[ CAS No. 5291-32-7 ] {[proInfo.proName]}

Name: 5291-32-7|2-(Hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one|97%
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3d Animation Molecule Structure of 5291-32-7

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Quality Control of [ 5291-32-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 5291-32-7 ]

SDS Specification

Alternatived Products of [ 5291-32-7 ]

Product Details of [ 5291-32-7 ]

CAS No. :	5291-32-7	MDL No. :	MFCD16294187
Formula :	C₁₀H₁₇NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BGBNULCRKBVAKL-UHFFFAOYSA-N
M.W :	199.25	Pubchem ID :	52918385
Synonyms :	PRIMA-1Met;APR-246;APR 246. PRIMA-1MET	Chemical Name :	2-(Hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one

Calculated chemistry of [ 5291-32-7 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	55.25
TPSA :	49.77 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.03
Log Po/w (XLOGP3) :	-0.09
Log Po/w (WLOGP) :	-0.72
Log Po/w (MLOGP) :	-0.35
Log Po/w (SILICOS-IT) :	0.84
Consensus Log Po/w :	0.34

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.82
Solubility :	30.1 mg/ml ; 0.151 mol/l
Class :	Very soluble
Log S (Ali) :	-0.5
Solubility :	62.6 mg/ml ; 0.314 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.17
Solubility :	13.5 mg/ml ; 0.0676 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.56

Safety of [ 5291-32-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 5291-32-7 ]

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

Downstream synthetic route of [ 5291-32-7 ]

[ 5291-32-7 ] Synthesis Path-Downstream 1~24

Yield	Reaction Conditions	Operation in experiment
	3-Chinuclidinon-hydrochlorid, 5 mol 6 H2O in wss. Me., K2CO3, 64grad, 2 h;
	(yield)16percent;

2
[ 5291-32-7 ]
[ 13734-41-3 ]
(2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (tert-butoxycarbonyl)-L-valinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 6h;	18 Synthesis of (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (tert- butoxycarbonyl)-L-valinate: Into a 50-mL round-bottom flask was placed 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (500.0 mg, 2.51 mmol, 1.0 equiv). This was followed by the addition of (tert-butoxycarbonyl)-L-valine (545.2 mg, 2.51 mmol, 1.00 equiv), DCC (932.1 mg, 4.52 mmol), DMAP (61.3 mg, 0.51 mmol), DCM (15.0 mL). The resulting solution was stirred for 6 h at room temperature. The resulting solution was extracted with 3x10 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with DCM/MeOH (10; 1). This resulted in 420 mg (42.00%) of (2-(methoxymethyl)-3- oxoquinuclidin-2-yl)methyl (tert-butoxycarbonyl)-L-valinate as a white solid. LC-MS: (ES, m/z): M+l: 399

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 83

3
[ 5291-32-7 ]
[ 13734-41-3 ]
(2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl L-valinate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide; dmap / dichloromethane / 6 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1

4
[ 5291-32-7 ]
[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-amino-3-methylbutanoate [ No CAS ]
[ 530-62-1 ]
[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-[([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy]carbonyl)amino]-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.15%	Stage #1: 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 50℃; for 3h; Stage #2: [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-amino-3-methylbutanoate With triethylamine at 50℃; for 5h;	18 Synthesis of (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (((2- (methoxymethyl)-3-oxoquinuclidin-2-yl)methoxy)carbonyl)-L-valinate: Into a 25mL round-bottom flask were added 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (150.00 mg, 0.753 mmol, 1.00 equiv) DCE (3.00 mL) and CDI (0692) (146.48 mg, 0.903 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 3 h at 50 degrees C. To the above mixture was added [2-(methoxymethyl)-3-oxo-l- azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-amino-3-methylbutanoate (224.63 mg, 0.753 mmol, 1 equiv) and TEA (152.36 mg, 1.506 mmol, 2 equiv) at 50 °C. The resulting mixture was stirred for additional 5 h at 50 °C. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with CH2CI2 (2 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: Atlantis Prep T3 OBD Column, 19* 150mm 5um; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; (0693) Flow rate: 20 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 202 nm;) and ACN (42% PhaseB up to 56% in 7 min); Detector, 254nm.) to afford [2- (methoxymethyl)-3-oxo-l-azabicyclo[2.2.2]octan-2-yl]methyl (2S)-2-[([[2-(methoxymethyl)- 3-oxo-l-azabicyclo[2.2.2]octan-2-yl]methoxy]carbonyl)amino]-3-methylbutanoate (40 mg, 10.15%) as a white solid. LC-MS: (ES, m/z ): M+l : 524. NMR (400 MHz, DMSO-d6) d 8.06 (dd, J= 19.3, 8.7 Hz, 1H), 4.84 - 4.33 (m, 4H), 4.06 (dd, J= 16.3, 7.9 Hz, 2H), 3.98 - 3.80 (m, 4H), 3.62 (d, J= 10.7 Hz, 4H), 3.32 (d, J= 10.7 Hz, 6H), 2.69 (d, J= 8.6 Hz, 2H), 2.34 - 2.00 (m, 9H), 0.90 (t, J= 6.5 Hz, 6H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 83-84

