[ CAS No. 194222-05-4 ]

Name: 194222-05-4|tert-Butyl 3-exo-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate|97%
Brand: Ambeed
SKU: A195767
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Quality Control of [ 194222-05-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 194222-05-4 ]

SDS Specification

Alternatived Products of [ 194222-05-4 ]

Product Details of [ 194222-05-4 ]

CAS No. :	194222-05-4	MDL No. :	MFCD16294321
Formula :	C₁₂H₂₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SEGZJJSZYOEABC-ULKQDVFKSA-N
M.W :	227.30	Pubchem ID :	11160507
Synonyms :

Calculated chemistry of [ 194222-05-4 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.92
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	65.25
TPSA :	49.77 Å²

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) :	-6.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.64
Log Po/w (XLOGP3) :	1.6
Log Po/w (WLOGP) :	1.53
Log Po/w (MLOGP) :	1.44
Log Po/w (SILICOS-IT) :	0.69
Consensus Log Po/w :	1.58

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.06
Solubility :	1.98 mg/ml ; 0.00872 mol/l
Class :	Soluble
Log S (Ali) :	-2.26
Solubility :	1.26 mg/ml ; 0.00554 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.8
Solubility :	36.4 mg/ml ; 0.16 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.94

Safety of [ 194222-05-4 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P301+P310	UN#:	2811
Hazard Statements:	H301	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 194222-05-4 ]

* 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 [ 194222-05-4 ]
Downstream synthetic route of [ 194222-05-4 ]

[ 194222-05-4 ] Synthesis Path-Upstream 1~6

1
[ 652148-00-0 ]
[ 34619-03-9 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	With hydrogen In ethanol for 72 h;	To a solution of 8- (4-fluoro-benzyl)-8-aza-bicyclo [3.2. 1] octanol (5.02 grams, 21.4 [MMOL)] in ethanol (150 ml) in a Par bottle was added carbonic acid di- ter-butyl ester (5.5 grams, 25.2 [MMOL)] and palladium hydroxide on carbon (0.3 grams, 20percent on carbon). The reaction mixture was subject to 50 psi hydrogen gas for 3 days. The reaction mixture was then filtered through a 0. [54, UM FILTER.] Concentration of the filtrate in vacuo followed by chromatography on silica gel gave the title compounds, (cis) (1.8 grams, 37percent yield) and (trans) (2.3 grams, 47percent yield)

Reference： [1] Patent: WO2004/9588, 2004, A1, . Location in patent: Page 49

2
[ 185099-67-6 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Yield	Reaction Conditions	Operation 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

3
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[ 194222-05-4 ]
[ 143557-91-9 ]

Yield	Reaction Conditions	Operation 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

4
[ 24424-99-5 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Reference： [1] Patent: US2012/53180, 2012, A1,

5
[ 28957-72-4 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Reference： [1] Patent: US2012/53180, 2012, A1,

6
[ 194222-05-4 ]
[ 17366-48-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride In 1,4-dioxane at 20℃; for 15 h;	Step 1. Preparation of (1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ol (hydrochloride) A mixture of (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 1.32 mmol) and 4 M HCl in 1,4-dioxane (4.0 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo to give the desired product (168 mg, quant) as a white solid, which was used for the next step without further purification. LC-MS Calcd. 127.1, Found 127.90 [M+H]⁺
93%	With hydrogenchloride In 1,4-dioxane; acetonitrile at 70℃; for 1 h;	General procedure: Bicyclic amine 2: 8-Aza-bic clo[3.2.1]octan-3-olA solution of HCI (4N in dioxane, 0.82 mL, 3.27 mmol) was added to a suspension of 3- hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in acetonitrile. The mixture was stirred at 70°C for 1 hour, cooled down and concentrated. The product (138 mg, 93percent) was isolated as a hydrochloric acid salt.1 H NMR (600 MHz, CDCI₃): 9.07 - 8.49 (m, 1 H), 3.94 (m, 2H), 3.85 (m, 1 H), 1 .97 - 1.74 (m, 6H), 1 .60 (t, 2H)

Reference： [1] Patent: US2012/53180, 2012, A1, . Location in patent: Page/Page column 35
[2] Patent: WO2013/61305, 2013, A1, . Location in patent: Page/Page column 44

[ 194222-05-4 ] Synthesis Path-Downstream 1~68

1
[ 652148-00-0 ]
[ 34619-03-9 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Yield	Reaction Conditions	Operation in experiment
37%; 47%	With hydrogen;20% Pd(OH)2 on carbon; In ethanol; under 2585.81 Torr; for 72h;	To a solution of 8- (4-fluoro-benzyl)-8-aza-bicyclo [3.2. 1] octanol (5.02 grams, 21.4 [MMOL)] in ethanol (150 ml) in a Par bottle was added carbonic acid di- ter-butyl ester (5.5 grams, 25.2 [MMOL)] and palladium hydroxide on carbon (0.3 grams, 20% on carbon). The reaction mixture was subject to 50 psi hydrogen gas for 3 days. The reaction mixture was then filtered through a 0. [54, UM FILTER.] Concentration of the filtrate in vacuo followed by chromatography on silica gel gave the title compounds, (cis) (1.8 grams, 37% yield) and (trans) (2.3 grams, 47% yield)

