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Product Details of [ 185099-67-6 ]

CAS No. :185099-67-6 MDL No. :MFCD00673779
Formula : C12H19NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :MENILFUADYEXNU-UHFFFAOYSA-N
M.W : 225.28 Pubchem ID :2794767
Synonyms :

Calculated chemistry of [ 185099-67-6 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 64.29
TPSA : 46.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.49
Log Po/w (XLOGP3) : 1.19
Log Po/w (WLOGP) : 1.74
Log Po/w (MLOGP) : 1.33
Log Po/w (SILICOS-IT) : 1.28
Consensus Log Po/w : 1.61

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.79
Solubility : 3.67 mg/ml ; 0.0163 mol/l
Class : Very soluble
Log S (Ali) : -1.76
Solubility : 3.87 mg/ml ; 0.0172 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.49
Solubility : 7.29 mg/ml ; 0.0324 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.66

Safety of [ 185099-67-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 185099-67-6 ]

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

  • Upstream synthesis route of [ 185099-67-6 ]
  • Downstream synthetic route of [ 185099-67-6 ]

[ 185099-67-6 ] Synthesis Path-Upstream   1~25

  • 1
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YieldReaction ConditionsOperation in experiment
94% With dmap; triethylamine In dichloromethane at 20℃; for 16 h; (0517) 8-Azabicyclo[3.2.1]octan-3-one (5.0 g, 40 mmol) was dissolved in dichloromethane (100 mL), and di-tert-butyl dicarbonate (10.5 g, 48 mmol), triethylamine (8.1 g, 80 mmol) and 4-dimethylaminopyridine (488 mg, 4 mmol) were added. The mixture was reacted at room temperature under stirring for 16 h. After the reaction, water (100 mL) was added, and the water phase and the organic phase were separated. The organic phase was dried with anhydrous sodium sulfate, filtrated, and concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to get the title compound (8.5 g, yield: 94percent).
86% With triethylamine In dichloromethane at 20℃; for 3 h; Nortropinone (10 g, 0.062 mol) was dissolved in DCM (100 ml) and triethylamine (13.5 ml, 0.13 mol) was added followed by Boc anhydride (21.8 g, 0.10 mol). The reaction mixture was stirred at 20 0C for 3h. It was then diluted with DCM (60 ml) and washed with IN HCI, then twice with water and finally with brine. The organic layer was dried over anhydrous sodium sulphate and was concentrated under vaccum to give 15 g (86percent) of 3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. 1HNMR (300 MHz, DMSOd6) : δ 4.2 (IH, s), 2.3 (2H, brs), 2.2 (2H, d), 2.0 (2H, brs), 1.6 (2H, d), 1.4 (9H, m).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3597 - 3600
[2] Patent: US2017/112833, 2017, A1, . Location in patent: Paragraph 0516-0517
[3] Patent: WO2008/101914, 2008, A2, . Location in patent: Page/Page column 68
[4] Tetrahedron, 2002, vol. 58, # 28, p. 5669 - 5674
[5] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 14, p. 4928 - 4934
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 515 - 518
[7] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5281 - 5284
[8] Patent: WO2004/100946, 2004, A1, . Location in patent: Page 58; 59
[9] Patent: WO2004/99178, 2004, A1, . Location in patent: Page 54-55
[10] Patent: WO2006/92268, 2006, A1, . Location in patent: Page/Page column 28-29
[11] Patent: EP1726590, 2006, A1, . Location in patent: Page/Page column 43-44
  • 2
  • [ 24424-99-5 ]
  • [ 25602-68-0 ]
  • [ 185099-67-6 ]
YieldReaction ConditionsOperation in experiment
99% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane; water at 20℃; for 3 h; Step 1
3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
8-Azabicyclo[3.2.1]octan-3-one hydrochloride (nortropinone hydrochloride, 10.0 g, 62 mmol) was dissolved in 1,4-dioxane (200 mL) and water (50 mL). N,N-diisopropylethylamine (20.0 g, 155 mmol) and di-tert-butyldicarbonate (20.3 g, 93 mmol) were added, and the reaction mixture was stirred at room temperature for three hours.
The mixture was diluted with water and extracted with ethyl acetate.
The combined organic extracts were with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as an off-white solid, 14 g (99percent yield).
98% With triethylamine In ethanol at 60℃; for 3 h; Step 2
To a solution of 8-aza-bicyclo[3.2.1]octan-3-one hydrochloride (4.5 g, 0.028 mol) in 100 ML of EtOH was added carbonic acid di-tert-butyl ester (12 g, 2 eq.) and 11 ML of TEA.
The resulting mixture was heated at 60° C. for 3 h.The volatile fraction was removed and the residue was partitioned between EtOAc and water.The EtOAc layer was washed with saturated sodium chloride, dried over Na2SO4 and concentrated.Silica gel column purification with 20percent EtOAc in hexane gave 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.25 g).
95% at 20℃; for 5 h; A mixture of 8-azabicyclo [3.2.1] octan-3-one hydrochloride (648 mg, 4 mmol)Was dissolved in dichloromethane (100 mL)(1.21 g, 12 mmol) and di-tert-butyl dicarbonate (1.05 g, 4.8 mmol) were added and reacted at room temperature for 5 hours. The crude silica gel column chromatography (ethyl acetate: petroleum ether = 1: 2) To give the title compound (855 mg, 95percent yield) as a pale yellow
94.5% With triethylamine In dichloromethane at 0℃; for 3 h; To dichloromethane (10 mL) was added After dissolving nortropinone hydrochloride (50 mg, 3.093 mmol), triethylamine (1.08 mL, 7.734 mmol) was added and the reaction was carried out at 0 ° C. Then, di-tert-butyl dicarbonate (743 mg, 3.043 mmol) And the mixture was allowed to react for 3 hours. The resulting mixture was extracted with dichloromethane (40 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 5) to obtain tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (94.5percent).

