mL ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200mL stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 20 hours at 30 C. Subsequent steps were carried out in the same manner as in Example 1. R-3-quinuclidinol was obtained at 21percent conversion and at an enantiomeric excess of 5. 2percent ee.

With hydrogen, (S)-BINAP, 1,5-cyclooctadienerhodium (I) chloride dimer, (1R,2R)-(+)-1,2-diphenylethylenediamine in tetrahydrofuran, ethanol, Time= 20h, T= 30 °C , p= 26252.6Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 1 : Comparative Example 1 4.9mg chloro (cyclooctadiene) rhodium (I) dimer, and 13.9mg (S)-1, 1'-bisnaphtyl-2, 2 -BIS (DIPHENYLPHOSPHINE) (REFERRED TO SIMPLY AS (S) -BINAP) WERE DISSOLVED IN 2ML THF IN a test tube to prepare a catalyst solution. In a separate test tube, 250mg 3-quinuclidinone was dissolved in 8mL ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200ML stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 20 hours at 30 C. Subsequent steps were carried out in the same manner as in Example 1. R-3-quinuclidinol was obtained at 79percent conversion and at an enantiomeric excess of 5. 6percent ee.

With hydrogen, (S)-BINAP, 1,5-cyclooctadienerhodium (I) chloride dimer in tetrahydrofuran, ethanol, Time= 20h, T= 30 °C , p= 26252.6Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 2 : Example 2 The process was carried out in the same manner as in EXAMPLE 1, EXCEPT THAT (R, S) -BPPFOH AND (1S, 2S) -DPEN WERE USED IN PLACE OF (S, R) -BPPFOH AND (1R, 2R) -DPEN. S-3-QUINUCLIDINOL was obtained at 100percent conversion and at an enantiomeric excess of 68. 0percent ee.

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With hydrogen, (R)-1-[(S)-1',2- bis (diphenylphosphino) ferrocenyl] ethanol, 1,5-cyclooctadienerhodium (I) chloride dimer, (1S,2S)-(-)-1,2-diphenylethylenediamine in ethanol, Time= 16h, T= 30 °C , p= 3.5Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 6 : Comparative Example 6 6. 1MG dichloro (p-cymene) ruthenium (II) dimer, 13.2mg (R, S) -BPPFOH, AND 4.5MG (1S, 2S) -DPEN WERE DISSOLVED IN 2ML ethanol in a test tube to prepare a catalyst solution. In a separate test tube, 250mg 3-quinuclidinone and 112mg potassium t-butoxide was dissolved in 8ML ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200mL stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 3 days at 30 C. Subsequent steps were carried out in the same manner as in Example 1. S- 3-quinuclidinol was obtained at 98percent conversion and at an enantiomeric excess of 9. 0percent ee.

With hydrogen, (R)-1-[(S)-1',2- bis (diphenylphosphino) ferrocenyl] ethanol, dichloro (p-cymene) ruthenium (II) dimer, (1S,2S)-(-)-1,2-diphenylethylenediamine in ethanol, Time= 72h, T= 30 °C , p= 26252.6Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 3 : Comparative Example 3 2.5mg chloro (cyclooctadiene) rhodium (I) dimer, and 6.6MG (S, R) -BPPFOH WERE DISSOLVED IN 2ML ETHANOL IN A TEST tube to prepare a catalyst solution. In a separate test tube, 313mg 3-quinuclidinone was dissolved in 8ML ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200mL stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 16 hours at 30°C. Subsequent steps were carried out in the same manner as in Example 1. R- 3-quinuclidinol was obtained at 95percent conversion and at an enantiomeric excess of 31.6percent ee With hydrogen, (S)-1-[(R)-1',2- bis (diphenylphosphino) ferrocenyl] ethanol, 1,5-cyclooctadienerhodium (I) chloride dimer in ethanol, Time= 16h, T= 30 °C , p= 3.5Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 5 : Comparative Example 5 1MG dichloro (p-cymene) ruthenium (II) dimer, 13.2mg (S, R) -BPPFOH, AND 4.5MG (1R, 2R) -DPEN WERE DISSOLVED IN 2ML ethanol in a test tube to prepare a catalyst solution. In a separate test tube, 500mg 3-quinuclidinone was dissolved in 8mL ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200ML stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 14 hours at 30°C. Subsequent steps were carried out in the same manner as in Example 1. R-3-quinuclidinol was obtained at 8percent conversion and at an enantiomeric excess of 22. 2percent ee.

With hydrogen, (S)-1-[(R)-1',2- bis (diphenylphosphino) ferrocenyl] ethanol, dichloro (p-cymene) ruthenium (II) dimer, (1R,2R)-(+)-1,2-diphenylethylenediamine in ethanol, Time= 14h, T= 30 °C , p= 26252.6Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 4 : Comparative Example 4 4.9mg chloro (cyclooctadiene) rhodium (I) dimer, 13.2mg (S, R) -BPPFOH, AND 4.5MG (1R, 2R) -DPEN WERE DISSOLVED IN 2ML ethanol in a test tube to prepare a catalyst solution. In a separate test tube, 313mg 3-quinuclidinone and 112mg potassium t-butoxide was dissolved in 8ML ethanol to prepare a substrate solution. The two solutions were then mixed with each other and the mixture was placed in a 200mL stainless steel, pressure-resistant reaction vessel. Hydrogen was then introduced into the vessel to a hydrogen pressure of 3.5MPa and the mixture was stirred for 16 hours at 30 C. Subsequent steps were carried out in the same manner as in Example 1. R- 3quinuclidinol was obtained at 100percent conversion and at an enantiomeric excess of 12. 1percent ee

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With potassium tert-butylate, hydrogen, (S)-1-[(R)-1',2- bis (diphenylphosphino) ferrocenyl] ethanol, 1,5-cyclooctadienerhodium (I) chloride dimer, (1R,2R)-(+)-1,2-diphenylethylenediamine in ethanol, Time= 16h, T= 30 °C , p= 26252.6Torr , Product distribution / selectivity Patent; KAWAKEN FINE CHEMICALS CO., LTD.; WO2004/78686; (2004); (A1) English View in Reaxys 17 :Example 17 RuBr2-[(S,S)-xylskewphos](pica) (0.5 mg, 0.54 μmol), 3-quinuclidinone (20.37 g, 162.7 mmol), KOC(CH3)3 (219 mg, 1.9 mmol) were placed in a 500-mL glass autoclave, replaced with argon, subsequently added with ethanol (65 mL), degassed and replaced with argon.

Hydrogen was introduced until the pressure became 10 atm at 30° C., and the reaction was started.

After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 89percent ee was formed with a yield of 98percent.