Reference： [1]Patent: WO2004/9588,2004,A1 .Location in patent: Page 49

2
[ 371-41-5 ]
[ 194222-05-4 ]
[ 652148-01-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;	General procedure: . Following GP1, under N2 atmosphere, to a 0C. solution of <strong>[194222-05-4]tert-butyl (1R,3s,5S)-3-hydroxybicyclo[3.2.1]octane-8-carboxylate</strong> (0.251 g, 1.05 eq., 1.11 mmol), 4-fluoro-phenol (0.118 g, 1 eq., 1.06 mmol), and PPh3 (0.290 g, 1.05 eq., 1.11 mmol) in dry THF (6 mL) was added dropwise diisopropyl azodicarboxylate (0.22 mL, 1.05 eq., 1.11 mmol). The reaction crude was allowed to warm to room temperature and stirred for 16 h. Then, the mixture was quenched with HCl (10 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (90:10) to give the pure title compound as a white solid (0.174 g, 62%). UPLC-MS: tR=1.98 min (apolar method); MS (ESI) m/z calcd for C14H17FNO3 (M-tBu+2H)+: 266.1, found: 266.1.
61%	With diethyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;	To a solution of (cis)-3-hydroxy-8-aza-bicyclo [3.2. 1] octane-8-carboxylic acid tert-butyl ester (1.8 grams, 7.92 [MMOL)] in tetrahydrofuran (40 ml) was added 4- [FLUORO] phenol (1.35 grams, 12 [MMOL), TRIPHENYL] phosphine (3.15 grams, 12 [MMOL)] followed by diethyl [AZIDOCARBOXYLATE] (1.9 ml, 12 [MMOL).] The reaction was stirred overnight at ambient temperature and then concentrated in vacuo followed by chromatography on silica gel to give the title compound (1.55 grams, [61 % YIELD).]

Reference： [1]Patent: US2019/135778,2019,A1 .Location in patent: Paragraph 0155; 0111
[2]Patent: WO2004/9588,2004,A1 .Location in patent: Page 49

3
[ 185099-67-6 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Yield	Reaction Conditions	Operation in experiment
30%; 56%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 1.0 eq., 9.74 mmol) was dissolved in 5 MeOH (25 mL) and the resulting solution was cooled to 0 C. 6 Sodium borohydride (0.9 g, 2.5 eq., 24.35 mmol) was slowly added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated solution of 7 NH4Cl (15 mL) and extracted with DCM (2×15 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 60%) to give the 8 endo product (0.12 g, 56%) and exo product (0.66 g, 30%) as white solids. UPLC-MS: Rt. 1.95 min (TIC), ionization ES+ 228 [M+H]+ endo product; Rt. 1.84 min (TIC), ionization ES+ 228 [M+H]+ exo product. Endo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=2.4 Hz, 1H), 4.03-3.95 (m, 2H), 3.94-3.87 (m, 1H), 2.20-2.07 (m, 2H), 1.93-1.70 (m, 4H), 1.69-1.57 (m, 2H), 1.39 (s, 9H). Exo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=5.5 Hz, 1H), 4.09-3.97 (m, 2H), 3.95-3.83 (m, 1H), 1.79 (d, J=16.8 Hz, 4H), 1.65-1.53 (m, 2H), 1.41 (s, 9H), 1.38-1.29 (m, 2H).
25%; 53%	With methanol; sodium tetrahydroborate; 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 (25% eq.) (400:40:40:1). The isomers were separated in this process and they were assigned by NMR analysis. Yield: endo 53% [reacted further in stage (N)], exo 25%
50%; 25%	With methanol; sodium tetrahydroborate; 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 (3×50 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 50% [reacted further in stage (ii)], exo 25%

37.2%; 47.3%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 16h;	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, 47.3%) and (1R,3S,5S)-tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate, exo product (1.18 g, 37.2%) 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) delta 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) delta 1.47 (9H, s). 1.56-1.62 (4H, m), 1.95 (4H, m), 4.11-4.28 (3H, m).
19.7%; 17.9%	With sodium tetrahydroborate; ethanol; at 20℃; for 24h;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, 17.9%) and (205 mg, 19.7%) 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)
	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 3h;	To a solution of N-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane (20 g, 93 mmol) in EtOAc (220 mL) were added t-BOC anhydride (24.2 g, 112 mmol) and 20% Pd(OH)2/C (4 g). The mixture was hydrogenolyzed at 38.5 psi. After the reaction was complete, catalyst was filtered and filtrate was evaporated to give a solid crude product (21 g). The crude material (19 g, 84 mmol) was dissolved in CH3OH (100 mL) and NaBH4 (4.8 g, 127 mmol) was added portion wise at 0 C. The reaction was stirred at 0 C and gradually warmed to RT. After 3 h, the reaction was quenched with acetic acid (8 mL) and CH3OH was evaporated. The residue was redissolved in CH2Cl2 (300 mL) and washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and evaporated to give a solid. The crude material was purified by flash chromatography (400 g silica gel), eluting with 25% EtOAc/ hexane to give exo compound 3 (9.8 g, 43.1 mmol, 51.4%) and endo compound 4 (5 g, 22 mmol, 26.2%) as white solids.
		An ice-cold mixture of Compound II (3.0 g), calcium chloride (1.78 g) and methanol (66 mL) was stirred for 30 minutes, and thereto was added portionwise sodium borohydride. The mixture was stirred for one hour, and water was added to the reaction mixture, and concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=80/20 to 40/60) to give the title compound III (840 mg) and the title compound IV (2.0 g).Compound III1H NMR (CDCl3) delta1.43 (s, 9H), 1.53 (m, 1H), 1.66-1.69 (m, 2H), 1.89-2.15 (m, 6H), 4.01-4.18 (m, 3H)Compound IV1H NMR (CDCl3) delta1.45 (s, 9H), 1.52-1.61 (m, 5H), 1.91-2.1.96 (m, 4H), 4.04-4.12 (m, 1H), 4.21 (m, 2H)

Reference： [1]Patent: US2019/135802,2019,A1 .Location in patent: Paragraph 0025-0029
[2]Patent: WO2010/99938,2010,A1 .Location in patent: Page/Page column 106
[3]Patent: US2010/152158,2010,A1 .Location in patent: Page/Page column 30
[4]Patent: US2012/53180,2012,A1 .Location in patent: Page/Page column 33
[5]Patent: WO2013/61305,2013,A1 .Location in patent: Page/Page column 44
[6]Patent: EP937069,2006,B1 .Location in patent: Page/Page column 65
[7]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3290 - 3296
[8]Patent: US2012/225876,2012,A1 .Location in patent: Page/Page column 32

Yield	Reaction Conditions	Operation in experiment
		The crude material was purified by flash chromatography (400 g silica gel), eluding with 25% EtOAc/hexane to give exo compound 3 (9.8 g, 43.1 mmol, 51.4%) and endo compound 4 (5 g, 22 mmol, 26.2%) as white solids.