Reference: [1] Patent: US2009/318493, 2009, A1, . Location in patent: Page/Page column 41-42
[2] Patent: US2004/176416, 2004, A1, . Location in patent: Page/Page column 9; 11
[3] Patent: CN104910137, 2017, B, . Location in patent: Paragraph 0417; 0419-0421
[4] Patent: KR101683061, 2016, B1, . Location in patent: Paragraph 0139-0141
[5] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1817 - 1820
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Reference: [1] Patent: US2006/100426, 2006, A1, . Location in patent: Page/Page column 18
[2] Patent: US2006/135764, 2006, A1, . Location in patent: Page/Page column 23
[3] Patent: US2006/100236, 2006, A1, . Location in patent: Page/Page column 21
[4] Patent: US2006/199839, 2006, A1, . Location in patent: Page/Page column 23
[5] Patent: US2007/117796, 2007, A1, . Location in patent: Page/Page column 7; 16
[6] Patent: US2009/23934, 2009, A1,
[7] Patent: US2004/14742, 2004, A1, . Location in patent: Page 31
[8] Patent: WO2005/80389, 2005, A1, . Location in patent: Page/Page column 39
[9] Patent: US2006/276482, 2006, A1, . Location in patent: Page/Page column 19
  • 4
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YieldReaction ConditionsOperation in experiment
85% With hydrogen In di-<i>tert</i>-butyl dicarbonate; ethyl acetate 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic Acid Tert-Butyl Ester
To a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (33 g, 0.153 mmol) in ethyl acetate (100 ml) in a par bottle is added di-tert-butyl-dicarbonate (40.15 g, 0.184 mmol) and palladium hydroxide on carbon (20percent, 20 g).
The reaction mixture is subjected to hydrogen gas (50 psi) at ambient temperature for 5 hours, filtered through a pad of celite, and the filter cake is washed with ethyl acetate.
The filtrate is concentrated in vacuo and silica gel chromatography gave the title compound (29.37 g, 85percent).
Reference: [1] Patent: US2002/119961, 2002, A1,
  • 5
  • [ 24424-99-5 ]
  • [ 532-24-1 ]
  • [ 185099-67-6 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: With carbonochloridic acid 1-chloro-ethyl ester In 1,2-dichloro-ethane at 80℃; for 5 h;
Stage #2: at 75℃; for 1.5 h;
Stage #3: With sodium hydroxide In water at 20℃;
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic Acid tert-butyl Ester
A mixture of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (50.5 g, 359 mmol) and 1-chloroethyl chloroformate (117 mL, 1.08 mol) in CH2ClCH2Cl (500 mL) was heated to 80° C. for 5 h.
The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure.
The residue was dried under high vacuum for 3 h, and was added in portions to MeOH (250 mL) over 30 min.
The mixture was stirred at 75° C. for 1 h, and allowed to cool to rt.
The solvents were removed under reduced pressure.
The residue was diluted with Et2O (250 mL), and the mixture was sonicated for 15 min.
The mixture was then stirred for 30 min, and filtered.
The precipitate was washed with Et2O (125 mL), and dried under high vacuum.
The residue was diluted with dioxane (400 mL), and the mixture was cooled to 0° C. Aq. 1M NaOH (400 mL) was added. Boc2O (82.3 g, 377 mmol) was added, and the mixture was stirred overnight while warming up to rt.
The mixture was extracted with Et2O (2*).
The combined org.
extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure.
Purification of the crude by FC (EtOAc/heptane 3:7) yielded the title compound (59.0 g, 73percent). LC-MS: tR=0.83 min.
Reference: [1] Patent: US2009/176823, 2009, A1, . Location in patent: Page/Page column 28
[2] Chemistry - A European Journal, 2013, vol. 19, # 1, p. 82 - 86
  • 6
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YieldReaction ConditionsOperation in experiment
73%
Stage #1: at 80℃; for 5 h;
Stage #2: at 20 - 75℃; for 1.5 h;
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester. A mixture of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (50.5 g, 359 mmol) and 1- chloroethyl chloroformate (117 mL, 1.08 mol) in CH2ClCH2Cl (500 mL) was heated to 80 0C for 5 h. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dried under high vacuum for 3 h, and was added in portions to MeOH (250 mL) over 30 min. The mixture was stirred at 75 0C for 1 h, and allowed to cool to rt. The solvents were removed under reduced pressure. The residue was diluted with Et2O (250 mL), and the mixture was sonicated for 15 min. The mixture was then stirred for 30 min, and filtered. The precipitate was washed with Et2O (125 mL), and dried under high vacuum. The residue was diluted with dioxane (400 mL), and the mixture was cooled to 0 0C. Aq. IM NaOH (400 mL) was added. BoC2O (82.3 g, 377 mmol) was added, and the mixture was stirred overnight while warming up to rt. The mixture was extracted with Et2O (2x). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtO Ac/heptane 3:7) yielded the title compound (59.0 g, 73percent). LC-MS: tR = 0.83 min.