5
[ 5291-32-7 ]
[ 100-21-0 ]
bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) terephthalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.32%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;	19 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) terephthalate: To a stirred solution of 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (150 mg, 0.753 mmol, 2.0 equiv) and terephthalic acid (75.04 mg, 0.452 mmol, 1.00 equiv) in DCM was added DCC (279.59 mg, 1.355 mmol, 3.6 equiv) and DMAP (18.39 mg, 0.151 mmol, 0.4 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was extracted with CH2C12 (2 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. (0698) The crude product was purified by Prep-HPLC with the following conditions (Column: Atlantis Prep T3 OBD Column, 19*150mm 5um; Mobile Phase A: Water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 202 nm;) and ACN (42% PhaseB up to 56% in 7 min); Detector, 254nm.) to afford bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) terephthalate (70 mg, 29.32%) as a white solid. LC-MS: (ES, m/z): M+l : 529. NMR (300 MHz, Chloroform- ) d 8.27 (s, 4H), 4.85 (d, J = 3.4 Hz, 4H), 4.47 (d, J= 11.2 Hz, 2H), 4.12 (s, 2H), 4.01 (d, J= 11.2 Hz, 2H), 3.86 (s, 2H), 3.55 (s, 4H), 3.41 (s, 6H), 2.84 (s, 2H), 2.32 (d, J= 32.6 Hz, 8H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 84-85

6
[ 676-97-1 ]
[ 5291-32-7 ]
bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.69%	With triethylamine In dichloromethane at 0℃; for 4h;	21 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate: To a stirred solution of 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (150 mg, 0.753 mmol, 1.0 equiv) and TEA (150.2 mg, 1.506 mmol, 2.00 equiv) in DCM was added methylphosphonic dichloride (60.0 mg, 0.452 mmol, 0.6 equiv) at 0 °C. The resulting mixture was stirred for 4 h at 0 °C. The resulting mixture was extracted with CH2CI2 (2 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO Cl 8 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220NM nm; RTl(min): 7.6;) to afford bis((2- (methoxymethyl)-3-oxoquinucli din-2 -yl)methyl) methylphosphonate (30 mg, 8.69%) as a white solid. LC-MS: (ES, m/z): M+l: 459. NMR (400 MHz, DMSO- is) d 4.75 - 4.61 (m, 1H), 4.47 (dd, J= 11.9, 5.7 Hz, 2H), 3.61 (t, J= 12.0 Hz, 5H), 3.53 - 3.39 (m, 5H), 3.32 (s, 6H), 2.76 - 2.65 (m, 3H), 2.19 (dd, J= 39.8, 12.1 Hz, 11H), 1.68 (d, J= 18.1 Hz, 3H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 90

7
[ 67-56-1 ]
[ 50-00-0 ]
3-quinuclidinone hydrochloride [ No CAS ]
[ 5291-32-7 ]

Yield	Reaction Conditions	Operation in experiment
13.82%	With potassium carbonate In water at 20 - 75℃;	14 Synthesis of 2-(hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3- one: Into a 1000-mL round-bottom flask, was placed 3-Quinuclidinone hydrochloride (50 g, 310.56 mmol, 1.00 equiv), H2O (200.00 mL), MeOH (600.00 mL). This was followed by the addition of K2CO3 (50 g, 362.32 mmol, 1.17 equiv), 37% CH2O (105 mL). The resulting solution was stirred for 5 h at 75 degrees C. Then the resulting solution was stirred overnight at room temperature. The resulting solution was adjusted PH=12 with 2N NaOH, extracted with 3x500 mL of dichloromethane and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 11 g (13.82%) of 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one as a white solid. LC- MS: (ES, in z): M+l: 200; H-NMR (300 MHz, Chloroforms/, ppm ) 3.98 (d, .7=1 1.7Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 2H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 74

8
[ 67-56-1 ]
[ 3731-38-2 ]
[ 5291-32-7 ]

Yield	Reaction Conditions	Operation in experiment
13.82%	With potassium carbonate In water at 75℃; for 5h;	12-13; 18-19; 21-22 Synthesis of 2-(hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3- one: A 1000-mL round-bottom flask was placed quinuclidin-3-one (50.00g, 399.45 mmol). This was followed by the addition of K2CO3 (55.21 g, 399.45 mmol, 1.00 equiv), H2O (200.00 mL), MeOH (300.00 mL). The resulting solution was stirred for 5 h at 75 degrees C. Then the resulting solution was stirred for overnight at room temperature. The resulting solution was extracted with 3x500 mL of dichloromethane concentrated. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1: 1). This resulted in 11 g (13.82%) of 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one as a white solid. LC- MS: (ES, in z): M+l: 200. NMR (CDCh, 300 ppm ) 3.98 (d, J=11.7Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 2H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 72-74; 83-84; 89-91