With potassium tert-butylate, hydrogen, C43H54Br2N2P2Ru in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Inert atmosphere, Autoclave, Product distribution / selectivity Patent; Kanto Kagaku Kabushiki Kaisha; US2009/216019; (2009); (A1) English View in Reaxys With trans-RuCl2((S)-BINAP)((S)-ipban), potassium tert-butylate, hydrogen in isopropyl alcohol, Time= 5h, T= 25 °C , p= 15201Torr , optical yield given as percent ee, enantioselective reaction Arai, Noriyoshi; Akashi, Masaya; Sugizaki, Satoshi; Ooka, Hirohito; Inoue, Tsutomu; Ohkuma, Takeshi; Organic Letters; vol. 12; nb. 15; (2010); p. 3380 - 3383 View in Reaxys With C48H54Cl2N2O6P2Ru, potassium tert-butylate, hydrogen in isopropyl alcohol, toluene, Time= 3h, T= 60 °C , p= 51716.2Torr , Autoclave, optical yield given as percent ee, enantioselective reaction Clark, George R.; Falshaw, Andrew; Gainsford, Graeme J.; Lensink, Cornelis; Slade, Angela T.; James Wright; Journal of Coordination Chemistry; vol. 63; nb. 3; (2010); p. 373 - 393 View in Reaxys With C44H46Cl2N2O2P2Ru, potassium tert-butylate, hydrogen in isopropyl alcohol, toluene, Time= 3h, T= 60 °C , p= 51716.2Torr , Autoclave, optical yield given as percent ee, enantioselective reaction Clark, George R.; Falshaw, Andrew; Gainsford, Graeme J.; Lensink, Cornelis; Slade, Angela T.; James Wright; Journal of Coordination Chemistry; vol. 63; nb. 3; (2010); p. 373 - 393 View in Reaxys 10 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that 2-propanol was used as the solvent in place of ethanol, and (R)-3-quinuclidinol with 78percent ee was formed with a yield of 99percent.

With potassium tert-butylate, hydrogen, RuBr2[(S,S)-xylskewphos](pica) in isopropyl alcohol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 12 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that RuBr2[(S,S)-tolskewphos](pica) was used as the catalyst in place of RuBr2 [(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 78percent ee was formed with a yield of 72percent.

With potassium tert-butylate, hydrogen, RuBr2[(S,S)-tolskewphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys

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13 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that RuBr2[(S,S)-4-t-Buskewphos](pica) was used as the catalyst in place of RuBr2[(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 57percent ee was formed with a yield of 96percent.

With potassium tert-butylate, hydrogen, RuBr2[(S,S)-4-t-buskewphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 14 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that RuBr2[(S,S)-skewphos] (pica) was used as the catalyst in place of RuBr2[(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 72percent ee was formed with a yield of 92percent.

With potassium tert-butylate, hydrogen, RuBr2[(S,S)-skewphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 16 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 except that RuCl2[(S,S)-xylskewphos](bnpica) was used as the catalyst in place of RuBr2[(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 66percent ee was formed with a yield of 90percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-xylskewphos](bnpica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 26 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 25 except that 2-propanol was used as the solvent in place of ethanol, and (S)-3-quinuclidinol with 66percent ee was formed with a yield of 99percent.

With potassium tert-butylate, hydrogen, RuCl2[(R,R)-xylskewphos][(S)-ampy] in isopropyl alcohol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 29 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 25 except that RuCl2[(S,S)-xylskewphos][(R)-ampy] was used as the catalyst in place of RuCl2[(R,R)-xylskewphos][(S)-ampy], and (R)-3-quinuclidinol with 65percent ee was formed with a yield of 89percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-xylskewphos][(R)-amepy] in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 1 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9 in which the synthesis was carried out by the method described in JP (A) No. 11-289600, except that RuCl2[(S,S)-xylskewphos][(S)-daipen] synthesized by the method described in JP (A) No. 2003-252884 was used as the catalyst in place of RuBr2[(S,S)-xylskewphos] (pica), and (R)-3-quinuclidinol with 38percent ee was formed with a yield of 50percent.Comparative example 2 With potassium tert-butylate, hydrogen, RuCl2[(S,S)-xylskewphos][(S)-daipen] in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity

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Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 2 :RuCl2[(R)-binap][(R,R)-dpen] (0.21 mg, 0.0021 mmol), 3-quinuclidinone (0.526 g, 4.2 mmol), KOC(CH3)3 (9.4 mg, 0.084 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with 2-propanol (10 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 14 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 40percent ee was formed with a yield of 5percent.

With potassium tert-butylate, hydrogen, RuCl2[(R)-binap][(R,R)-dpen] in isopropyl alcohol, Time= 14h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 5 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 25, except that RuCl2[(S)-tolbinap][(S)ampy] synthesized by the method described in the Example 19 was used as the catalyst in place of RuBr2[(R,R)xylskewphos] [(S)-ampy], and (S)-3-quinuclidinol with 32percent ee was formed with a yield of 3percent.

With potassium tert-butylate, hydrogen, RuCl2[(S)-tolbinap][(S)-ampy] in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 6 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9, except that RuCl2[(S,S)-meduphos] (pica) synthesized by the method described in the Example 19 was used as the catalyst in place of RuBr2[(S,S)xylskewphos](pica), and (R)-3-quinuclidinol with 14percent ee was formed with a yield of 95percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-meduphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 8 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9, except that RuCl2[(S,S)-chiraphos] (pica) synthesized by the method described in the Example 1 was used as the catalyst in place of RuBr2[(S,S)-xylskewphos](pica), and (R)-3-quinuclidinol with 24percent ee was formed with a yield of 89percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-chiraphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 9 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 25, except that RuCl2[(S,S)-chiraphos] [(S-ampy] synthesized by the method described in the Example 19 was used as the catalyst in place of RuBr2[(R,R)xylskewphos] [(S)-ampy], and (R)-3-quinuclidinol with 7percent ee was formed with a yield of 91percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-chiraphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys

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7 :Hydrogenation of 3-quinuclidinone was carried out similar to the Example 9, except that RuCl2[(S,S)-norphos] (pica) synthesized by the method described in the Example 19 was used as the catalyst in place of RuBr2[(S,S)xylskewphos](pica), and (R)-3-quinuclidinol with 12percent ee was formed with a yield of 94percent.

With potassium tert-butylate, hydrogen, RuCl2[(S,S)-norphos](pica) in ethanol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 4 :RuCl2[(S)-binap][(R,R)-dpen] (0.2 mg, 0.002 mmol) synthesized by the method described in JP (A) No. 11-289600, 3-quinuclidinone (0.250 g, 2 mmol), KOC(CH3)3 (9 mg, 0.08 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with 2-propanol (4 mL), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 19 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 9percent ee was formed with a yield of 52percent.