Reference: [1] Patent: WO2007/88514, 2007, A1, . Location in patent: Page/Page column 75-76
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Reference: [1] Patent: US2007/167442, 2007, A1, . Location in patent: Page/Page column 45
  • 8
  • [ 532-24-1 ]
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5281 - 5284
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 515 - 518
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3597 - 3600
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1817 - 1820
[5] Tetrahedron, 2002, vol. 58, # 28, p. 5669 - 5674
[6] Patent: EP1726590, 2006, A1,
  • 9
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Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 19, p. 6095 - 6109
  • 10
  • [ 185099-67-6 ]
  • [ 194222-05-4 ]
  • [ 143557-91-9 ]
YieldReaction ConditionsOperation in experiment
25% at 20℃; Inert atmosphere Stage (i): (1 R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate Boc-nortropinone (2,5 g, 11 ,097 mmol) was dissolved in methanol (20 ml) and cooled with an ice bath. Sodium boron hydride (1.26 g, 33.291 mmol) was added slowly under protective gas. After stirring for 4 h at RT the mixture was hydrolysed with saturated sodium hydrogen carbonate solution (30 ml), the methanol was removed under vacuum and the aqueous phase extracted with ethyl acetate (3 x 50 ml). The combined organic phases were dried over magnesium sulfate and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/dichloromethane/ ammonia (25percent eq.) (400:40:40:1). The isomers were separated in this process and they were assigned by NMR analysis. Yield: endo 53percent [reacted further in stage (N)], exo 25percent
25% at 20℃; Cooling; Inert atmosphere Stage (i): (1R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3s,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylateBoc-nortropinone (2.5 g, 11.097 mmol) was dissolved in methanol (20 ml) and the solution was cooled with an ice bath. Sodium borohydride (1.26 g, 33.291 mmol) was added slowly under an inert gas. After stirring at room temperature for 4 h, hydrolysis was carried out with saturated sodium bicarbonate solution (30 ml), methanol was removed in vacuo and the aqueous phase was extracted with ethyl acetate (3.x.50 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/methylene chloride/ammonia (25 aq) (400:40:40:1). The isomers were separated by this procedure; this was assigned by NMR analysis. Yield: endo 50percent [reacted further in stage (ii)], exo 25percent
47.3% at 0 - 20℃; for 16 h; Step 2. Preparation of (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate To a stirred solution of (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxy late (3.14 g, 13.9 mmol) in MeOH (25 mL) was added sodium borohydride (0.791 g, 20.9 mmol) portion wise at 0° C. The ice bath was removed and the stirring continued for 16 hours at room temperature. The mixture was diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give the (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, endo product (1.50 g, 47.3percent) and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, exo product (1.18 g, 37.2percent) as a white solid each.Endo isomer; (1R,3R,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate1H-NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 1.69 (2H, d), 1.94-2.16 (6H, m), 4.14-4.22 (3H, m).Exo isomer; (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate1H-NMR (400 MHz, CDCl3) δ 1.47 (9H, s). 1.56-1.62 (4H, m), 1.95 (4H, m), 4.11-4.28 (3H, m).
19.7% at 20℃; for 24 h; Inert atmosphere Synthesis of bicyclic amine intermediates Bicyclic amine 1 : 3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl esterTo a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.03 g, 4.57 mmol) in EtOH (20 mL) was added NaBH4 dropwise. The mixture was stirred for 4.5 hours at room temperature under nitrogen, followed by a second addition of NaBH4 (0.36 g, 9.60 mmol). The reaction was stirred at room temperature for 17.5 hours and a last addition of NaBH4 (0.36 g, 9.60 mmol) was performed. The solution was stirred at room temperature for 2 hours, then a saturated solution of ammonium chloride was added and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over Na2S04, filtered and concentrated. The crude was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluent to yield, after evaporation, to the axial and equatorial isomers (186 mg, 17.9percent) and (205 mg, 19.7percent) as white solids. 1 H NMR (600 MHz, CDCI3): 4.57 (d, 1 H), 4.02 (m, 2H), 3.89 (d, 1 Hax), 1.89 - 1.71 (m, 5H), 1.65 - 1 .54 (m, 1 H), 1.47 - 1.28 (m, 1 1 H) and 4.60 (d, 1 H) 3.99 (m, 2H), 3.91 (m, 1 Heq), 2.18 - 2.03 (m, 2H), 1 .92 - 1 .72 (m, 4H), 1.67 - 1.56 (m, 2H), 1 .39 (s, 9H)

Reference: [1] Patent: WO2010/99938, 2010, A1, . Location in patent: Page/Page column 106
[2] Patent: US2010/152158, 2010, A1, . Location in patent: Page/Page column 30
[3] Patent: US2012/53180, 2012, A1, . Location in patent: Page/Page column 33
[4] Patent: WO2013/61305, 2013, A1, . Location in patent: Page/Page column 44
[5] Patent: EP937069, 2006, B1, . Location in patent: Page/Page column 65
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3290 - 3296
[7] Patent: US2012/225876, 2012, A1, . Location in patent: Page/Page column 32
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YieldReaction ConditionsOperation in experiment
46% at 0 - 20℃; Example 5 Preparation of Intermediate Compounds 5 A and 5B; iV-BOC-nortropinone (1.38 g, 6.13mmol) was dissolved in methanol (21 niL) and the resulting solution was cooled to 0 0C. Sodium borohydride (0.59 g, 15.68 mmol) was slowly added to the cooled solution and the resulting reaction was allowed to stir for 1 hour at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted 2 times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide a residue which was purified using flash column chromatography on silica gel (hexane/ ethyl acetate (60/40)) to provide endo-product 5A (0.63 g, 46percent) and exo-product alcohol 5B (0.64 g, 46percent).
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4111 - 4114
[2] Patent: WO2010/9195, 2010, A1, . Location in patent: Page/Page column 82
[3] Patent: WO2008/101914, 2008, A2, . Location in patent: Page/Page column 68
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YieldReaction ConditionsOperation in experiment
45% at 20℃; Cooling with ice A stirred solution of Boc-nortropinone (930 mg, 4.1 mmol) in MeOH (40 mL) was cooled in an ice bath and a NaBH4 caplet (1 g, 26.7 mmol) was added. The ice bath was allowed to melt and stirring was continued overnight at rt. The mixture was concentrated to leave a white solid which was partitioned between EtOAc (100 mL), brine (10 mL) and water (10 mL). The organic layer was separated, dried over Na2SO4 and concentrated to leave an oil (966 mg). Chromatography on a 40-g silica gel cartridge eluted with a 0-100percent EtOAc in hexanes gradient afforded two isomeric alcohols. The less polar alcohol, (1R,3r,5S)-tert-butyl 3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate, was isolated (462 mg, 45percent).