9
[ 5291-32-7 ]
tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.17%	With triethylamine; trichlorophosphate In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;	22 Synthesis of Synthesis of tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (389.84 mg, 1.956 mmol, 3 equiv), DCM (10 mL), TEA (263.98 mg, 2.608 mmol, 4 equiv). This was followed by the addition of POCb (100 mg, 0.652 mmol, 1.00 equiv) at 0 degrees C. The resulting solution was stirred for 16 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2x20 mL of dichloromethane/methanol (10:1) and washed with 2 x30 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep Cl 8 OBD Column, 50*250mm 5um lOnm; mobile phase, phase A: H20 (0.05% TFA); phase B: CFECN (10% CFECN up to 40% CFECN in 12 min). This resulted in 30mg (7.17%) of tris((2-(methoxymethyl)-3-oxoquinuclidin-2- yl)methyl) phosphate hydrochloride as a white solid. LC-MS: (ES, m/z): M+l: 678. 1HNMR (400 MHz, DMSO-i/e) d 11.84 (s, 2H), 4.96 (dd, J= 12.0, 4.1 Hz, 3H), 4.58 (dt, J= 12.7, 3.9 Hz, 3H), 4.10-3.97 (m, 6H), 3.79-3.57 (m, 6H), 3.47 (s, 6H), 3.39- 3.25 (m, 9H), 2.70 (s, 3H), 2.27-2.14 (m, 12H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 91

10
[ 5291-32-7 ]
2-(iodomethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.67%	With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃;	14 Synthesis of 2-(iodomethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one: Into a 250-mL round-bottom flask, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (2.00 g, 10.038 mmol, 1.00 equiv), DCM (30.00 mL), PPh3 (3.42 g, 13.039 mmol, 1.30 equiv), h (3.32 g, 13.081 mmol, 1.30 equiv), imidazole (923.00 mg, 13.558 mmol, 1.35 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 1.2 g (38.67%) of 2-(iodomethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one as yellow oil. LC-MS: (ES, m/z): M+l: 310; H-NMR (300 MHz, Chloroform-7, ppm ) d 3.77 - 3.50 (m, 3H), 3.45 - 3.28 (m, 5H), 3.15 (ddt, J= 14.5, 9.3, 4.1 Hz, 1H), 2.93 (dddd, 7= 31.6, 15.4, 10.2, 6.2 Hz, 2H), 2.58 - 2.44 (m, 1H), 2.05 (ddddt, J= 22.3, 18.7, 13.2, 5.4, 3.1 Hz, 4H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 75

11
[ 5291-32-7 ]
2-(methoxymethyl)-2-([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triphenylphosphine; iodine; 1H-imidazole / dichloromethane / 20 °C 2: silver trifluoromethanesulfonate; 2,6-di-tert-butyl-4-methylpyridine / dichloromethane / -78 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1

12
[ 110-85-0 ]
[ 5291-32-7 ]
[ 530-62-1 ]
bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) piperazine 1,4-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20 mg	Stage #1: APR-246; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 50℃; for 4h; Stage #2: piperazine In 1,2-dichloro-ethane at 50℃; for 24h;	13 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) piperazine- 1, 4-dicarboxylate A 50 ml round bottom flask was placed 2-(hydroxymethyl)-2- (methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (300 mg, 1.5 mmol) ,CDI (317 mg, 1.95 mmol ) and DCE(10 ml). The resulting solution was stirred for 4 h at 50°C. Piperazine (77 mg, 0.9 mmol) was added and the mixture was stirred for 24 h at 50°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO Cl 8 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220NM nm; RTl(min): 7.6;) to afford bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) piperazine- 1, 4-dicarboxylate (20 mg) as a white solid. LC-MS (ES, m/z ): M+l: 537. 1HNMR (300 MHz, Chloroform- ) d 4.57 (d, J= 11.7 Hz, 2H), 4.44 (d, J= 11.7Hz, 2H), 3.70 (s, 4H), 3.51 (s, 8H), 3.42 - 3.23 (m, 10H), 2.94 (dt, J= 15.2, 8.3 Hz, 4H), 2.47 - 2.38 (m, 2H), 2.04 (td, J= 7.8, 6.3, 3.3 Hz, 8H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 73