With potassium tert-butylate, hydrogen, RuCl2[(S)-binap][(R,R)-dpen] in isopropyl alcohol, Time= 19h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys 3 :RuCl2[(R)-binap][(R,R)-dpen] (0.21 mg, 0.0021 mmol), 3-quinuclidinone (0.526 g, 4.2 mmol), KOC(CH3)3 (9.4 mg, 0.084 mmol) were placed in a 100-mL glass autoclave, replaced with argon, subsequently added with 2-propanol (10 mL) and B(Oi-Pr)3 (0.0079 g, 0.042 mmol), degassed and replaced with argon. Hydrogen was introduced until the pressure became 10 atm at 30° C, and the reaction was started. After the reaction solution was stirred for 14 h, the reaction pressure was decreased to a normal pressure, and the quantity and optical purity of the product 3-quinuclidinol were determined by gas chromatography of the reaction solution; the result showed that (R)-3-quinuclidinol with 47percent ee was formed with a yield of 36percent.

With tri-isopropoxy-borane, potassium tert-butylate, hydrogen, RuCl2[(R)-binap][(R,R)-dpen] in isopropyl alcohol, Time= 14h, T= 30 °C , p= 7600.51Torr , Product distribution / selectivity Patent; Nagoya Industrial Science Research Institute; Kanto Kagaku Kabushiki Kaisha; EP1867654; (2007); (A1) English View in Reaxys With (C20H12)(PC16H18)2RuCl2(C19H26N2O2), potassium tert-butylate, hydrogen in isopropyl alcohol, p= 22801.5Torr , optical yield given as percent ee, enantioselective reaction Matsumura, Kazuhiko; Arai, Noriyoshi; Hori, Kiyoto; Saito, Takao; Sayo, Noboru; Ohkuma, Takeshi; Journal of the American Chemical Society; vol. 133; nb. 28; (2011); p. 10696 - 10699 View in Reaxys With trans-[ruthenium(II)dichloride(rac-BIMIP)((R,R)-1,2-diphenylethane-1,2-diamine)], hydrogen, T= 20 °C , p= 7600.51Torr Facchetti, Giorgio; Cesarotti, Edoardo; Pellizzoni, Michela; Zerla, Daniele; Rimoldi, Isabella; European Journal of Inorganic Chemistry; nb. 27; (2012); p. 4365 - 4370 View in Reaxys With cis-[ruthenium(II)dichloride(rac-BIMIP)((R,R)-1,2-diphenylethane-1,2-diamine)] in isopropyl alcohol, T= 20 °C , p= 7600.51Torr Facchetti, Giorgio; Cesarotti, Edoardo; Pellizzoni, Michela; Zerla, Daniele; Rimoldi, Isabella; European Journal of Inorganic Chemistry; nb. 27; (2012); p. 4365 - 4370 View in Reaxys

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O

HO

Cl

H

N

N

Rx-ID: 22228699 View in Reaxys 8/43 Yield

Conditions & References

93 %

2.7. Preparation of 3-quinuclidinol General procedure: For Nocardia sp. WY1202, 3-quinuclidinone hydrochloride (1.6 g, 9.9 mmol) and glucose (2.7 g) were added into suspension of resting cells (8 g, wet weight) in 100 ml of phosphate buffer (100 mM, pH 8.0). The resulting mixture was incubated at 30 °C and 200 rpm for 48 h. For R. erythropolis WY1406, 3-quinuclidinone hydrochloride (1.0 g, 6.2 mmol) and glucose (3.3 g) were added into suspension of resting cells (8.5 g, wet weight) in 125 ml of phosphate buffer (100 mM, pH 8.0). The resulting mixture was incubated at 37 °C and 200 rpm for 30 h. After centrifugation at 7875×g for 20 min, the bacterial cells were washed with water and centrifuged again. The supernatantswere combined and alkalified by addition of K2CO3 (pH 12). The mixture was evaporated under vacuum, then CH2Cl2 was added to the residue. The mixture was stirred and filtrated. The filtrate was concentrated under vacuum to give crude product. Then acetone was added to the crude product, stirred and concentrated under vacuum to yield 3-quinuclidinol as white powder. 1.17 g(9.20 mmol) (R)-3-quinuclidinol (93percent yield) and 0.73 g (5.74 mmol) (S)-3-quinuclidinol (92percent yield) were obtained. The ee value were all >99percent. 1H NMR: (600 MHz, CDCl3) δppm: 1.33 (m, 1H), 1.43 (m, 1H),1.65 (m, 1H), 1.80 (m, 1H), 1.90 (m, 1H), 2.25 (br, 1H), 2.60 (m, 1H),2.65 (m, 1H), 2.74 (m, 2H), 2.89 (m, 1H), 3.12 (m, 1H), 3.85 (m, 1H).

With D-glucose in aq. phosphate buffer, Time= 30h, T= 37 °C , pH= 8, Concentration, Temperature, pH-value, Time Wang, Yu; Li, Jianjiong; Wu, Qiaqing; Zhu, Dunming; Journal of Molecular Catalysis B: Enzymatic; vol. 88; (2013); p. 14 - 19 View in Reaxys Reaction Steps: 2 1: sodium; ethanol 2: (1S)-2-oxo-bornane-10-sulfonic acid With ethanol, camphor-10-sulfonic acid, sodium Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys 2 :To a 100-mL autoclave were added 3-quinuclidinone hydrochloride (500 mg, 3.1 mmol), [RuCl(p-cymene) [(R)DM-SEGPHOS]]Cl (3.2 mg, 0.003 mmol), and (R)-DAIPEN (3.9 mg, 0.012 mmol). Under a nitrogen atmosphere, added were IPA (1 mL) and potassium t-butoxide/IPA solution (1.0 mol/L, 3.1 mL) were added thereto. Then, the mixture was stirred under a hydrogen pressure of 3 MPa at 30° C. for 8 hours. After analysis of the reaction solution, (R)-3-quinuclidinol was obtained at an optical purity of 86.3percent ee and a conversion ratio of 92.3percent.