Reference: [1] Patent: WO2009/131669, 2009, A2, . Location in patent: Page/Page column 107-108
[2] Patent: US2007/179158, 2007, A1, . Location in patent: Page/Page column 22
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Reference: [1] Patent: WO2010/75273, 2010, A1, . Location in patent: Page/Page column 87-88
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3290 - 3296
  • 14
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YieldReaction ConditionsOperation in experiment
95%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -50 - -30℃; for 1 h; Inert atmosphere
Stage #2: at -30 - 25℃; for 4 h; Inert atmosphere
To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.2 mmol) in THF (21.1 mL) was added LHMDS (4.64 mL, 4.64 mmol) dropwise under N2 at-50 °C and the solution was warmed to-30 °C and stirred for 1 h. 1,1,1-trilluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.66 g, 4.64 mmol) in THF (1.0 mL) was added dropwise at-30 °C and the resulting mixture was warmed to 25 °C and stirred for 4 h. Aqueous sat. NH4CI (10 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 - 30 percent) EtOAc in hexanes to afford the title compound (2.2 g, 95 percent yield)MS (ES+) C13H18F3NO5S requires: 357, found 358 [M+H]+.
90%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.166667 h;
Stage #2: at -78 - 20℃; for 2 h;
Stage #3: With ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene for 0.0833333 h;
To a solution of N-Boc-nortropinone (6 g, 26.6 mmol) in THF (70 ml) at -78°C was added LDA (2 M in haptane/TBF/ethyl benzene, 20ml, 40 mmol) slowly and the reaction mixture was stirred for 10 min. A solution of N-phenylbis(trifluoromethanesulfonimide) (10.5 g, 29.3 mmol) in THF (48 ml) was added. The reaction mixture was stirred at -78°C for 30 min and the cooling bath was removed to warm it up to room temperature for 1.5 h until all N-Boc- nortropinone was utilized. Saturated NH4CI solution (~10 mL) was added and stirring was continued for 5 minutes before the reaction mixture was transferred to a separatory funnel using EtOAc (150 mL). The organics were then extracted with EtOAc (2 x 125 ml), and washed with water (2 x 30 ml), brine (1 x 30 ml), and dried over MgS04. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution withEtOAc/Hexanes (0-35percent) gave the desired product, tert-butyl 3-(trifluoromethylsulfonyloxy)-8- azabicyclo[3.2.1]oct-3-ene-8-carboxylate (8.5 g, 90percent).
84%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃;
Stage #2: at -78 - 20℃;
Example 108 - Preparation of Intermediate 35 The synthesis of Intermediate 35 followed the procedure of General Procedure 23 following: Intermediate 35 To a cooled solution (-78°C) of tert-butyl-3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylate (30 g, 133.3 mmol) in dry THF (300 mL) was added LiHMDS (lithium hexamethyldisilazide, 1M in THF, 146 mL, 146.7 mmol). After stirring for 30 minutes, a solution of N-phenyl-bis(trifluoromethanesulfonimide) (PhNTf2, 52 g, 146.7 mmol) in dry THF (30 mL) was added and the mixture stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated ammonium chloride solution (80 mL), and extracted with EtOAc (2 x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 3-5percent EtOAc/n-hexane, to afford tert- butyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (Intermediate 35, 40 g, yield: 84percent) as a pale yellow liquid; TLC System: 20percent ethyl acetate in hexane. Rf-0.5.
72.6%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.166667 h;
Stage #2: at 20℃; for 2.5 h;
(0519) Tert-butyl 3-oxo-8-azabicyclo[3.2.1]octan-8-carboxylate (8.5 g, 37.8 mmol) was dissolved in tetrahydrofuran (80 mL), and a solution of lithium diisopropylamide in tetrahydrofuran/ n-heptane/ ethylbenzene (28 mL, 56 mmol, 2 M) was added slowly to the system at −78° C. After stirring for 10 min, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14.8 g, 41.6 mmol) in tetrahydrofuran (50 mL) was added. After stirring for 30 min, the reaction was carried out at room temperature for 2 h. After the reaction, the mixture was concentrated to get the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to get the title compound (9.8 g, yield: 72.6percent).
63%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.916667 h;
Stage #2: at 20℃; for 18 h;
A. A 300 mL round bottom flask was charged with Compound 6a (1.0 g,4.44 mmol) and THF (30 mL). The mixture was cooled to -78 0C using a dry ice/acetone bath. A 20percent solution of LiN(SiMe3)2 in THF (5.OmL, 5.32 mmol) was added dropwise over 15 min. The mixture was stirred at- 78 0C for 40 min. A solution of PhN(SO2CF3)2 (1.6 g, 4.48 mmol) in THF (33 mL) was added dropwise via addition funnel. The mixture was stirred for 18 h with gradual warming to room temperature. The mixture was concentrated in vacuo and purified via flash chromatography (230-400 mesh silica gel 60, 95:5 hexanes:EtOAc ) to give 1.O g (63percent) of Compound 6b as a white solid. 1H NMR (300 MHz, CDCI3) δ 6.08 (d, J = 5.3 Hz, 1 H), 4.31-4.45 (m, 2 H), 3.04-3.21 (m, 2 H), 1.97-2.24 (m, 4 H), and 1.46 (s, 9 H).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at 20℃; for 3 h;
1360A. tert-Butyl 3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate
To a stirred solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 4.44 mmol) in tetrahydrofuran (10 mL) at -78° C. was added LDA (3.33 mL, 6.66 mmol) and stirred at that temperature for 30 min.