13
[ 5291-32-7 ]
[ 26772-34-9 ]
[ 530-62-1 ]
bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) ((1R,3S)-cyclohexane-1,3-diyl)dicarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20 mg	Stage #1: 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 50℃; for 4h; Stage #2: (1R,3S)-cyclohexane-1,3-diamine In 1,2-dichloro-ethane at 50℃; for 48h;	13 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) ((1R,3S)- cyclohexane-l,3-diyl)dicarbamate: A 50 ml round bottom flask was placed 2- (hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (300 mg, 1.5 mmol) ,CDI (317 mg, 1.95 mmol ) and DCE(10 ml). The resulting solution was stirred for 4 h at 50°C. (lR,3S)-cyclohexane-l,3-diamine(103mg, 0.9 mmol) was added and the mixture was stirred for 48 h at 50°C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220NM nm; RTl(min): 7.6;) to afford bis((2-(methoxymethyl)-3-oxoquinuclidin-2- yl)methyl) ((lR,3S)-cyclohexane-l,3-diyl)dicarbamate (20 mg) as a white solid. LC-MS: (0631) (ES, m/z ): M+l : 565. NMR (300 MHz, Chloroforms/) d 4.99 - 4.64 (m, 2H), 4.49 (d, J = (0632) 11.7 Hz, 2H), 4.30 (d, J= 11.7 Hz, 2H), 3.72 (s, 4H), 3.61 - 3.48 (m, 2H), 3.48 - 3.25 (m, 10H), 3.04 - 2.81 (m, 4H), 2.43 (q, 7= 3.1 Hz, 2H), 2.20 - 1.95 (m, 10H), 1.90 - 1.75 (m, 4H), 1.20 - 0.85(m, 2H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 74

14
[ 5291-32-7 ]
2-(iodomethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]
2-(methoxymethyl)-2-([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-1-azabicyclo[2.2.2]octan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.75%	With 2,6-di-tert-butyl-4-methylpyridine; silver trifluoromethanesulfonate In dichloromethane at -78 - 20℃; Inert atmosphere;	14 Synthesis of 2-(methoxymethyl)-2-([[2-(methoxymethyl)-3-oxo-l- azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-l-azabicyclo[2.2.2]octan-3-one: Into a 100- mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (400.00 mg, 2.008 mmol, 1.00 equiv), DCM (20.00 mL). This was followed by the addition of 2-(iodomethyl)-2-(methoxymethyl)-l-azabicyclo[2.2.2]octan-3-one (807.00 mg, 2.610 mmol, 1.30 equiv) at -78 degrees C. To this was added 2,6-di-tert-butyl-4-methylpyridine (935.00 mg, 4.553 mmol, 2.27 equiv) at -78 degrees C, then followed by AgSChCF3 (1.14 g, 4.453 mmol, 2.22 equiv) at -78 degrees C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (32: 1). The crude product was purified by Prep-HPLC with the following conditions (2 SHIM ADZU (HPLC-01)): Column, X Bridge Shield RP18 OBD Column, 5um,19*150mm; mobile phase, Water (0.05% NH3.H2O) and ACN (14% Phase B up to 36% in 7 min); Detector, UV. This resulted in 21 mg (2.75%) of 2-(methoxymethyl)-2-([[2- (methoxymethyl)-3-oxo-l-azabicyclo[2.2.2]octan-2-yl]methoxy]methyl)-l- azabicyclo[2.2.2]octan-3-one as a white solid. LC-MS: (ES, m/z): M+l: 381; H-NMR (300 MHz, Chloroform -7, ppm ) d 4.00 (dd, J= 44.8, 10.0 Hz, 1H), 3.75 - 3.37 (m, 8H), 3.34 (s, 6H), 3.18 - 2.73 (m, 7H), 2.58 - 2.32 (m, 2H), 2.14 - 1.59 (m, 8H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 75