5
[ 194222-05-4 ]
NaBH₃ CN [ No CAS ]
[ 100-46-9 ]
[ 944123-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	In CF3 CH2 OH; ethyl acetate;	EXAMPLE 65 1,1-Dimethylethyl 3-[(phenylmethyl)amino]-8-azabicyclo[3.2.1]octane-8-carboxylate (exo and endo products) STR236 To a solution of compound 2 from Example 52 (10 g, 44.4 mmol) in CF3 CH2 OH (50 mL) was added benzylamine (4.8 g, 44.4 mmol) and NaBH3 CN (5.7 g, 62.84 mmol). The mixture was stirred at RT for 20 h. After completion of the reaction, solvent was removed and the residue was redissolved in EtOAc (200 mL), washed with saturated NaHCO3 solution (150 mL, 2*), dried (Na2 SO4), filtered and concentrated to give the product as an oil. The crude material was purified by flash chromatography on silica gel (300 g), eluding with 2% [(NH4 OH:CH3 OH) (1:9)]/98% CH2 Cl2 to give endo product (3.6 g, 11.73 mmol, 25.6%) as a white solid, FAB MS [M+1]+ 314.4 and exo product (3.6 g, 11.73 mmol, 25.6%) as a clear oil, FAB MS [M+1]+ 313.3.

Reference： [1]Patent: US5968929,1999,A

6
[ 24424-99-5 ]
[ 7087-68-5 ]
[ 194222-05-4 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	Step 2 To a suspension of compound 2 (3.93 g, 29.8 mmol) (obtained from two batches) in CH2 Cl2 (40 mL) was added Hunig's base (5.6 g, 29.8 mmol). To this solution of compound 2 was slowly added a solution of t-BOC anhydride (6.5 g, 29.8 mmol) in CH2 Cl2 (30 mL) at RT under N2. After stirring at RT overnight, the reaction was washed with water (100 mL, 2*), dried with Na2 SO4, and filtered. The filtrate was evaporated to dryness under vacuum to give compound 3 (5.5 g, 28.17 mmol, 94.5%) as a brown liquid. FAB MS [M+1]+ 196.4.

Reference： [1]Patent: US5968929,1999,A

7
[ 194222-05-4 ]
[ 124-63-0 ]
[ 939789-42-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2.5h;	To a mixture of ferf -butyl 3-exo-hydroxy-8-azabicyclo[3.2.i]octane-8-carboxylate (3.0 g, 13.2 mmol, 1.0 equiv.) and Lambda ,Lambda -diisopropylethylamine (3.0 mL, 17.2 mmol, 1.3 equiv.) in dichloromethane (66 mL) was added methanesulfonyl chloride (1.1 mL, 14.5 mmol, 1.1 equiv.). The reaction mixture was stirred for 2.5 hours at room temperature and then the solution was washed twice with water, once with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (4.08 g, 13.2 mmol, quantitative yield). (0879) NMR (CDCI3) : delta = 5·theta8 (m, 1 H), 4.28 (br s, 2 H), 3.00 (s, 3 H), 2.10 (br d, 4 H), 1.82 (br s, 2 H), 1.63 (d, 2 H) and 1.44 (s, 9 H).
97%	With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	A solution of 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid terf-butyl ester (230mg, LOmmol) and triethylamine (0.148ml_, 1.1 mmol) in DCM (4ml_) was stirred under a nitrogen atmosphere and cooled to 0C. Methanesulfonyl chloride (0.082ml_, 1.1 mmol) was added dropwise to the reaction mixture, which was allowed to rise to ambient temperature. The reaction mixture was stirred for a further 18h. The reaction mixture was evaporated in vacuo and the residue purified by chromatography on silica gel. Elution with DCM with a gradient to 2:98 acetone:DCM afforded 3-exo-methanesulfonyloxy-8- azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (298mg, 0.98mmol, 97%).
	With triethylamine; In tetrahydrofuran; at 0℃; for 1h;	To a tetrahydrofuran (500 mL) solution of 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (49.37 g) were added triethylamine (45.4 mL) and methanesulfonyl chloride (20.17 mL) at 0C, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel flash chromatography (hexane/ethyl acetate = 4:1 to 0:1) to give the title compound as a colorless solid (59.44 g). 1H-NMR (400 MHz, CDCl3, deltappm): 1.48 (9H, s), 1.53-1.62 (2H, m), 1.64-1.72 (2H, m), 1.78-2.18 (5H, m), 3.01 (3H, s), 4.18-4.37 (1H, m), 5.02 (1H, m)

	With triethylamine; In Dichlorodifluoromethane; at 0 - 20℃;	Example 26Preparation of Compound 37260 26E 37 Step A - Synthesis of Compound 26BCompound 26A (0.64 g, 2.8 mmol, prepared as described in US Patent No. 968929) and Et3N (0.47 mL, 3.4 mmol) were combined in CH2CI2 (10 mL). The solution was cooled to 0 C, and methanesulfonyl chloride (0.26 mL, 3.3 mmol) was added. The reaction was allowed to stir at 0 C for 1 hour, then was warmed to warm to room temperature, and stirred for an additional 2 hours. The reaction mixture was diluted with ether (20 mL) was added and the resulting solution was filtered. The filtrate was concentrated in vacuo and the resulting residue was taken up in DMF (15 mL). To the resulting solution was added NaN3 (0.37 g, 5.6 mmol) and the mixture was heated to 80 C and allowed to stir at this temperature for 18 hours, then cooled to room temperature and partitioned between EtOAc and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide Compound 26B, which was used without further purification.
	With triethylamine; In dichloromethane; at 20℃;Cooling with ice;	To an ice-cold solution of Compound I (6.02 g) in dichloromethane (30 mL) were added triethylamine (10 mL), methanesulfonyl chloride (2.7 mL), and then the mixture was allowed to warm up to room temperature and was stirred overnight. The reaction mixture was diluted with brine, extracted with ethyl acetate, dehydrated with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give Compound II (7.5 g).