Then N,N-bis(trifluoromethylsulfonyl) aniline (1.586 g, 4.44 mmol) in tetrahydrofuran (5 mL) was added and stirred for 1 h.
The reaction mixture was warmed to room temperature and stirred for 2 h.
Reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2*100 mL).
The organic layer was washed with brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude, which was purified by silica gel flash chromatography to afford 1360A (brown oil, 1 g, 2.80 mmol, 63.0percent yield).

Reference: [1] Patent: WO2018/218197, 2018, A2, . Location in patent: Paragraph 0372; 0373
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1817 - 1820
[3] Patent: WO2012/27234, 2012, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2016/138532, 2016, A1, . Location in patent: Paragraph 0343
[5] Patent: US2017/112833, 2017, A1, . Location in patent: Paragraph 0518-0519
[6] Patent: WO2007/81995, 2007, A2, . Location in patent: Page/Page column 186
[7] Patent: US2016/289171, 2016, A1, . Location in patent: Paragraph 2867
[8] Patent: US2009/62333, 2009, A1, . Location in patent: Page/Page column 12
[9] Patent: US2009/170894, 2009, A1, . Location in patent: Page/Page column 7-8
[10] Patent: US2011/294809, 2011, A1, . Location in patent: Page/Page column 7
[11] Patent: WO2012/27240, 2012, A1, . Location in patent: Page/Page column 49
[12] Patent: WO2014/139328, 2014, A1, . Location in patent: Page/Page column 458
[13] Patent: WO2014/146490, 2014, A1, . Location in patent: Page/Page column 146; 147
  • 15
  • [ 145100-51-2 ]
  • [ 185099-67-6 ]
  • [ 185099-68-7 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃; for 3.5 h;
Part A:
Tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate
To a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1 ]octane-8-carboxylate (450 mg, 2.0 mmol) in THF (15 ml) at -78° C. was added lithium bis(trimethylsilyl)amide (1 M in THF, 2.2 ml, 2.2 mmol) and the reaction solution was stirred for 1 h.
A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (864 mg, 2.2 mmol) in THF (20 ml) was added drop wise.
The reaction mixture was stirred for another 0.5 h and allowed to warm to room temperature over 3 h and quenched with saturated sodium bicarbonate.
The reaction mixture was diluted with ethyl acetate and washed with 15percent potassium hydrogen sulfate, saturated sodium bicarbonate solution, 1 N sodium hydroxide, water and brine.
The combined organic layers were dried over magnesium sulfate and concentrated in vacuo.
Flash chromatography (silica gel, 10percent ethyl acetate/hexane) gave the product as a colorless oil (659 mg, 92percent yield)
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 6.08 (s, 1H), 4.32-4.58 (m, 2H), 2.90-3.15 (m, 1H), 2.23 (br. s, 1H), 1.98-2.07 (m, 3H), 1.67-1.78 (m, 1H), 1.57 (s, 1H), 1.45 (s, 9H).
80%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.5 h;
Stage #2: at -78 - 20℃;
3.2 3-Trifluorosulfonyl-8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]-oct-2-ene (N-Boc-nortropanone enol triflate) (104KS22).
LDA was generated by adding BuLi (20 mL, 1.68M, 32.6 mmol) to a solution of diisopropylamine (2.38 g, 32.6 mmol) in dry THF (10 mL) at -78° C. under argon.
The mixture was kept at that temperature for 30 min followed by the addition of a solution of N-Bocnortropinone (5.27 g, 23.4 mmol) in dry THF (20 mL).
The mixture was then left stirring for 1 h while maintaining the temperature at 78° C. Then a solution of 2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (10.08 g, 25.7 mmol) in dry THF (20 mL) and the mixture was slowly allowed to reach room temperature overnight and subsequently concentrated and exposed to column chromatography (SiO2; EtOAc/heptane 1:6, Rf(product)=0.31) to give the title compound (104KS22) (6.68 g, 80percent) which on prolonged standing crystallized into a white solid. 1H NMR (CDCl3) δ 1.43 (s, 9H, Boc-C3), 1.72 (m, 1H), 1.93-2.03 (m, 2H), 2.07 (d, J=16.6 Hz, 1H), 2.23 (broad m, 1H), 3.05 (broad s, 1H), 4.42 (broad m, 2H, H1+H5), 6.10 (broad s, 1H, H2).
13C NMR (CDCl3) δ 28.4 (Boc H3), 30.1 and 29.2 (rotameric), 34.7 and 34.9 (rotameric), 36.5 and 37.1 (rotameric), 51.9, (broad s), 80.5 ((CH3)3-), 118.7 (-F3, q, J=300 Hz), 124.0 (broad s, C2), 148.0 (broad s, C3), 153.9 (Boc C=O).