15
[ 261909-49-3 ]
[ 5291-32-7 ]
isopropyl (2S)-2-([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methoxy(phenoxy)phosphoryl]amino)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.51%	With NMI In tetrahydrofuran at 0 - 20℃; for 1h;	1 Synthesis of isopropyl (2S)-2-([[2-(methoxymethyl)-3-oxo-l- azabicyclo[2.2.2]octan-2-yl]methoxy(phenoxy)phosphoryl]amino)propanoate: Into a 50- mL 3 -necked round-bottom flask, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-l- azabicyclo[2.2.2]octan-3-one (100 mg, 1.00 equiv), THF (5 mL), NMI (82.4 mg, 2.0 equiv). (0484) This was followed by the addition of a solution of isopropyl (2S)-2- (0485) [[chloro(phenoxy)phosphoryl]amino]propanoate (230 mg, 1.5 equiv) in THF (1 mL) dropwise with stirring at 0 degrees C. The resulting solution was stirred for 1 hr at room temperature. The resulting mixture was concentrated under lower temperature. The residue was dissolved in 4 mL of CH3CN. The crude was purified by Prep-HPLC with the following conditions (IntelFlash-1): Column, C18; mobile phase, CH3CN:H20 (0.5%CF3COOH); Detector, 220. 20 mg product was obtained. This resulted in 20 mg (8.51%) of isopropyl (2S)-2-([[2-(methoxymethyl)-3-oxo-l-azabicyclo[2.2.2]octan-2- yl]methoxy(phenoxy)phosphoryl]amino)propanoate as colorless oil. LC-MS: (ES, m/z ): [M+l]=469. H-NMR: (300 MHz, Chloroform- ) d 7.34 (t, J= 7.8 Hz, 2H), 7.28 - 7.12 (m, 3H), 5.12 - 4.90 (m, 1H), 4.78 - 4.36 (m, 3H), 4.15 - 3.83 (m, 4H), 3.76 - 3.46 (m, 2H), 3.31 (d, J= 9.3 Hz, 3H), 2.74 (d, J= 3.4 Hz, 1H), 2.47 - 1.97 (m, 4H), 1.42 (dd, J= 7.1, 5.2 Hz, 2H), 1.36 - 1.14 (m, 6H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2021/158948, 2021, A1 Location in patent: Page/Page column 46-47

16
[ 5291-32-7 ]
[ CAS Unavailable ]
[ 530-62-1 ]
[ 2682934-95-6 ]

Yield	Reaction Conditions	Operation in experiment
10.15 %	Stage #1: APR-246; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 25 - 50℃; Stage #2: (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl L-valinate hydrochloride With triethylamine In 1,2-dichloro-ethane at 50℃;	20 Synthesis of (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (((2- (methoxymethyl)-3-oxoquinuclidin-2-yl)methoxy)carbonyl)-L-valinate: Into a 25 mL round-bottom flask were added 2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (150 mg, 0.75 mmol, 1.0 equiv), DCE (3 mL) and CDI (146.5 mg, 0.9 mmol, 1.2 equiv) at 25 degrees C. The resulting mixture was stirred for 3 h at 50 . To the above mixture was added [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methyl (2S)-2-amino-3-methylbutanoate (224.6 mg, 0.75 mmol, 1.0 equiv) and TEA (152.4 mg, 1.5 mmol, 2.0 equiv) at 50 oC. The resulting mixture was stirred for additional 5 h at 50 oC. The reaction was quenched with water at 25 degrees C. The resulting mixture was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Atlantis Prep T3 OBD Column, 19*150 mm 5 um; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 202 nm;) and CH3CN (42% PhaseB up to 56% in 7 min); Detector, 254 nm.) to afford [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methyl (2S)-2-[([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methoxy]carbonyl)amino]-3-methylbutanoate (40 mg, 10.15%) as a white solid. LC-MS (ES, m/z): M+1: 524. NMR (DMSO-d6, 400 MHz) δ 8.06 (dd, J = 19.3, 8.7 Hz, 1H), 4.74 - 4.58 (m, 8H), 4.08-3.74 (m, 4H), 3.59 - 3.30 (m, 8H), 3.16 (m, 6H), 2.69 (d, J = 8.6 Hz, 2H), 2.34 - 2.00 (m, 8H), 0.90 (t, J = 6.5 Hz, 6H).
10.15 %	Stage #1: APR-246; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 25 - 50℃; Stage #2: (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl L-valinate hydrochloride With triethylamine In 1,2-dichloro-ethane at 50℃;	20 Synthesis of (2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl (((2- (methoxymethyl)-3-oxoquinuclidin-2-yl)methoxy)carbonyl)-L-valinate: Into a 25 mL round-bottom flask were added 2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (150 mg, 0.75 mmol, 1.0 equiv), DCE (3 mL) and CDI (146.5 mg, 0.9 mmol, 1.2 equiv) at 25 degrees C. The resulting mixture was stirred for 3 h at 50 . To the above mixture was added [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methyl (2S)-2-amino-3-methylbutanoate (224.6 mg, 0.75 mmol, 1.0 equiv) and TEA (152.4 mg, 1.5 mmol, 2.0 equiv) at 50 oC. The resulting mixture was stirred for additional 5 h at 50 oC. The reaction was quenched with water at 25 degrees C. The resulting mixture was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Atlantis Prep T3 OBD Column, 19*150 mm 5 um; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 202 nm;) and CH3CN (42% PhaseB up to 56% in 7 min); Detector, 254 nm.) to afford [2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methyl (2S)-2-[([[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methoxy]carbonyl)amino]-3-methylbutanoate (40 mg, 10.15%) as a white solid. LC-MS (ES, m/z): M+1: 524. NMR (DMSO-d6, 400 MHz) δ 8.06 (dd, J = 19.3, 8.7 Hz, 1H), 4.74 - 4.58 (m, 8H), 4.08-3.74 (m, 4H), 3.59 - 3.30 (m, 8H), 3.16 (m, 6H), 2.69 (d, J = 8.6 Hz, 2H), 2.34 - 2.00 (m, 8H), 0.90 (t, J = 6.5 Hz, 6H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 99-101
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 99-101