With R-DAIPEN, potassium tert-butylate, hydrogen, [RuCl(p-cymene)((R)-DM-SEGPHOS)]Cl in isopropyl alcohol, Time= 8h, T= 30 °C , p= 22502.3Torr , Conversion of starting material Patent; Takasago International Corporation; US2006/47122; (2006); (A1) English View in Reaxys With Agrobacterium tumefaciens 3-quinuclidionone reductase, Reduced nicotinamide-adenine dinucleotide in aq. phosphate buffer, T= 37 °C , pH= 7.0, Enzymatic reaction, enantioselective reaction Hou, Feng; Miyakawa, Takuya; Kataoka, Michihiko; Takeshita, Daijiro; Kumashiro, Shoko; Uzura, Atsuko; Urano, Nobuyuki; Nagata, Koji; Shimizu, Sakayu; Tanokura, Masaru; Biochemical and Biophysical Research Communications; vol. 446; nb. 4; (2014); p. 911 - 915 View in Reaxys

HO

HO

N

N

Rx-ID: 25064 View in Reaxys 9/43 Yield

Conditions & References With camphor-10-sulfonic acid

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Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys Reaction Steps: 3 1: 90 percent / 4 h / Heating 3: 2.5N aq. NaOH / 1 h / 50 °C With sodium hydroxide Langlois; Meyer; Soulier; Synthetic Communications; vol. 22; nb. 13; (1992); p. 1895 - 1911 View in Reaxys Preparation of (R)-3-Quinuclidinol (2a) General procedure: A mixture of dibenzoyl-D(+)-tartaric acid monohydrate (150.0 g, 0.4 mol), methanol(300 ml) and 3-quinuclidinol (100.0 g, 0.79 mol) was stirred for 30 min and then heatedto 60–65C and maintained at reflux for 3 h.

The suspension containing the precipitatedsolid was cooled to 0–5C and stirred for 1 h. The (R)-3-quinuclidinol dibenzoyl-D(+)-tartrate salt was collected and washed with 100 ml of chilled methanol to yield 130.0 gof a white crystalline solid. It was dissolved in methanol (600 ml) at 55–60C and stirredfor 30 min. The clear solution was cooled to 0–5C and stirred for 1 h. The resultingsolid was collected, washed with chilled methanol (100 ml), dried under vacuum to affordpure (R)-3-quinuclidinol dibenzoyl-D(+)-tartrate salt (100.0 g, 83percent) as a white solid, mp.174– 178C, [α]D25=+550 (c = 2, MeOH).The salt was dissolved in water (100 ml) and ethyl acetate was then added (250 ml),and the mixture was stirred for 10 min. It was then treated with conc. HCl (42 ml) to adjustthe pH to 1–2 and stirred for 1 h at 25–30C. The aqueous and organic layers were separatedand then the organic layer was saved to recover dibenzoyl-D(+)-tartaric acid. The aqueouslayer was treated with aqueous NaOH (23.0 g in 50 ml of water) to adjust the pH 12–13and extracted with chloroform (4 × 200 ml). The combined chloroform extracts were driedover sodium sulfate and the solvent was evaporated completely under vacuum below 50Cto give a white solid (40.0 g). It was treated with mixture of methanol (10 ml) and acetone(90 ml) and stirred at 55–60C for 30 min. The suspension containing the solid was cooledto 0–5C and stirred for 1 h. The product was collected, washed with chilled acetone (30ml)to yield 38.0 g (91percent) of a white crystalline solid, mp. 221–224C., lit.9 220–222C. [α]D25=−43.6 (c = 3, 1N HCl)., lit.9 [α]D25=−43.8 (c = 3, 1N HCl). 99.9percent chiral purity byHPLC. IR (cm−1): 3400, 3095, 2940, 1445, 1340; 1HNMR: δ 1.25–2.0 (5H, m), 2.50–2.90(5H, m), 3.05 (1H, m), 3.75 (1H, m, CH-OH); MS (ESI): m/z 128 (M +H).

Stage 1: With (-)-O,O′-dibenzoyl-L-tartaric acid monohydrate in methanol, Reflux, Resolution of racemate Stage 2: With hydrogenchloride in water, ethyl acetate, T= 25 - 30 °C , pH= 1 - 2, Resolution of racemate Chavakula, Ramadas; Mutyala, Narayana Rao; Chennupati, Srinivasa Rao; Organic Preparations and Procedures International; vol. 45; nb. 6; (2013); p. 507 - 509 View in Reaxys

O

OH

HO OH

HO OH

O

HO

N

N

Rx-ID: 23336118 View in Reaxys 10/43 Yield

Conditions & References

86 %

13.D : (3S)-guinuclidin-3-ol Example 13D (3S)-guinuclidin-3-ol The product of Example 13C (7.0 g, 18.4 mmol) was treated with NaOH (aqueous) according to the procedure of Example 1B. The title product was obtained as white solid (2.0 g, yield, 86percent) MS (DCl/NH3) m/z 128 (M+H)+.

With sodium hydroxide Patent; Ji, Jianguo; Li, Tao; US2005/137184; (2005); (A1) English View in Reaxys

O

HO

N

N

Rx-ID: 73794 View in Reaxys 11/43

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Yield

Conditions & References

92.8 %

30 : 3-Hydroxyquinuclidine EXAMPLE 30 3-Hydroxyquinuclidine A 100 ml autoclave ("Magnedrive II", Autoclave Engineers Europe) fitted with a hollow-shaft high-speed stirrer (Dispersimax.(R).) was charged with 5.0 g of quinuclidin-3-one (prepared from the hydrochloride by reaction with sodium methoxide and extraction with diethyl ether), 45 ml of isopropyl alcohol and 0.25 g of catalyst (from Example 1), flushed with nitrogen and placed under a nitrogen pressure of 10 bar at room temperature.

While stirring (1500 min-1), the mixture was heated to 200° C. and held at this temperature for 8 hours.

The yield was determined as 97.3 percent by means of GC. Repeating the experiment using the same catalyst still gave a yield of 92.8 percent after a reaction time of 13 hours.