Reference： [1]Patent: WO2019/8025,2019,A1 .Location in patent: Page/Page column 137; 138
[2]Patent: WO2007/63071,2007,A1 .Location in patent: Page/Page column 16
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 4111 - 4114
[4]Patent: EP2204368,2010,A1 .Location in patent: Page/Page column 16
[5]Patent: WO2010/75273,2010,A1 .Location in patent: Page/Page column 108-109
[6]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5405 - 5410
[7]Patent: US2012/225876,2012,A1 .Location in patent: Page/Page column 35-36
[8]Journal of Medicinal Chemistry,2014,vol. 57,p. 7499 - 7508

8
[ 194222-05-4 ]
[ 179898-34-1 ]
[ 945565-37-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	3-Bromo-5-fluorobenzonitrile (8.62g, 43mmol) was dissolved in DMF (2OmL). Sodium hydride (2.46g, 62mmol) was added portionwise to the stirred solution under an atmosphere of nitrogen. Exo tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (7.Og, 31 mmol) was then added and then reaction was stirred at ambient temperature for15 30 minutes. The reaction was quenched with water then the solution was extracted with DCM. The organic layers were combined and dried over MgSO4. The organic layer was concentrated to leave a brown gum, which was dissolved in DCM (5OmL) and washed with water (3x40mL). The organic layer was combined and dried over MgSO4. The organic layer was concentrated in vacuo to leave a brown gum. The crude material was then20 purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded exo terf-butyl 3-(3-bromo-5-cyanophenoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (7.23g, 17.8mmol, 58%) as a pale yellow solid.

Reference： [1]Patent: WO2007/63071,2007,A1 .Location in patent: Page/Page column 54
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 271 - 275

9
[ 194222-05-4 ]
[ 5111-66-0 ]
exo-3-(6-methoxy-naphthalen-2-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triphenylphosphine; diethylazodicarboxylate; In 1,4-dioxane; at 15 - 32℃; for 15h;	exo-3-(6-Methoxy-naphthalen-2-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ferf-butyl ester Triphenylphosphine (13.8 g, 52.8 mmol) was solved in dioxane (100 ml) and cooled to 8C. Diethylazodicarboxylate (9.2 g, 52.8 mmol) was added to the mixture below 15C,15 followed by stirring for 15 minutes. endo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8- carboxylic acid te/f-butyl ester (10.0 g, 44.0 mmol) and 6-methoxy-2-naphthol (8.4 g, 48.4 mmol) was added to the mixture. The temperature raised to 32C due to an exothermic reaction. The mixture was allowed to stir for 15 h at room temperature. Hydrochloric acid (300 ml, 1 M) was added followed by extraction with diethylether (2 x20 200 ml). The mixture was dried and evaporated. Chromatography on silica gel with dichloromethane and 5% methanol as solvent. The crude product was solved in diethylether (500 ml) and washed with aqueous sodium hydroxide (3 x 200 ml, 1 M). The product was dried and evaporated. Yield 11.0 g (65%).

Reference： [1]Patent: WO2007/54531,2007,A1 .Location in patent: Page/Page column 14

10
[ 68963-75-7 ]
[ 194222-05-4 ]
[ 939789-43-2 ]

Yield	Reaction Conditions	Operation in experiment
82%	4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium; In tetrahydrofuran; for 16.0h;	2,4-Dichloro-6-hydroxypyridine (696mg, 4.2mmol), 3-exo-hydroxy-8- azabicyclo[3.2.1]octane-8-carboxylic acid terf-butyl ester (965mg, 4.2mmol) and (4,4- Dimethyl-1 ,1-dioxido-1 ,2,5-thiadiazolidin-2-yl)triphenylphosphonium (4.31g, 10.5mmol) in THF (2OmL) were stirred for 16h. Ethyl acetate (5OmL) and water (2OmL) were added and the organic and aqueous layers were separated. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 10:90 ethyl acetate:heptane afforded 3-exo-(4,6-dichloropyridin-2- yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid terf-butyl ester (1.29g, 3.6mmol, 82percent). M.S. (ESI) m/z: 373,375 [M+H]+.

Reference： [1]Patent: WO2007/63071,2007,A1 .Location in patent: Page/Page column 46-47

11
[ 194222-05-4 ]
[ 937734-13-9 ]
[ 937734-26-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 168h;	Step 4: 3-endo-3-[2-(Morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indol-5-yloxy]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a cooled (ice-bath) mixture of [5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 1, step 4, 200 mg, 1.0 eq.), 3-exo-<strong>[194222-05-4]3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester</strong> (166 mg, 1.2 eq.) and triphenylphosphine (200 mg, 1.25 eq.) in tetrahydrofuran (5 mL) was added a solution of diethylazodicarboxylate in tetrahydrofuran (1 mL) dropwise. The yellow mixture was stirred 1 week at room temperature. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel eluding with 19:1 chloroform/tert-butylmethyl ether to yield 212 mg (64%) of the title product as pale yellow foam. MS (m/e) 538.5 (M+H)+.

Reference： [1]Patent: US2007/123525,2007,A1 .Location in patent: Page/Page column 21

12
endo-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]
[ 194222-05-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydroxide; ethanol; at 20℃; for 72h;	endo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester A mixture of endo-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid te/f-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g 199 mmol) and ethanol (99%, 5 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evaporated. The product was triturated with petroleum. Yield 30.0 g (80%). Mp 139.5- 140.80C.