17
[ 5291-32-7 ]
[ 13113-88-7 ]
[ 2682935-01-7 ]

Yield	Reaction Conditions	Operation in experiment
8.69 %	With triethylamine In dichloromethane at 0℃;	23 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate: To a stirred solution of 2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (150 mg, 0.75 mmol, 1.0 equiv) and TEA (150.2 mg, 1.5 mmol, 2.0 equiv) in DCM was added methylphosphonic dichloride (60.0 mg, 0.45 mmol, 0.6 equiv) at 0 oC. The resulting mixture was stirred for 4 h at 0 oC. The resulting mixture was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3•H2O), Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220 nm; RT1(min): 7.6;) to afford bis((2- (methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate (30 mg, 8.69%) as a white solid. LC-MS (ES, m/z): M+1: 459. NMR (400 MHz, DMSO-d6) δ 11.60 - 11.52 (m, 2H), 4.70 - 4.63 (m, 2H), 4.50 - 4.42 (m, 2H), 3.89 - 3.86 (m, 4H), 3.64 - 3.56 (m, 4H), 3.45 - 3.32 (m, 4H), 2.69 (m, 2H), 2.32- 2.12 (m, 8H), 1.68 (d, J = 18.1 Hz, 3H).
8.69 %	With triethylamine In dichloromethane at 0℃;	23 Synthesis of bis((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate: To a stirred solution of 2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (150 mg, 0.75 mmol, 1.0 equiv) and TEA (150.2 mg, 1.5 mmol, 2.0 equiv) in DCM was added methylphosphonic dichloride (60.0 mg, 0.45 mmol, 0.6 equiv) at 0 oC. The resulting mixture was stirred for 4 h at 0 oC. The resulting mixture was extracted with CH2Cl2 (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Kinetex EVO C18 Column, 21.2*150, 5um; Mobile Phase A: Water(0.05%NH3•H2O), Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 13% B to 26% B in 8 min, 26% B; Wave Length: 220 nm; RT1(min): 7.6;) to afford bis((2- (methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) methylphosphonate (30 mg, 8.69%) as a white solid. LC-MS (ES, m/z): M+1: 459. NMR (400 MHz, DMSO-d6) δ 11.60 - 11.52 (m, 2H), 4.70 - 4.63 (m, 2H), 4.50 - 4.42 (m, 2H), 3.89 - 3.86 (m, 4H), 3.64 - 3.56 (m, 4H), 3.45 - 3.32 (m, 4H), 2.69 (m, 2H), 2.32- 2.12 (m, 8H), 1.68 (d, J = 18.1 Hz, 3H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 106-107
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 106-107

18
[ 5291-32-7 ]
[ 110-17-8 ]
[ 2842821-30-9 ]

Yield	Reaction Conditions	Operation in experiment
2 %	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃;	29 Synthesis of 1,4-bis[[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methyl] (2E)-but-2-enedioate hydrochloride: Into a 40-mL vial, was placed 2- (hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one (200 mg, 1.0 mmol, 1.0 equiv), DCM (8.0 mL), fumaric acid (69.9 mg, 0.6 mmol, 0.6 equiv), DMAP (24.5 mg, 0.20 mmol, 0.2 equiv), DCC (373 mg, 1.8 mmol, 1.8 equiv). The resulting solution was stirred for overnight at 25 degrees C. The resulting solution was extracted with 3x10 mL of dichloromethane concentrated. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-003): Column, SunFire Prep C18 OBD Column, 19*150mm 5um 10nm; mobile phase, Water (0.1%FA) and CH3CN (5% PhaseB up to 45% in 7 min); Detector=220 nm. This resulted in 11.3 mg (2 %) of 1,4-bis[[2-(methoxymethyl)- 3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl] (2E)-but-2-enedioate hydrochloride as a yellow solid. LC-MS (ES, m/z): M-HCl+1: 479. 7.00 (s, 2H), 4.72 (d, J = 12.9 Hz, 2H), 4.59 (d, J = 12.9 Hz, 2H), 3.91 (s, 4H), 3.51 (s, 4H), 3.33 (s, 4H), 3.29 (s, 6H), 2.61 (s, 2H), 2.16 (s, 8H).
2 %	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃;	29 Synthesis of 1,4-bis[[2-(methoxymethyl)-3-oxo-1-azabicyclo[2.2.2]octan-2- yl]methyl] (2E)-but-2-enedioate hydrochloride: Into a 40-mL vial, was placed 2- (hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one (200 mg, 1.0 mmol, 1.0 equiv), DCM (8.0 mL), fumaric acid (69.9 mg, 0.6 mmol, 0.6 equiv), DMAP (24.5 mg, 0.20 mmol, 0.2 equiv), DCC (373 mg, 1.8 mmol, 1.8 equiv). The resulting solution was stirred for overnight at 25 degrees C. The resulting solution was extracted with 3x10 mL of dichloromethane concentrated. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-003): Column, SunFire Prep C18 OBD Column, 19*150mm 5um 10nm; mobile phase, Water (0.1%FA) and CH3CN (5% PhaseB up to 45% in 7 min); Detector=220 nm. This resulted in 11.3 mg (2 %) of 1,4-bis[[2-(methoxymethyl)- 3-oxo-1-azabicyclo[2.2.2]octan-2-yl]methyl] (2E)-but-2-enedioate hydrochloride as a yellow solid. LC-MS (ES, m/z): M-HCl+1: 479. 7.00 (s, 2H), 4.72 (d, J = 12.9 Hz, 2H), 4.59 (d, J = 12.9 Hz, 2H), 3.91 (s, 4H), 3.51 (s, 4H), 3.33 (s, 4H), 3.29 (s, 6H), 2.61 (s, 2H), 2.16 (s, 8H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 119-120
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 119-120