With sodium methylate Patent; Lonza AG; US6075145; (2000); (A1) English View in Reaxys

80 %

With sodium hydroxide, zinc diacetate, Time= 45h, T= 20 - 25 °C , electrochemical reduction; lead cathode Osadchenko; Tomilov; Russian Journal of Applied Chemistry; vol. 71; nb. 4; (1998); p. 719 - 721 View in Reaxys

65 %

With CuCl2·2H2O, lithium in tetrahydrofuran, mineral oil, Time= 24h, T= 20 °C , Inert atmosphere, Reagent/catalyst, stereoselective reaction Kennedy, Nicole; Cohen, Theodore; Journal of Organic Chemistry; vol. 80; nb. 16; (2015); p. 8134 - 8141 View in Reaxys With lithium aluminium tetrahydride, diethyl ether Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys With tropinone reductase I from B. candida x aurea, Enzymatic reaction, Reduction, Enzyme kinetics, Further Variations: Reagents Boswell, Henry D.; DraI ger, Birgit; McLauchlan, W. Russell; Portsteffen, Andreas; Robins, David J.; Robins, Richard J.; Walton, Nicholas J.; Phytochemistry; vol. 52; nb. 5; (1999); p. 871 - 878 View in Reaxys

O

HO

Cl N

H N

Rx-ID: 538751 View in Reaxys 12/43 Yield

Conditions & References With water, nickel, p= 36775.4 - 73550.8Torr , Hydrogenation Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys With sodium hydroxide, water, nickel, p= 88260.9Torr , Hydrogenation Grob et al.; Helvetica Chimica Acta; vol. 40; (1957); p. 2170,2176 View in Reaxys With water, platinum, p= 36775.4 - 73550.8Torr , Hydrogenation Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys With acetic acid, platinum, p= 36775.4 - 73550.8Torr , Hydrogenation Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys

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With ethanol, sodium Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys

O OH O

E

O

OH

O

N

HO

O O

N

N

Rx-ID: 25857120 View in Reaxys 13/43 Yield

Conditions & References 1 :(S)-3-Quinuclidinol free base; Potassium hydroxide (14.7 g, 262 mmol) was added in small portions during10 minutes to a mixture of 4-nitro-benzoic acid (S)-(I -aza-bicyclo[2.2.2]oct-3-yl) ester fumaric acid salt (33.3 g, 84.9 mmol) and ethanol (99percent, 500 ml). The mixture was stirred for 30 minutes at room temperature. The mixture was filtered (4-nitrobenzoic acid was separated). The filtrate was evaporated and combined and stirred with petroleumether (400 ml). The precipitated 4-nitrobenzoic acid was removed by filtration. Once again the filtrate was evaporated and combined and stirred with petroleumether (100 ml). The precipitated 4-nitrobenzoic acid was removed by filtration.

Yield 1 1.2 g (100percent).

With potassium hydroxide, ethanol, Time= 0.5h, T= 20 °C Patent; NeuroSearch A/S; WO2007/93602; (2007); (A1) English View in Reaxys 2 Cl –

O

2 Rh +

(R)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine

2 Z

N

HO

Z N

Rx-ID: 24718828 View in Reaxys 14/43 Yield 3.40 g (67 %)

Conditions & References 10 : (S)-3-Quinuclidinol EXAMPLE 10 (S)-3-Quinuclidinol In an autoclave (160 ml), a solution of 200 mg (0.41 mmol) of bis(1,5-cyclooctadiene)dirhodium(I) dichloride and 480 mg (0.81 mmol) of (R)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine (IIIb, corresponding to an educt/catalyst molar ratio of 50) in 70 ml of degassed methanol was added to 5.00 g (40 mmol) of 3-quinuclidinone under argon.

The mixture was hydrogenated for 22 hours at 75° C. and 50 bar of H2.

After evaporation of the reaction solution, the pH was adjusted to 1 with 1N hydrochloric acid and the mixture was extracted three times with 50 ml of dichloromethane.

The aqueous phase was adjusted to pH 14 with sodium hydroxide solution (30 percent) and evaporated to dryness.

The residue was extracted four times with 100 ml of dichloromethane and the combined organic extracts were dried over MgSO4 and evaporated to give 3.40 g (67 percent) of (S)-3-quinuclidinol in the form of a white crystalline solid.

Recrystallization from ethyl acetate gave 2.65 g (52 percent) of (S)-3-quinuclidinol with 7 percent ee.

Other data concerning the product was: EQU7 With H2 in methanol Patent; Lonza AG; US5744606; (1998); (A1) English View in Reaxys

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2 Cl –

2 Rh + 2 Z

(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine

Z

O

HO

Cl

H

N

N

Rx-ID: 24731290 View in Reaxys 15/43 Yield

Conditions & References 8 : (S) -3-Quinuclidinol EXAMPLE 8 (S) -3-Quinuclidinol 30.0 g (186 mmol) of 3-quinuclidinone hydrochloride, 18.3 mg (0.0371 mmol) of bis(1,5-cyclooctadiene)dirhodium(I) dichloride, 40.3 mg (0.0743 mmol) of (R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine(IIIa, corresponding to an educt/catalyst molar ratio of 2500) and 300 ml of degassed methanol were introduced into an autoclave (450 ml) under argon.

The reaction mixture was hydrogenated for 19 hours at 70° C.and 50 bar of H2.

It was evaporated and the residue was dissolved in 250 ml of 2N hydrochloric acid.

After extraction twice with 40 ml of dichloromethane, the pH was adjusted to 14 with sodium hydroxide solution (30 percent) and the mixture was evaporated.

The residue was refluxed with350 ml of ethyl acetate and filtered off hot.

The aqueous phase was separated off and the organic phase was evaporated.

Recrystallization fromethyl acetate (150 ml) gave 22.3 (94 percent) of (S)-3-quinuclidinol with 24 percent ee.

Other data concerning the product was: With H2 in hydrogenchloride, methanol, dichloromethane Patent; Lonza AG; US5744606; (1998); (A1) English View in Reaxys

O

O

HO

N

N

Rx-ID: 1807185 View in Reaxys 16/43 Yield

Conditions & References

80 %

With sodium hydroxide, Time= 1h, T= 50 °C Langlois; Meyer; Soulier; Synthetic Communications; vol. 22; nb. 13; (1992); p. 1895 - 1911 View in Reaxys

O

HO

O N

N

Rx-ID: 9422891 View in Reaxys 17/43 Yield 5.3 g

Conditions & References With sodium carbonate in methanol, Time= 16h, T= 65 °C Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys With water, sodium hydroxide in methanol, optical yield given as percent ee Brossat, Maude; Moody, Thomas S.; Taylor, Stephen J.C.; Wiffen, Jonathan W.; Tetrahedron Asymmetry; vol.

20; nb. 18; (2009); p. 2112 - 2116 View in Reaxys

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HO

HO

N

N

Rx-ID: 25065 View in Reaxys 18/43 Yield

Conditions & References With camphor-10-sulfonic acid Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys Reaction Steps: 3 1: 90 percent / 4 h / Heating 3: 80 percent / 2.5N aq. NaOH / 1 h / 50 °C With sodium hydroxide Langlois; Meyer; Soulier; Synthetic Communications; vol. 22; nb. 13; (1992); p. 1895 - 1911 View in Reaxys

O

HO

O

HO

O

O

O

N

N

N

O N

N

Rx-ID: 9384916 View in Reaxys 19/43 Yield

Conditions & References With Aspergillus melleus protease in phosphate buffer, Time= 16h, T= 25 °C , pH= 7.5, Title compound not separated from byproducts Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys With Bacillus licheniformis subtilisin, water, Time= 16h, T= 20 °C , Enzymatic reaction, optical yield given as percent ee, enantioselective reaction Brossat, Maude; Moody, Thomas S.; Taylor, Stephen J.C.; Wiffen, Jonathan W.; Tetrahedron Asymmetry; vol.