Reference： [1]Patent: WO2007/54531,2007,A1 .Location in patent: Page/Page column 14

13
[ 937734-25-3 ]
[ 194222-05-4 ]

Yield	Reaction Conditions	Operation in experiment
99%		Step 3: 3-exo-3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester To a solution of 3-exo-3-(4-nitro-benzoyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (575 mg, 1.0 eq.) in tetrahydrofuran was added a solution of lithium hydroxide hydrate (77 mg, 1.2 eq.) in water (1 mL). The heterogeneous mixture was stirred overnight at room temperature and poured into aqueous potassium dihydrogen phosphate (1M). The organics were extracted with ethyl acetate, the combined organic phases washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The solid residue was purified by column chromatography on silica gel eluding with 4:1 ethyl acetate/heptane eluant to yield 345 mg (99%) of the title product as white solid. MS (m/e) 227.2 (M+)
89%	With sodium hydroxide; water; In tetrahydrofuran; at 20℃; for 72h;	Diethylazodicarboxylate (1.74ml_, 1 1 mmol) was added dropwise to a solution of 3-endo- hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.09g, 9.2mmol), <n="17"/>triphenylphosphine (2.89g, 11 mmol) and 4-nitrobenzoic acid (1.69g, lOmmol) in THF (25mL). The reaction mixture was stirred under a nitrogen atmosphere for 18h at ambient temperature. Volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel. Elution with DCM afforded the ester as a pale yellow solid (2.6g, 6.9mmol, 75%). 4N sodium hydroxide (aq) (3.6ml_, 14mmol) was added to a solution of the ester in THF (25ml_) and the reaction mixture stirred at ambient temperature for 3 days. Diethyl ether (35ml_) and water (1OmL) were added to the reaction mixture. 2N sodium hydroxide (aq) solution was added to the organic layer which was removed, dried over NaaSCu and the solvent evaporated in vacuo. The crude material was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanokDCM afforded 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester (1.4g, 6.2mmol, 89%) M.S. (ESI) (m/z): 228[M+H]+
	With lithium hydroxide; water; In tetrahydrofuran; at 20℃; for 5h;	tert-butyl 3beta-hydroxy-8-azabicyclof3.2.1]octane-8-carboxylate[0340] A reaction flask was charged with 3alpha-hydroxy-8-azabicyclo[3.2.1]octane- 8-carboxylic acid tert-butyl ester (3.94 g, 17.3 mmol), 4-nitrobenzoic acid (1 1.3 g, 67.8 mmol), PPh3 (18.8 g, 68.6 mmol) in dry THF (140 mL) and cooled to 0 0C. Diisopropylazodicarboxylate (13.8 mL, 70.1 mmol) was added drop wise over 15 min. After 1 h cooling was removed and the mixture stirred at rt overnight. The mixture was then stirred at 45 0C for 5 h followed by cooling to rt and the mixture was diluted with diethylether and washed with several portions of saturated aqueous NaHCO3. The combined aqueous layers were extracted with diethyl ether and the combined organic layers dried over Na2SO4 and evaporated to dryness. The resulting gum was stirred with diethyl ether (80 mL) while n- heptane (40 mL) was added slowly to cause crystallization. The mixture was filtered and the filter cake extracted with diethyl ethern-heptane 1 :1 (300 mL). The filtrate was adsorbed onto celite and purified by flash column chromatography (SiO2; n-heptane ? n-heptane/ethyl acetate 7:3) to give the intermediate benzoic acid ester. The ester was dissolved in THF (40 mL) and LiOH-H2O (0.60 g, 14.3 mmol) in water (7 mL) was added. After stirring at rt for 5 h saturated aqueous NaHCO3 was added and the mixture extracted with diethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and evaporated to dryness to give the title compound as colorless crystals (3.33 g, 82%).

Reference： [1]Patent: US2007/123525,2007,A1 .Location in patent: Page/Page column 20
[2]Patent: WO2007/63071,2007,A1 .Location in patent: Page/Page column 15-16
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 271 - 275
[4]Patent: WO2007/79239,2007,A2 .Location in patent: Page/Page column 104
[5]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3290 - 3296

14
[ 194222-05-4 ]
[ 24985-85-1 ]
[ 1044761-10-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triphenylphosphine; diethylazodicarboxylate; at 0 - 20℃; for 168h;	To a cooled (ice-bath) solution of <strong>[24985-85-1]ethyl 5-hydroxyindole-2-carboxylate</strong> (2.227 g, 11 mmol) (1R,3S,5S)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1 eq, 2.467 g) and triphenylphosphine (1.2 eq, 3.416 g) in tetrahydrofuran (50 ml), was added dropwise a solution of diethyl azodicarboxylate in tetrahydrofuran (10 ml). When the addition was complete, the mixture was slowly allowed to reach room temperature and stirred 1 week at room temperature. The solvent was evaporated under reduced pressure and the residue purified twice by column chromatography on silica gel (49:1 CHCl3/tBuOMe eluant) to afford the product as an off-white solid (2.72 g, 60%). MS (m/z): 414.3 M+.

Reference： [1]Patent: US2008/188484,2008,A1 .Location in patent: Page/Page column 21-22

15
[ 185099-67-6 ]
[ 194222-05-4 ]
[ 143557-91-9 ]

Yield	Reaction Conditions	Operation in experiment
30%; 56%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate. tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.22 g, 1 eq., 9.74 mmol) was dissolved in MeOH (25 mL) and the resulting solution was cooled to 0C. Sodium borohydride (0.9 g, 2.5 eq., 24.35 mmol) was slowly added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated solution NH4Cl (15 mL) and extracted with DCM (215 mL). The organic extracts were dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (0 to 60%) to give the endo product (0.12 g, 56%) and exo product (0.66 g, 30%) as white solids. UPLC-MS (method A): Rt. 1.95 min (TIC), ionization ES+228 [M+H]+ endo product; Rt. 1.84 min (TIC), ionization ES+228 [M+H]+ exo product. Endo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=2.4 Hz, 1H), 4.03-3.95 (m, 2H), 3.94-3.87 (m, 1H), 2.20-2.07 (m, 2H), 1.93-1.70 (m, 4H), 1.69-1.57 (m, 2H), 1.39 (s, 9H). Exo: 1H NMR (400 MHz, DMSO-d6): delta 4.60 (d, J=5.5 Hz, 1H), 4.09-3.97 (m, 2H), 3.95-3.83 (m, 1H), 1.79 (d, J=16.8 Hz, 4H), 1.65-1.53 (m, 2H), 1.41 (s, 9H), 1.38-1.29 (m, 2H).
46%; 46%	With methanol; sodium tetrahydroborate; 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, 46%) and exo-product alcohol 5B (0.64 g, 46%).
	With sodium tetrahydroborate; In ethanol; at 0 - 20℃;	NaBH4 (8.8 g, 0.23 mol) was added to a 0 0C solution of 3-oxo-8-azabicyclo[3.2.1]octane-8- carboxylic acid tert-butyl ester (35 g, 0.16 mol) in ethanol (200 ml). The reaction mixture was stirred for 45 min at 00C, whereupon it was allowed to reach 20 0C. After stirring overnigth the suspension was evaporated to dryness. EtOAc (350 ml) was added, and the precipitate was filtered off. Water (200 ml) was added to the filtrate, and the layers were separated. The aqueous layer was extracted with EtOAc (100 ml), and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 29.5 g of an oil, which crystallised on standing. The two isomers were separated by flash chromatography (EtOAc/heptane 1 :5 D 1 : 1), affording 5 g of the title compound. LC-MS (m/z) : 250 (M+ 23 (Na)).