19
[ 67-56-1 ]
[ 50-00-0 ]
[ 1193-65-3 ]
[ 5291-32-7 ]

Yield	Reaction Conditions	Operation in experiment
13.82 %	With potassium carbonate In water at 25 - 70℃;	1; 14; 15; 16; 20; 21; 23; 24; 29; 32 Synthesis of 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3- one: Into a 1000 mL round-bottom flask, was placed 1-azabicyclo[2.2.2]octan-3-one HCl salt (65.00 g, 399.478 mol, 1.00 equiv), K2CO3 (276 g, 2.00 mol, 5.00 equiv), H2O (200.00 mL) and MeOH (300.00 mL). This was followed by the addition of formaldehyde (33% aq) (363.6 g, 4.00 mol, 10 eq) at 25 degrees C. The resulting solution was stirred for 5 h at 70 degrees C. Then the resulting solution was cooled to 25 degrees C and extracted with 3x500 mL of dichloromethane. The mixture was dried over anhydrous sodium sulfate, the resulting solution was filtred. The filtrate was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:1). This resulted in 11 g (13.82%) of 2- (hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one as white solid. LC-MS (ES, m/z): M+1: 200.1HNMR (CDCl3, 300 MHz) δ 3.98 (d, J = 11.7 Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 2H).
13.82 %	With potassium carbonate In water at 25 - 70℃;	1; 14; 15; 16; 20; 21; 23; 24; 29; 32 Synthesis of 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3- one: Into a 1000 mL round-bottom flask, was placed 1-azabicyclo[2.2.2]octan-3-one HCl salt (65.00 g, 399.478 mol, 1.00 equiv), K2CO3 (276 g, 2.00 mol, 5.00 equiv), H2O (200.00 mL) and MeOH (300.00 mL). This was followed by the addition of formaldehyde (33% aq) (363.6 g, 4.00 mol, 10 eq) at 25 degrees C. The resulting solution was stirred for 5 h at 70 degrees C. Then the resulting solution was cooled to 25 degrees C and extracted with 3x500 mL of dichloromethane. The mixture was dried over anhydrous sodium sulfate, the resulting solution was filtred. The filtrate was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:1). This resulted in 11 g (13.82%) of 2- (hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one as white solid. LC-MS (ES, m/z): M+1: 200.1HNMR (CDCl3, 300 MHz) δ 3.98 (d, J = 11.7 Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 2H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 62-63; 89-91; 99-101; 106-107; 119-120; 126
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 62-63; 89-91; 99-101; 106-107; 119-120; 126

20
[ 5291-32-7 ]
[ 2682935-03-9 ]