Reference: [1] Patent: US2006/235037, 2006, A1, . Location in patent: Page/Page column 59
[2] Patent: US2004/67931, 2004, A1, . Location in patent: Page/Page column 13
  • 16
  • [ 185099-67-6 ]
  • [ 185099-68-7 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With potassium hexamethylsilazane In toluene at -78℃; for 5.16667 h;
Stage #2: With phenylbis[(trifluoromethyl)sulfonyl]amine In tetrahydrofuran; toluene at -78 - 20℃; for 7 h;
To a solution of potassium bis(trimethylsilyl)amide (60 mL, 30 mmol, 0.5 M in toluene) at -78 °C was added a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (6.1 g, 27.2 mmol) dropwise over a 10 min period. After 5 h, a solution of N-phenyl bistrifluoromethanesulfonamide (10.2 g, 28.7 mmol) in THF (10 mL) was added. After 5 h, the cooling bath was removed, and the mixture was stirred at rt for 2 h. The mixture was partitioned between H2O and EtOAc. The two layers were separated, and the organic layer was washed with 1 M NaOH and brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 7.6 g (78percent) of the product as clear colorless oil. 1H NMR (CDCl3, 282.2 MHz) δ 6.10 (d, J = 4.2 Hz, 1H), 4.65-4.30 (m, 2H), 3.15-2.90 m, 1H), 2.35-1.90 (m, 4H), 1.85-1.50 (m, 2H), 1.46 (s, 9H); 19F NMR (CDCl3, 282.2 MHz) δ-73.20 and -73.32 (total 3F)
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1606 - 1610
  • 17
  • [ 185099-67-6 ]
  • [ 744183-20-8 ]
  • [ 207405-68-3 ]
Reference: [1] Patent: US2006/199839, 2006, A1, . Location in patent: Page/Page column 23-24
  • 18
  • [ 185099-67-6 ]
  • [ 744183-20-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 67 - 77
[2] Patent: US2012/225876, 2012, A1,
[3] Patent: WO2006/113471, 2006, A2,
  • 19
  • [ 185099-67-6 ]
  • [ 207405-68-3 ]
YieldReaction ConditionsOperation in experiment
84%
Stage #1: With titanium(IV) isopropylate; ammonia In methanol at 20℃; for 6 h;
Stage #2: With sodium tetrahydroborate In methanol at 20℃; for 3 h;
tert-butyl (1R,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate
A mixture of tert-Butyl (1S,5R)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.89 mmol) and a 7M solution of NH3 in MeOH (630 μL, 4.44 mmol) was treated with Ti(iPrO)4 (526 mL, 1.78 mmol) and stirred 6h at rt. The resulting mixture was treated with NaBH4 (30 mg, 1.33 mmol) and the mixture was stirred 3h at rt. The resulting mixture was diluted with a 2M solution of NH4OH (20 mL) and the resulting solid was filtered and washed with EtOAc (2 x 25 mL). The layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed extracted with a 1M solution of HCl in water(30 mL) and the aqueous layer was washed with EtOAc (50 mL). The aqueous layer was then treated with a 2M solution of NaOH until the pH reached 12 and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated to dryness affording the title compound (169 mg, 0.748, 84percent) as a colorless oil which was used in the next step without further purification.
70% With ammonium formate In methanol; water To a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, ~50percent wet with water; Degussa type E101NE/W) under a stream of N2 while stirring via mechanical stirrer.
After 24 and 48 hours, additional portions of ammonium formate (132 g, 2.1 mol) were added each time.
Once reaction progression ceased, as monitored by anal. HPLC, Celite.(R). (>500 g) was added and the resulting thick suspension was filtered and then the collected solid was rinsed with methanol (~500 mL).
The filtrates were combined and concentrated under reduced pressure until all methanol had been removed.
The resulting cloudy, biphasic solution was then diluted with 1M phosphoric acid to a final volume of ~1.5 to 2.0 L at pH 2 and washed with dichloromethane (3*700 mL).
The aqueous layer was basified to pH 12 using 40percent aq.
NaOH, and extracted with dichloromethane (3*700 mL).
The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation, then high-vacuum leaving 52 g (70percent) of the title intermediate, commonly N-Boc-endo-3-aminotropane, as a white to pale yellow solid.
The isomer ratio of endo to exo amine of the product was >99:1 based on 1H-NMR analysis (>96percent purity by analytical HPLC).
1H NMR (CDCl3) δ (ppm) 4.2-4.0 (broad d, 2H, CHNBoc), 3.25 (t, 1H, CHNH2), 2.1-2.05 (m, 4H), 1.9 (m, 2H), 1.4 (s, 9H, (CH3)3OCON), 1.2-1.1 (broad, 2H).
(m/z): [M+H]+ calcd for C12H22N2O2) 227.18; found, 227.2.
Analytical HPLC (isocratic method; 2:98 (A:B) to 90:10 (A:B) over 5 min): retention time=3.68 min.
70% With ammonium formate In methanol; water for 48 h; c.
Preparation of (1S,3R,5R)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic Acid tert-butyl ester
To a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, ~50percent wet with water; Degussa type E101NE/W) under a stream of N2 while stirring via mechanical stirrer.
After 24 and 48 hours, additional portions of ammonium formate (132 g, 2.1 mol) were added each time.
Once reaction progression ceased, as monitored by anal. HPLC, Celite.(R). (>500 g) was added and the resulting thick suspension was filtered and then the collected solid was rinsed with methanol (~500 mL).
The filtrates were combined and concentrated under reduced pressure until all methanol had been removed.
The resulting cloudy, biphasic solution was then diluted with 1M phosphoric acid to a final volume of ~1.5 to 2.0 L at pH 2 and washed with dichloromethane (3*700 mL).
The aqueous layer was basified to 5 pH 12 using 40percent aq.
NaOH, and extracted with dichloromethane (3*700 mL).
The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation, then high-vacuum leaving 52 g (70percent) of the title intermediate, commonly N-Boc-endo-3-aminotropane, as a white to pale yellow solid.
The isomer ratio of endo to exo amine of the product was >99 based on 1H-NMR analysis (>96percent purity by analytical HPLC).
1H NMR (CDCl3) δ (ppm) 4.2-4.0 (broad d, 2H, CHNBoc), 3.25 (t, 1H, CHNH2), 2.1-2.05 (m, 4H), 1.9 (m, 2H), 1.4 (s, 9H, (CH3)3OCON), 1.2-1.1 (broad, 2H).
(m/z): [M+H]+ calcd for C12H22N2O2 227.18; found, 227.2.