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4111 - 4114
[2]Patent: US2019/135778,2019,A1 .Location in patent: Paragraph 0068
[3]Patent: WO2010/9195,2010,A1 .Location in patent: Page/Page column 82
[4]Patent: WO2008/101914,2008,A2 .Location in patent: Page/Page column 68

16
[ 4991-65-5 ]
[ 194222-05-4 ]
(1R,3S,5S)-3-(2-oxo-benzo[1,3]oxathiol-6-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		Diethylazodicarboxylate (5.2 g, 12.0 mmol) was added dropwise to an ice-cooled, stirred mixture of triphenylphosphine (3.1 g, 12.0 mmol) and toluene (50 ml) at a temperature below 20 0C, followed by stirring 10 min at room temperature, endo-3- Hydroxy-8-aza-bicyclo[3.2.1] octane-8-carboxylic acid te/t-butyl ester (2.27 g, 10 mmol) was added followed by 10 min stirring at room temperature. 6-Hydroxy-1 ,3- benzoxathiol-2-one (1.85 g, 11.0 mmol) was added to the mixture. The temperature increased to 28 0C during 30 min and was then allowed to stir for 15 h. Water (50 ml) and sodium hydroxide (10 ml, 1 M) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (50 ml). The organic phases were pooled and washed with water (50 ml). Crystals precipitated and was filtered. Yield 1.15 g (30 %). The mother-liqour was evaporated and boiled in ethanol (25 ml), cooled and the precipitate was filtered and was washed with ethanol (5 ml). Yield 1.33 g (35%). Total yield 2.48 g (65%).

Reference： [1]Patent: WO2009/34042,2009,A1 .Location in patent: Page/Page column 12

17
endo-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]
[ 194222-05-4 ]
[ 582-25-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydroxide; In ethanol; at 20℃; for 72h;	A mixture of enc/o-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid te/f-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g 199 mmol) and ethanol (99%, 30 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evaporated. The product was triturated with petroleum. Yield 30.0 g (80%). Mp 139.5- 140.80C
80%	With potassium hydroxide; In ethanol; at 20℃; for 72h;	A mixture of enc/o-3-benzoyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid te/f-butyl ester (55.0 g, 166 mmol), potassium hydroxide (11.2 g 199 mmol) and ethanol (99%, 400 ml) was stirred for 3 days at room temperature. Potassium benzoate was separated by filtration and the filtrate was evaporated. Diethylether (200 ml) was added and remaining potassium benzoate was separated by filtration and the filtrate was evapo- rated. The product was triturated with petroleum. Yield 30.0 g (80%). Mp 139.5- 140.80C.

Reference： [1]Patent: WO2009/34042,2009,A1 .Location in patent: Page/Page column 11
[2]Patent: WO2009/34043,2009,A1 .Location in patent: Page/Page column 11

18
[ 194222-05-4 ]
[ 635-78-9 ]
(1R,3S,5S)-3-(7-oxo-7H-phenoxazin-3-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Diethylazodicarboxylate, 40% in toluene (0.885 g, 5.08 mmol) was added to a cold mixture (10 0C) of triphenylphosphine (1.33 g, 5.08 mmol) and dioxane (20 ml).The temperature was kept below 15 0C during the addition. The cooling was removed and enc/o-3-hydroxy-8-aza-bicyclo[3.2.1] octane-8-carboxylic acid te/t-butyl ester (0.888 g, 3.91 mmol) and resofurin (7-hydroxy-phenoxazin-3-one) (1.00 g, 4.69 mmol) was added to the mixture at room-temperature and was allowed to stir for 15 h. The intermediate (1 R,3S,5S)-3-(7-oxo-7/-/-phenoxazin-3-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid te/t-butyl ester was not isolated.

Reference： [1]Patent: WO2009/34043,2009,A1 .Location in patent: Page/Page column 11

19
[ 194222-05-4 ]
[ 930093-72-4 ]
[ 1147552-11-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 3.5h;	A solution of KOBut (5.8 mL. 1.0 M in THF. 5.8 mmol) was added to a solution of compound IA (Ll g, 4.8 mmol, made according to the method described in International Publication No. WO 98/18788 to Blythin, et al.) and compound IB (1.4 g. 5.8 mmol, made according to the method described in International Publication No. WO 07 035355 to Jones, ct at.) in anhydrous THF (100 mL) under nitrogen at 0 CC. The reaction was allowed to warm to room temperature on its own and was stirred for a total of 3.5 hours after the addition took place. The reaction was then quenched with water and extracted with 5% MeOH in dichloromethane. The organic layer was dried (MgSO4) and concentrated in vacuo to provide a crude residue which was chromatographed on a silica gel cartridge (40 - 100% EtOAc in Hexanes) to provide compound 48 (1.0 g, 40%). LCMS: 427.2 (MH').