20; nb. 18; (2009); p. 2112 - 2116 View in Reaxys

O

HO

O

HO

O

O

N

N

N

N

Rx-ID: 9424195 View in Reaxys 20/43 Yield

Conditions & References With Aspergillus melleus protease in phosphate buffer, Time= 16h, T= 25 °C , pH= 7.5, Title compound not separated from byproducts Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys

O

HO O

HO

O

HO

O N

O N

N

N

Rx-ID: 9434236 View in Reaxys 21/43 Yield

Conditions & References With calcium hydroxide powder, Aspergillus melleus protease in water, Time= 24h, T= 25 °C , Title compound not separated from byproducts

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Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys

O O N

HO

N

O

O

Rx-ID: 22219409 View in Reaxys 22/43 Yield

Conditions & References Reaction Steps: 3 1: potassium; toluene / anschliessend mit konz. Salzsaeure 2: lithium alanate; diethyl ether 3: (1S)-2-oxo-bornane-10-sulfonic acid With lithium aluminium tetrahydride, diethyl ether, camphor-10-sulfonic acid, potassium, toluene Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys

O O N

HO

N

O

O

Rx-ID: 22219410 View in Reaxys 23/43 Yield

Conditions & References Reaction Steps: 3 1: potassium; toluene / anschliessend mit konz. Salzsaeure 2: lithium alanate; diethyl ether 3: (1S)-2-oxo-bornane-10-sulfonic acid With lithium aluminium tetrahydride, diethyl ether, camphor-10-sulfonic acid, potassium, toluene Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys

O O HO

N

N

O

O

Rx-ID: 22219411 View in Reaxys 24/43 Yield

Conditions & References Reaction Steps: 2 1: potassium; toluene / anschliessend mit konz. Salzsaeure 2: lithium alanate; diethyl ether With lithium aluminium tetrahydride, diethyl ether, potassium, toluene

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Sternbach; Kaiser; Journal of the American Chemical Society; vol. 74; (1952); p. 2219 View in Reaxys O

N

O

O

HO

N O

N

N+

HO

Rx-ID: 3051006 View in Reaxys 25/43 Yield

Conditions & References With potassium hydroxide, potassium chloride in water, T= 25 °C , Mechanism, Rate constant, Equilibrium constant Alunni, Sergio; Jencks, William P.; Journal of the American Chemical Society; vol. 102; nb. 6; (1980); p. 2052 2060 View in Reaxys

O

HO

HO

O

O N

N

O

O

N

O N

N

Rx-ID: 9422125 View in Reaxys 26/43 Yield

Conditions & References With Aspergillus melleus protease in phosphate buffer, Time= 16h, T= 25 °C , pH= 7.5, Title compound not separated from byproducts Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys

O

HO

O

HO

O

O

O

N

N

N

O N

N

Rx-ID: 9422902 View in Reaxys 27/43 Yield

Conditions & References With Aspergillus melleus protease in phosphate buffer, Time= 16h, T= 25 °C , pH= 7.5, Title compound not separated from byproducts Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys

O O N

HO

O

HO

O

O N

N

O N

N

Rx-ID: 9426357 View in Reaxys 28/43 Yield

Conditions & References With Aspergillus melleus protease in phosphate buffer, Time= 16h, T= 25 °C , pH= 7.5, Title compound not separated from byproducts

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Nomoto, Fumiki; Hirayama, Yoshihiko; Ikunaka, Masaya; Inoue, Toru; Otsuka, Koutaro; Tetrahedron Asymmetry; vol. 14; nb. 13; (2003); p. 1871 - 1877 View in Reaxys

HO

HO

HO

N

N

N

Rx-ID: 10443560 View in Reaxys 29/43 Yield

Conditions & References Stage 1: With acetic anhydride, Time= 3h, T= 160 °C Stage 2: With sodium hydroxide, Time= 2h, T= 75 °C Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Synthetic Communications; vol. 36; nb. 13; (2006); p. 1815 1822 View in Reaxys Resolution of racemate Chavakula, Ramadas; Rao, Mutyala Narayana; Rao, Chennupati Srinivasa; Journal of the Indian Chemical Society; vol. 90; nb. 2; (2013); p. 261 - 262 View in Reaxys

O

O

HO

N

N

Rx-ID: 1807184 View in Reaxys 30/43 Yield

Conditions & References With sodium hydroxide, Time= 1h, T= 50 °C Langlois; Meyer; Soulier; Synthetic Communications; vol. 22; nb. 13; (1992); p. 1895 - 1911 View in Reaxys

O

OH

O

HO

OH

HO

O OH

N

O

N

Rx-ID: 10264384 View in Reaxys 31/43 Yield

Conditions & References With sodium hydroxide, Time= 2h, T= 75 °C Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Journal of Chemical Research; nb. 5; (2006); p. 335 - 337 View in Reaxys

O

OH

O

HO

OH

HO

O OH

O

N

N

Rx-ID: 10264385 View in Reaxys 32/43 Yield

Conditions & References With sodium hydroxide, Time= 2h, T= 75 °C Liu, Yu-Min; Liu, He; Zhong, Bo-Hua; Liu, Ke-Liang; Journal of Chemical Research; nb. 5; (2006); p. 335 - 337 View in Reaxys

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HO

O HO OH

N

N

Rx-ID: 29040188 View in Reaxys 33/43 Yield

Conditions & References With water, sodium carbonate in hexane, optical yield given as percent ee Brossat, Maude; Moody, Thomas S.; Taylor, Stephen J.C.; Wiffen, Jonathan W.; Tetrahedron Asymmetry; vol.