Analytical HPLC (isocratic method; 2:98 (A:B) to 90:10 (A:B) over 5 min): retention time=2.14 min.
70% With ammonium formate In methanol; water for 48 h; c.
Preparation of (1S,3R,5R)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
To a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, ~50percent wet with water; Degussa type E101NE/W) under a stream of N2 while stirring via mechanical stirrer.
After 24 and 48 hours, additional portions of ammonium formate (132g, 2.1 mol) were added each time.
Once reaction progression ceased, as monitored by anal. HPLC, Celite.(R). (>500 g) was added and the resulting thick suspension was filtered and then the collected solid was rinsed with methanol (~500 mL).
The filtrates were combined and concentrated under reduced pressure until all methanol had been removed.
The resulting cloudy, biphasic solution was then diluted with 1M phosphoric acid to a final volume of 1.5 to 2.0 L at pH 2 and washed with dichloromethane (3*700 mL).
The aqueous layer was basified to pH 12 using 40percent aq.
NaOH, and extracted with dichloromethane (3*700 mL).
The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation, then high-vacuum leaving 52 g (70percent) of the title intermediate, commonly N-Boc-endo-3-aminotropane, as a white to pale yellow solid.
The isomer ratio of endo to exo amine of the product was >99 based on 1H-NMR analysis (>96percent purity by analytical HPLC).
1H NMR (CDCl3) δ (ppm) 4.2-4.0 (broad d, 2H, CHNBoc), 3.25 (t, 1H, CHNH2), 2.1-2.05 (m, 4H), 1.9 (m, 2H), 1.4 (s, 9H, (CH3)3OCON), 1.2-1.1 (broad, 2H).
(m/z): [M+H]+ calcd for C12H22N2O2 227.18; found, 227.2.
Analytical HPLC (isocratic method; 2:98 (A:B) to 90:10 (A:B) over 5 min): retention time=2.14 min.
70% With ammonium formate In methanol; water for 72 h; To a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, 50percent wet with water; Degussa type E101NE/W) under a stream of N2 while stirring via mechanical stirrer. After 24 and 48 hours, additional portions of ammonium formate (132 g, 2.1 mol) were added each time. Once reaction progression ceased, as monitored by anal. HPLC, Celite.(R). (>500 g) was added and the resulting thick suspension was filtered and then the collected solid was rinsed with methanol (500 mL). The filtrates were combined and concentrated under reduced pressure until all methanol had been removed. The resulting cloudy, biphasic solution was then diluted with 1M phosphoric acid to a final volume of 1.5 to 2.0 L at pH 2 and washed with dichloromethane (3.x.700 mL). The aqueous layer was basified to pH 12 using 40percent aq. NaOH, and extracted with dichloromethane (3.x.700 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation, then high-vacuum leaving 52 g (70percent) of the title intermediate, commonly NBoc-endo-3-aminotropane, as a white to pale yellow solid. The isomer ratio of endo to exo amine of the product was >99 based on 1H-NMR analysis (>96percent purity by analytical HPLC). 1H NMR (CDCl3) δ (ppm) 4.2-4.0 (broad d, 2H, CHNBoc), 3.25 (t, 1H, CHNH2), 2.1-2.05 (m, 4H), 1.9 (m, 2H), 1.4 (s, 9H, (CH3)3OCON), 1.2-1.1 (broad, 2H). (m/z): [M+H]+ calcd for C12H22N2O2 227.18; found, 227.2. Analytical HPLC (isocratic method; 2:98 (A:B) to 90:10 (A:B) over 5 min): retention time=2.14 min.

Reference: [1] Patent: WO2015/58163, 2015, A2, . Location in patent: Paragraph 314
[2] Patent: US2005/228014, 2005, A1, . Location in patent: Page/Page column 16
[3] Patent: US2006/183901, 2006, A1, . Location in patent: Page/Page column 10
[4] Patent: US2006/229332, 2006, A1, . Location in patent: Page/Page column 9
[5] Patent: US2008/287486, 2008, A1, . Location in patent: Page/Page column 5
[6] Patent: WO2012/116965, 2012, A1,
[7] Patent: WO2016/191412, 2016, A1, . Location in patent: Page/Page column 34
[8] Patent: US2017/44187, 2017, A1,
[9] Patent: WO2006/113471, 2006, A2,
  • 20
  • [ 185099-67-6 ]
  • [ 207405-68-3 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With ammonium formate In methanol; water
Stage #2: With phosphoric acid In methanol; water
Stage #3: With sodium hydroxide In methanol; water
To a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, 50percent wet with water; Degussa type E101NE/W) under a stream of N2 while stirring via mechanical stirrer. After 24 and 48 hours, additional portions of ammonium formate (132 g, 2.1 mol) were added each time. Once reaction progression ceased, as monitored by anal. HPLC, Celite.(R). (>500 g) was added and the resulting thick suspension was filtered and then the collected solid was rinsed with methanol (500 mL). The filtrates were combined and concentrated under reduced pressure until all methanol had been removed. The resulting cloudy, biphasic solution was then diluted with IM phosphoric acid to a final volume of 1.5 to 2.0 L at pH 2 and washed with dichloromethane (3.x.700 mL). The aqueous layer was basified to pH 12 using 40percent aq. NaOH, and extracted with dichloromethane (3.x.700 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation, then high-vacuum leaving 52 g (70percent) of the title intermediate, commonly N-Boc-endo-3-aminotropane, as a white to pale yellow solid. The isomer ratio of endo to exo amine of the product was >99 based on 1H-NMR analysis (>96percent purity by analytical HPLC). 1H NMR (CDCl3) δ (ppm) 4.2-4.0 (broad d, 2H, CHNBoc), 3.25 (t, 1H, CHNH2), 2.1-2.05 (m, 4H), 1.9 (m, 2H), 1.4 (s, 9H, (CH3)3OCON), 1.2-1.1 (broad, 2H). (m/z): [M+H]+ calcd for C12H22N2O2) 227.18; found, 227.2. Analytical HPLC (isocratic method; 2:98 (A:B) to 90:10 (A:B) over 5 min): retention time=3.68 min.