Reference： [1]Patent: WO2009/55331,2009,A2 .Location in patent: Page/Page column 152
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3290 - 3296

20
[ 4316-97-6 ]
[ 194222-05-4 ]
[ 1147557-54-7 ]

Yield	Reaction Conditions	Operation in experiment
93%		To a solution of IA (8.5 grams, 37.4 mmol) in THF (200 mL) chilled to 0 C was added sodium hydride in 60% oil (6 grams, 150 mmol) and allowed to stir for 30 minutes. The reaction mixture was warmed to room temperature and 4,6-dichloro-5-methylpyrirnidine (6.8 grams, 41.1 mmol) was added. This was permitted to stir for seven hours. The caide reaction mixture was quenched with water and extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified using a silica gel cartridge with hexanes/ethyl acetate (50/50) to provide compound 34A as a light brown solid (12.3 grams, 93%). LCMS: 354.2 (MH').
		A solution of alcohol IA (2.0 g. 8.8 mmol, made according to the method described in International Publication No. WO 98/ 18788 to Blythin, et al.) in 20 ml THF was added to a suspension of sodium hydride (0.44 g, 1 1 mmol) in THF (10 mL) at room temperature. The reaction was stirred for 30 minutes. A solution of the commercially available dichloride 9A (1.2 g, 7.3 mmol) and 10 ml of THF was added dropwise to the reaction. The reaction was allowed to stir for three hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried (NaSO-O and concentrated in vacuo. A portion of the crude intermediate was carried on to the next step.The crude intermediate (70 mg, 0.20 mmol) was added to a mixture of potassium carbonate (55 mg, 0.40 mmol) and 2-chloro-3-hydroxypyridine (40 mg, 0.30 mmol) in DMF (2 mL) in a microwave vial. The vial was sealed and heated on high absorbance in a microwave reactor for eight minutes at a temperature of 190 C. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried (NaSO4) and concentrated in vacuo. The residue was chromatographed on preparative TLC plates with dichloromethane/MeOH (97/3) to provide compound 42 (40 mg, 45%). LCMS: 447.2. (MH+).

Reference： [1]Patent: WO2009/55331,2009,A2 .Location in patent: Page/Page column 169
[2]Patent: WO2009/55331,2009,A2 .Location in patent: Page/Page column 155
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3290 - 3296

21
[ 832714-38-2 ]
[ 194222-05-4 ]
[ 1206177-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; mineral oil; for 1.5h;	Step 4 - Synthesis of Compound 39; A solution of compound 2OC (0.080g, 0.25mmol), compound SB (0.067g, 0.30mmol) and NaH (60% in oil, 0.018g=0.01 Ig NaH, 0.45rnmol) in THF (4mL), was stirred for 1.5 hours, then concentrated in vacuo. The resulting residue was purified using preparative thin- layer chromatography (30% acetone/hexanes) to provide compound 39 as a yellow solid, LC/MS m/e 518 (M+l).

Reference： [1]Patent: WO2010/9195,2010,A1 .Location in patent: Page/Page column 90

22
[ 194222-05-4 ]
[ 1147885-39-9 ]
[ 1206177-42-5 ]

Yield	Reaction Conditions	Operation in experiment
59%		Step 2 - Synthesis of compound 12C; To compound 12B (0.050 g, 0.22 mmol) was added a solution of NaH (0.044 g of 60%) in tetrahydrofuran (2.0 mL) and the resulting mixture was allowed to stir stirred for 30 minutes. A solution of compound 12A (0.079 g, 0.22 mmol) in tetrahydrofuran (2.0 mL) was added and the resulting reaction was allowed to stir for about 15 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over MgStheta4, filtered and concentrated in vacuo and the resulting residue was purified using preparative TLC (30% acetone / hexanes) to provide compound 12C (0.075 mg, 59%).

Reference： [1]Patent: WO2010/9195,2010,A1 .Location in patent: Page/Page column 85-86

23
[ 194222-05-4 ]
(1R,3s,5S)-3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; In methanol; for 0.5h;Reflux;	Stage (iii): (1R,3s,5S)-3-(Pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane dihydrochloride(1R,3s,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq) was added to hydrogen chloride in methanol (4 eq, 1.25 mol/l) and the reaction mixture was refluxed for 30 min. The solvent was removed in vacuo and the residue was taken up in a little ethanol (5 ml), and acetone (30 ml) was then added. The mixture was stirred at room temperature for 30 min and diethyl ether (20 ml) was then added. The precipitate was filtered off with suction, washed with diethyl ether and dried in vacuo. Yield: 90%

Reference： [1]Patent: US2010/152158,2010,A1 .Location in patent: Page/Page column 31

24
[ 626-64-2 ]
[ 194222-05-4 ]
[ 1226970-47-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃;	Stage (ii): (1R,3s,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate(1R,3r,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq) was dissolved in tetrahydrofuran (50 eq), and <strong>[626-64-2]4-hydroxypyridine</strong> (1 eq) and triphenylphosphine (1.25 eq) were added. Thereafter, diisopropyl azodicarboxylate (1.25 eq) was added dropwise and the reaction mixture was heated to 55 C. After 15 h tetrahydrofuran was removed in vacuo, the residue was taken up in ethyl acetate (50 ml) and the mixture was extracted with aqueous hydrogen chloride solution (2×40 ml, 1 mol/l). The aqueous phase was rendered alkaline (pH=8) with sodium hydroxide solution and extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane (3:1). Yield: 65% The other isomer can be obtained analogously from the corresponding exo product from stage (i).
65%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃;	Stage (ii): (1 R,3S,5S)-tert-Butyl 3-(pyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8- carboxylate(1 R,3R,5S)-tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1 eq.) was dissolved in tetrahydrofuran (50 eq.) and <strong>[626-64-2]4-hydroxypyridine</strong> (1 eq.) and triphenylphosphine (1.25 eq.) were added. Diisopropyiazodicarboxylate (1.25 eq.) was then added dropwise and the reaction mixture was heated to 55C. After 15 h tetrahydrofuran was removed under vacuum, the residue was taken up in ethyl acetate (50 ml) and extracted with aqueous hydrogen chloride solution (2 x 40 ml, 1 mol/l). The aqueous phase was alkalised with sodium hydroxide solution (pH = 8) and extracted with ethyl acetate (3 x 50 ml). These organic phases were combined, dried over Na2SO4 and concentrated to small volume under vacuum. The crude product was purified by column chromatography (silica gel) with ethyl acetate/hexane(3:1).Yield: 65%

Reference： [1]Patent: US2010/152158,2010,A1 .Location in patent: Page/Page column 30-31
[2]Patent: WO2010/99938,2010,A1 .Location in patent: Page/Page column 106-107