20; nb. 18; (2009); p. 2112 - 2116 View in Reaxys

O O

HO

HO N

O N

Rx-ID: 9217638 View in Reaxys 34/43 Yield

Conditions & References With horse serum butyrycholinesterase, water in phosphate buffer, T= 30 °C , pH= 7.4, Enzyme kinetics Primozic, Ines; Hrenar, Tomica; Tomic, Srdanka; Meic, Zlatko; Journal of Physical Organic Chemistry; vol. 15; nb. 8; (2002); p. 608 - 614 View in Reaxys

O O

HO

HO N

O N

Rx-ID: 9217639 View in Reaxys 35/43 Yield

Conditions & References With horse serum butyrylcholinesterase, water in phosphate buffer, T= 30 °C , pH= 7.4, Enzyme kinetics Primozic, Ines; Hrenar, Tomica; Tomic, Srdanka; Meic, Zlatko; Journal of Physical Organic Chemistry; vol. 15; nb. 8; (2002); p. 608 - 614 View in Reaxys

O

O

HO

N

N

Rx-ID: 20268335 View in Reaxys 36/43 Yield

Conditions & References Reaction Steps: 2 2: 2.5N aq. NaOH / 1 h / 50 °C With sodium hydroxide Langlois; Meyer; Soulier; Synthetic Communications; vol. 22; nb. 13; (1992); p. 1895 - 1911 View in Reaxys

O

O

HO

N

N

Rx-ID: 20268336 View in Reaxys 37/43 Yield

Conditions & References Reaction Steps: 2

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2: 80 percent / 2.5N aq. NaOH / 1 h / 50 °C With sodium hydroxide Langlois; Meyer; Soulier; Synthetic Communications; vol. 22; nb. 13; (1992); p. 1895 - 1911 View in Reaxys

O

O

HO

HO

N

N

N

Rx-ID: 5039212 View in Reaxys 38/43 Yield

Conditions & References With hydrogenchloride, water, Time= 0.25h, Heating, Yield given. Yields of byproduct given. Title compound not separated from byproducts Knight, David W.; Lewis, Neil; Share, Andrew C.; Haigh, David; Journal of the Chemical Society - Perkin Transactions 1; nb. 22; (1998); p. 3673 - 3683 View in Reaxys

N+

N+ –

O

H

HO I–

N+

N

HO I–

Rx-ID: 4012688 View in Reaxys 39/43 Yield

Conditions & References in water, T= 25 °C , ionic strength 0.1 mol dm-3, Rate constant Heo, Christina K. M.; Bunting, John W.; Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999); nb. 11; (1994); p. 2279 - 2290 View in Reaxys

HO

N

Rx-ID: 5703703 View in Reaxys 40/43 Yield 86 %

Conditions & References 6.6D Patent; Ji, Jianguo; Li, Tao; US2005/137203; (2005); (A1) English View in Reaxys

86 %

13D : (3S)-Quinuclidin-3-ol Patent; Abbott Laboratories; US2005/137204; (2005); (A1) English View in Reaxys

86 %

R.2.D : Reference Example 2D; (S)-quinuclidin-3-ol Patent; Abbott Laboratories; US2005/137226; (2005); (A1) English View in Reaxys

86 %

R.2.D : (S)-quinuclidin-3-ol Patent; Ji, Jianguo; Li, Tao; US2005/137398; (2005); (A1) English View in Reaxys

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86 %

6D Patent; Abbott Laboratories; US2005/159597; (2005); (A1) English View in Reaxys

86 %

13.13D Patent; ABBOTT LABORATORIES; WO2006/65233; (2006); (A1) English View in Reaxys Ringdahl; Resul; Dahlbom; Acta Pharmaceutica Suecica; vol. 16; nb. 4 suppl; (1979); p. 281 - 283 View in Reaxys 13 : Synthesis of (S)-(-)-1-azabicyclo[2.2.2]oct-3-yl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate EXAMPLE 13 Synthesis of (S)-(-)-1-azabicyclo[2.2.2]oct-3-yl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate After a suspension of 760 mg (0.76 mmol) of (S)-(+)-3-quinuclidinol, which had been prepared in accordance with the procedure disclosed in "Eur. J. Med. Chem.", 14, 111-114 (1979), in 60 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.2 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours.

Unreacted sodium was removed and 440 mg (2.2 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 Patent; Asahi Kasei Kogyo Kabushiki Kaisha; US5200415; (1993); (A1) English View in Reaxys 13.D : (3S)-Quinuclidin-3-ol Example 13D (3S)-Quinuclidin-3-ol The product of Example 13C (7.0 g, 18.4 mmol) was treated with NaOH (aqueous) according to the procedure of Example 1B. The title product was obtained as white solid (2.0 g, yield, 86percent) MS (DCI/NH3) m/z 128 (M+H)+.

Patent; Abbott Laboratories; US2005/245531; (2005); (A1) English View in Reaxys

HO

N

Rx-ID: 5703704 View in Reaxys 41/43 Yield

Conditions & References Ringdahl; Resul; Dahlbom; Acta Pharmaceutica Suecica; vol. 16; nb. 4 suppl; (1979); p. 281 - 283 View in Reaxys 14 : Synthesis of (R)-(+)-1-azabicyclo[2.2.2]oct-3-yl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate EXAMPLE 14 Synthesis of (R)-(+)-1-azabicyclo[2.2.2]oct-3-yl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate After a suspension of 90 mg (0.71 mmol) of (R)-(-)-3-quinuclidinol, which had been prepared in accordance with the procedure disclosed in "Eur. J. Med. Chem.", 14, 111-114 (1979), in 15 ml of benzene was refluxed for 1.5 hours by using a Dean-Stark apparatus, 0.05 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2.5 hours.

Unreacted sodium was removed and 100 mg (0.49 mmol) of ethyl 7-methylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 24 hours.

Patent; Asahi Kasei Kogyo Kabushiki Kaisha; US5200415; (1993); (A1) English View in Reaxys

33.0 g (96.6 %)

9 : (R)-3-Quinuclidinol EXAMPLE 9 (R)-3-Quinuclidinol 100 g (268 mmol) of 1-(diphenylmethyl)-3-oxoquinuclidinium bromide, 66 mg (0.133 mmol) of bis(1,5-cyclooctadiene)dirhodium(I) dichloride, 145 mg (0.267 mmol) of (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butyl-

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phosphine (IIIa, mirror image; corresponding to an educt/catalyst molar ratio of 1000) and 500 ml of degassed methanol were introduced into an autoclave (1liter) under argon.

The reaction mixture was hydrogenated for 19 hours at 75° C. and 10-14 bar of H2.

The mixture was then cooled, filtered and evaporated.

The residue was taken up with 200 ml of water and100 ml of ethyl acetate and the aqueous phase was washed again twice with 50 ml of ethyl acetate.

The aqueous phase was adjusted to pH 14 with sodium hydroxide solution (30 percent) and evaporated to dryness.

The residue was extracted four times with 100 ml of dichloromethane and the combined organic extracts were dried over MgSO4 and evaporated to give 33.0 g (96.6 percent) of (R)-3-quinuclidinol in the form of a white crystalline solid.