5.60 g With palladium 10% on activated carbon; ammonium formate In methanol; water at 20℃; for 48 h; To a solution of compound ii-35a (5.00 g, 22.19 mmol) in methanol (100 mL) and water (10 mL) were added ammonium formate (13.99 g, 222 mmol) and 10percent-palladium/carbon (2.362 g) in turn. The resultant was stirred at room temperature for 2 days. Celite was used to filtrate the reaction liquid, and then the filtrate was diluted with chloroform, washed with an aqueous sodium hydroxide solution and a saturated salt solution, and dried over magnesium sulfate. Magnesium sulfate was filtrated off, and then the liquid was concentrated under reduced pressure to yield compound ii-35b (5.60 g). Compound ii-35b yielded was used as it was, without being purified, in the next reaction.The total amount of compound ii-35b yielded was dissolved in methanol (50 mL) and acetic acid (5 mL). Thereto were then added a 36percent aqueous formalin solution (8.49 mL, 111 mmol) and hydrogenated sodium triacetoxyborate (9.41 g, 44.4 mmol) in turn. The resultant was stirred at room temperature for 1 hour. To the reaction liquid was added an 8 N aqueous sodium hydroxide solution to set the pH thereof to 10. Thereafter, this liquid system was subjected to extraction with chloroform. To the organic phase was added a 0.5 N aqueous hydrochloric acid solution, and then the liquid-system was separated to two phases. Thereafter, the water phase was made into basicity, and then subjected to extraction with chloroform. The organic phase was washed with a saturated salt solution, and dried over magnesium sulfate. Magnesium sulfate was filtrated off, and then the organic phase was concentrated under reduced pressure to yield compound ii-35c (2.43 g, 43percent).1H-NMR (CDCl3) δ: 4.16 (2H, d, J = 29.04 Hz), 2.22 (6H, s), 2.12-1.59 (9H, m), 1.46 (9H, s).
Reference: [1] Patent: US2006/100426, 2006, A1, . Location in patent: Page/Page column 18-19
[2] Patent: US2006/135764, 2006, A1, . Location in patent: Page/Page column 23
[3] Patent: US2006/100236, 2006, A1, . Location in patent: Page/Page column 21
[4] Patent: US2007/117796, 2007, A1, . Location in patent: Page/Page column 7; 16
[5] Patent: EP2557082, 2013, A1, . Location in patent: Paragraph 0398; 0399
  • 21
  • [ 185099-67-6 ]
  • [ 744183-20-8 ]
  • [ 207405-68-3 ]
Reference: [1] Patent: US2006/199839, 2006, A1, . Location in patent: Page/Page column 23-24
  • 22
  • [ 185099-67-6 ]
  • [ 17366-48-2 ]
Reference: [1] Patent: US2012/53180, 2012, A1,
[2] Patent: WO2013/61305, 2013, A1,
  • 23
  • [ 185099-67-6 ]
  • [ 478837-18-2 ]
YieldReaction ConditionsOperation in experiment
92% at 20℃; for 1 h; Sodium borohydride (178 mg, 4.7 mmol) was added to a solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for one hour. The mixture was quenched with saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (3x 20 mL). The combined extract was washed with water then brine, dried over sodium sulfate, filtered and concentrated to give tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (463 mg, 92percent yield) as a mixture of endo and exo stereoisomers. GC-MS (EI) for C12H21NO3: 227 (M+).
92%
Stage #1: at 20℃; for 1 h;
Stage #2: at 20℃;
Sodium borohydride ( 178 mg, 4.7 mmol) was added to a solution of tert- butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for one hour. The mixture was quenched with saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (3x 20 mL). The combined extract was washed with water then brine, dried over sodium sulfate, filtered and concentrated to give tert-butyl 3-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylate (463 mg, 92percent yield) as a mixture of endo and exo stereoisomers. GC-MS (EI) for Ci2H2iN03: 227 (M+).
79% at 0℃; for 2.5 h; N-Boc-nortrophinone (6.3 g) was dissolved in MeOH (150 mL) and cooled to 0° C. NaBH4 was added in portions and the reaction mixture was stirred at 0° C. for 2.5 h. The reaction was quenched with water, acidified to pH3 and extracted with DCM (.x.3). The combined organic layers were dried over Na2SO4 and concentrated yielding the desired product (5.0 g, 79percent, white solid). Rf: 0.38 (EtOAc/Hx: 1/1).
Reference: [1] Patent: WO2010/138490, 2010, A1, . Location in patent: Page/Page column 33
[2] Patent: WO2012/71509, 2012, A2, . Location in patent: Page/Page column 166
[3] Patent: US2007/249672, 2007, A1, . Location in patent: Page/Page column 21
[4] Patent: WO2010/75269, 2010, A1, . Location in patent: Page/Page column 44
[5] Patent: WO2010/138487, 2010, A1, . Location in patent: Page/Page column 131
  • 24
  • [ 185099-67-6 ]
  • [ 900503-08-4 ]
Reference: [1] Patent: US2011/136833, 2011, A1,
[2] Patent: WO2012/27240, 2012, A1,
[3] Patent: WO2012/27234, 2012, A1,
[4] Patent: WO2014/139328, 2014, A1,
[5] Patent: US2017/112833, 2017, A1,
  • 25
  • [ 185099-67-6 ]
  • [ 179022-43-6 ]
Reference: [1] Patent: WO2016/138532, 2016, A1,
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