25
[ 185099-67-6 ]
[ 194222-05-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; cerium(III) chloride heptahydrate; In ethanol; water;	To an ethanol solution (100 mL) of sodium borohydride (2.27 g) were added water (100 mL) and cerium chloride 6-hydrate (22.35 g) at 0C, and the mixture was stirred for 1 hour. tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (11.17 g) was added thereto at the same temperature, stirred at 0C for 1 hour, then heated to room temperature, and stirred for 14 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with diethyl ether. The organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel flash chromatography (hexane/ethyl acetate = 4/1 to 1/2) to give the title compound as a colorless solid (8.58 g). 1H-NMR (400 MHz, CDCl3, deltappm): 1.31 (1H, d, J = 5.9 Hz), 1.47 (9H, s), 1.58-1.67 (3H, m), 1.88-2.01 (4H, m), 4.06-4.14 (1H, m), 4.15-4.33 (2H, m)

Reference： [1]Patent: EP2204368,2010,A1 .Location in patent: Page/Page column 16
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3290 - 3296
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3290 - 3296

26
[ 7343-33-1 ]
[ 194222-05-4 ]
[ 1233323-97-1 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h;	Example 52Preparation of Compound 71 Step A - Synthesis of Compound 52BCompound 52A (1.08 g, 4.8 mmol) was combined with 3-brorno-[1 ,2,4]triazole (0.70 g, 4.7 mmol), trtphenylphosphine (1.49 g, 5.7 mmol) and diisopropyl azodicarboxylate (1.12 mL, 5.7 mmol) in THF (15 mL). The resulting reaction was allowed to stir at room temperature for 18 hours, then the reaction mixture was concentrated in vacuo to provide Compound 52B, which was used without further purification.

Reference： [1]Patent: WO2010/75273,2010,A1 .Location in patent: Page/Page column 129-130

27
[ 194222-05-4 ]
[ 939771-54-7 ]
3-exo-(6-methylbiphenyl-3-yloxy)-8-azabicyclo[3.2.1]octane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		A solution of 3-exo-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid terf-butyl ester (122mg, 0.563mmol) in DMF (1.5ml_) was added to a stirred suspension of 60% sodium hydride in mineral oil (22mg, 0.536mmol) in DMF (0.5ml_) under an atmosphere of nitrogen. The reaction was stirred at ambient temperature for 1 h. A solution of 3-fluoro-6- methylbiphenyl (50mg, 0.268mmol) in DMF (0.5ml_) was then added and the reaction was heated in a microwave at 18O0C for 1200s. The reaction mixture was concentrated in vacuo, DCM (1 mL) and TFA (1 mL) were added, and the reaction was stirred for 2h. The crude reaction mixture was loaded onto a SCX cartridge. The cartridge was eluted with methanol (3x1 OmL) to remove impurities. Elution with ammonia in methanol (2M, 1OmL) followed by evaporation in vacuo afforded crude 3-exo-(6-methylbiphenyl-3-yloxy)-8- azabicyclo[3.2.1]octane. The crude material was then purified by preparative LCMS to afford 3-exo-(6-methylbiphenyl-3-yloxy)-8-azabicyclo[3.2.1]octane as the trifluoracetic acid salt (13mg, 0.032mmol, 12%). M.S. (ESI) (m/z): 294 [M+H]+.

Reference： [1]Patent: WO2007/63071,2007,A1 .Location in patent: Page/Page column 43-44

28
[ 194222-05-4 ]
[ 106-48-9 ]
[ 1442691-54-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;	General procedure: . Following GP1, under N2 atmosphere, to a 0C. solution of <strong>[194222-05-4]tert-butyl (1R,3s,5S)-3-hydroxybicyclo[3.2.1]octane-8-carboxylate</strong> (0.251 g, 1.05 eq., 1.11 mmol), 4-chloro-phenol (0.135 g, 1 eq., 1.06 mmol), and PPh3 (0.290 g, 1.05 eq., 1.11 mmol) in dry THF (6 mL) was added dropwise diisopropyl azodicarboxylate (0.22 mL, 1.05 eq., 1.11 mmol). The reaction crude was allowed to warm to room temperature and stirred for 16 h. Then, the mixture was quenched with HCl (10 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (90:10) to give the pure title compound as a white solid (0.29 g, 81%). UPLC-MS: tR=2.45 min (apolar method); MS (ESI) m/z calcd for C14H17ClNO3 (M-tBu+2H)+: 282.1, found: 282.1.
		Typical procedure 7 (TP7): 3alpha-(4-chlorophenoxyV8-azabicvclor3.2.1 loctane[0226] 4-Chlorophenol (395 mg, 3 mmol) and resin bound triphenylphosphine (1.20 g, 3.75 mmol, 3 mmol/g) was taken up in THF (10 mL) and cooled to 0 0C, before drop wise addition of diisopropylazodicarboxylate (787 mg, 3.9 mmol). After 40 min at 0 0C tert- butyl 3beta-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.2 mmol) in THF (5 mL) was added slowly. The reaction was continued for 2 h at 0 C, then the cooling was removed and the reaction left at room temperature over night. The reaction mixture was filtered and concentrated onto celite, then purified by flash chromatography 0-30% EtOAc in heptane. The product was taken up in DCM (5 mL), TFA (5 mL) was added and the reaction <n="81"/>mixture left stirring for 1 h and concentrated in vacuo. The product was taken up in EtOAc, then washed with NaOH (2 N), dried over sodium sulphate, filtered and concentrated in vacuo. Yield: 370 mg (71 % over two steps).[0227] 1H NMR (400 MHz, CD3OD) delta: 7.29-7.26 (m, 2H)5 6.90-6.88 (m, 2H), 4.67 (bt, J= 4.4 Hz, IH), 3.92-3.91 (m, 2H), 2.39-2.00 (m, 7H).102281 13C NMR (100 MHz, CD3OD) delta: 159.7, 133.5, 129.9, 120.8, 72.4, 58.0, 37.0, 30.2.

Reference： [1]Patent: US2019/135778,2019,A1 .Location in patent: Paragraph 0153; 0111
[2]Patent: WO2007/79239,2007,A2 .Location in patent: Page/Page column 78-79

29
[ 194222-05-4 ]
[ 1147558-98-2 ]