Recrystallization from ethyl acetate gave 28.3 g (83 percent) of (R)-3-quinuclidinol with 58 percent ee.

Other data concerning the product was: Patent; Lonza AG; US5744606; (1998); (A1) English View in Reaxys 7 : EXAMPLE 7.

EXAMPLE 7.

Conversion of (R)-3-quinuclidinol hydrochloride to its free form The crystals of (R)-3-quinuclidinol hydrochloride prepared in Example 6 (25.0 g) was dissolved in 25.0 g water, then the pH of the solution was adjusted to 13.0 by adding 25percent sodium hydroxide.

Toluene (500 g) was added to the solution, and the mixture was treated by azeotropic dehydration at 60 to 70OEC under 170 Torr.

After dehydration, (R)-3-quinuclidinol was completely dissolved in toluene at 80OEC under normal pressure, and the residual inorganic salts were removed by filtration with heating at 80OEC. (R)-3-quinuclidinol crystals were obtained by cooling the toluene solution.

The resulting crystals were collected by filtration, and dried under reduced pressure.

The quantity of crystals thus obtained was 16 g.

Patent; Daicel Chemical Industries, Ltd.; EP1318200; (2003); (A2) English View in Reaxys 4.A : (3R)-3-Quinuclidinol Example 4A (3R)-3-Quinuclidinol (3R)-3-Quinuclidinol hydrochloride (Aldrich, 20 g, 12.2 mmol) was treated with NaOH aqueous solution(20percent, 50 mL) at ambient temperature for 10 min.

It was then extracted with CHCl3/PrOH (v. 10:1, 3*200 mL).

The extracts were combine, washed with brine (50 mL) and dried over MgSO4.

The drying agents were removed by filtration and the filtrates was concentrated under reduced pressure to give the title compound as white solid (15.5 g, yield, 99percent).

1H NMR (300 MHz, CD OD) δ 1.36-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.76-1.85 (m, 2H), 1.90-2.05 (m, 1H), 3 2.50-2.95(m, 5H), 3.10 (ddd, J=14.2, 8.4, 2.3 Hz, 1H), 3.82-3.88 (m, 1H) ppm. MS (DCI/NH3): m/z 128 (M+H)+.

Patent; Abbott Laboratories; US2005/245531; (2005); (A1) English View in Reaxys 13.B : (3R)-Quinuclidin-3-ol Example 13B (3R)-Quinuclidin-3-ol The product of the Example 13A (4.5 g, 11.8 mmol) was treated with Hydrolysis was NaOH (15percent, 40 mL) MeOH (40 mL)at 50° C. for 10 h.

The methanol was removed under reduced pressure and the residue was extracted with chloroform (4*80 mL).

The extracts were combined and dried over MgSO4 (anhydrous).

The drying agents were filtered off and the filtrate was concentrated to give the title product as white solid (1.35 g, yield, 90percent). MS (DCI/NH3) m/z 128 (M+H)+.

Patent; Abbott Laboratories; US2005/245531; (2005); (A1) English View in Reaxys

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HO

N

Rx-ID: 5405791 View in Reaxys 42/43 Yield

Conditions & References Micklina,E.E.; Rubtsov,M.V.; J. Gen. Chem. USSR (Engl. Transl.); vol. 30; (1960); p. 163 - 171,174 - 181 View in Reaxys Vorobeva et al.; Chemistry of Heterocyclic Compounds (New York, NY, United States); vol. 6; (1970); p. 964; Khimiya Geterotsiklicheskikh Soedinenii; vol. 6; (1970); p. 1037 View in Reaxys Palecek; Collection of Czechoslovak Chemical Communications; vol. 36; (1971); p. 2070 View in Reaxys Michlina; Rubzow; J. Gen. Chem. USSR (Engl. Transl.); vol. 30; (1960); p. 163,174; ; nb. 22632; (1960) View in Reaxys Grob; Zergenyi; Helvetica Chimica Acta; vol. 46; (1963); p. 2658,2663 View in Reaxys Levine; Diassi; Journal of Organic Chemistry; vol. 30; (1965); p. 1325 View in Reaxys Patent; Sokolovsky et al.; US3997543; (1976); ; vol. 87; nb. 23087 View in Reaxys Patent; United States Dept. of the Army; US3464997; (1969); ; vol. 72; nb. 43495u; (1970) View in Reaxys 1 : EXAMPLE 1 The R-isomer of 3-quinuclidinol was prepared by dissolving 15 g of the (+) hydrogen tartrate salt in 150 ml 2M NaOH and saturating the solution with K2 CO3.

The solution was heated for 50 min at 60° C., then extracted with CHCl3.

The extracts were dried over anhydrous Na2 SO4 and evaporated in vacuo to yield a white solid.

The solid was recrystallized in acetone to yield 5.11 g colorless crystals (m.p. 220°-221° C.; [α]D -44.41° (C 3.22, 1N HCl)).

In like manner 4 g of S-3-quinuclidinol (m.p. 220.5°-221° C.; [α]D +44.18° (C 3.22, 1N HCl)) were prepared from 12.5 g (-) hydrogen tartrate salt.

Patent; The United States of America represented by the Secretary Department of Health and Human Services; US5569447; (1996); (A1) English View in Reaxys Br

HO

HO

N

N

Rx-ID: 25362039 View in Reaxys 43/43 Yield

Conditions & References 14 : EXAMPLE 14 The 3-(4-bromophenyl)quinuclidin-3-ol was prepared as follows.

A suspension of magnesium turnings (12.0g) in anhydrous ether (500ml) was treated with a few crystals of iodine and dropwise with a solution of 1,4-dibromobenzene (118g) in anhydrous ether (300ml).

Stirring was continued for 1 hour until the Grignard reagent had completely formed.

The mixture was cooled to 5°C and a solution of 3-quinuclidone (56.2g) in tetrahydrofuran (150ml) was added portionwise.

After stirring for a further 2 hours at room temperature, the reaction mixture was poured onto ice (300g) and a saturated solution of ammonium chloride (500ml), The mixture was extracted with ether (4 x 200ml).

The ether extracts were combined, dried (MgS04), and evaporated.

The solid residue was triturated with ethyl acetate to give 3-(4-bromopenyl)quinuclidin-3-ol as a solid, m.p.

188-191°C; NMR ([CD3]2SO): 1.1-1.50(3H,m), 1.87(1H,m), 2.13(1H,m), 2.55-2.83(4H,m), 2.84-2.90(1H,d), 3.25-3.40(1H, d of d), 5.18(1H,s), and 7.4-7.55(4H,m).

Patent; Syngenta Limited; EP674635; (2001); (B1) English

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View in Reaxys

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