Yield	Reaction Conditions	Operation in experiment
7.17 %	With trichlorophosphate In dichloromethane at 0 - 25℃; Inert atmosphere;	24 Synthesis of Synthesis of tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (389.8 mg, 1.9 mmol, 3.0 equiv), DCM (10 mL), TEA (264.0 mg, 2.6 mmol, 4.0 equiv). This was followed by the addition of POCl3 (100 mg, 0.65 mmol, 1.0 equiv) at 0 . The resulting solution was stirred for 16 h at 25 degrees C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2 x 20 mL of dichloromethane/methanol (10:1) and washed with 2 x30 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, phase A: H2O (0.05% TFA); phase B: CH3CN (10% CH3CN up to 40% CH3CN in 12 min). This resulted in (30 mg, 7.17%) of tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride as a white solid. LC-MS (ES, m/z): M+1: 678. NMR (400 MHz, DMSO-d6) δ 11.84 (s, 2H), 4.96 (dd, J = 12.0, 4.1 Hz, 3H), 4.58 (dt, J = 12.7, 3.9 Hz, 3H), 4.10-3.97 (m, 6H), 3.79-3.57 (m, 6H), 3.47 (s, 6H), 3.39- 3.25 (m, 9H), 2.70 (s, 3H), 2.27-2.14 (m, 12H).
7.17 %	With trichlorophosphate In dichloromethane at 0 - 25℃; Inert atmosphere;	24 Synthesis of Synthesis of tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride: Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (389.8 mg, 1.9 mmol, 3.0 equiv), DCM (10 mL), TEA (264.0 mg, 2.6 mmol, 4.0 equiv). This was followed by the addition of POCl3 (100 mg, 0.65 mmol, 1.0 equiv) at 0 . The resulting solution was stirred for 16 h at 25 degrees C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2 x 20 mL of dichloromethane/methanol (10:1) and washed with 2 x30 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep C18 OBD Column, 50*250mm 5um 10nm; mobile phase, phase A: H2O (0.05% TFA); phase B: CH3CN (10% CH3CN up to 40% CH3CN in 12 min). This resulted in (30 mg, 7.17%) of tris((2-(methoxymethyl)-3-oxoquinuclidin-2-yl)methyl) phosphate hydrochloride as a white solid. LC-MS (ES, m/z): M+1: 678. NMR (400 MHz, DMSO-d6) δ 11.84 (s, 2H), 4.96 (dd, J = 12.0, 4.1 Hz, 3H), 4.58 (dt, J = 12.7, 3.9 Hz, 3H), 4.10-3.97 (m, 6H), 3.79-3.57 (m, 6H), 3.47 (s, 6H), 3.39- 3.25 (m, 9H), 2.70 (s, 3H), 2.27-2.14 (m, 12H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 107-108
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 107-108

21
[ 5291-32-7 ]
[ 2266582-96-9 ]

Yield	Reaction Conditions	Operation in experiment
41.9 %	With D-(+)-camphoric acid In acetonitrile at 25 - 50℃;	32 Synthesis of (S)-2-(hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one (assumed): Into a 2 L 3-necked round-bottom flask were added 2-(hydroxymethyl)-2- (methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one (80.0 g, 401.5 mmol, 1.0 eq), CH3CN (800 mL) and (1R,3S)-(+)-camphoric acid (80.4 g, 401.5 mmol, 1.0 eq) at 25°C. The resulting mixture was stirred for 3 hours at 50°C and then stirred for 16 hours at 25°C. The precipitated solids were collected by filtration and washed with CH3CN (80 mL) and then dried under infrared light. This collected solid was dissolved in water (300 mL) and basified to pH=8 with saturated aq. Na2CO3, and then extracted with CH2Cl2 (5×400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced vacuum to give (S)-2- (hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one (assumed) as a white solid (33.5 g, ee>99%, 41.9%). LC-MS (ES, m/z) M+1: 200.1HNMR (300 MHz, Chloroform-d) 3.98 (d, J=11.7Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 4H).246-S, TR=0.822 min in CHIRAL-SFC, Column: CHIRALPACK IG-3 50*3.0mm,3.0um. mobile phase A: CO2; mobile phase B: MeOH (20mM NH3), Aq. Method Set: 10% to 50%_B2_2_2200, Oven Temperature: 35oC.
190 mg	With Lux Cellulose-4,100*4.6 mm,3 μm In ethanol; hexane Resolution of racemate;	13 Synthesis of (2S)-2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (Assumed) : 450 mg of 2-(hydroxymethyl)-2- (methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one was purified by Chiral-Prep-HPLC with the following conditions: Column, Lux Cellulose-4,100*4.6 mm,3 um H19-381245; mobile phase A:n-Hexane(0.1%DEA); mobile phase B: Ethanol; Flow rate: 1.0 ml/min; Gradient: 0%B to 15%B in 7 min; Detector, 220 nm. This resulted in 190 mg of (2S)-2- (hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo [2.2.2]octan -3-one(Assumed) as an off- white solid. LC-MS (ES, m/z): M+1: 200; ee = 100%.1HNMR (300 MHz, Methanol-d4) δ 3.86 (d, J = 4.8 Hz, 2H), 3.83 - 3.64 (m, 2H), 3.44 - 3.47 (m, 2H), 3.33 - 3.32 (m, 3H), 2.97 - 2.81 (m, 2H), 2.36-2.32 (m, 1H), 2.10-2.02 (m, 4H).
41.9 %	With D-(+)-camphoric acid In acetonitrile at 25 - 50℃;	32 Synthesis of (S)-2-(hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one (assumed): Into a 2 L 3-necked round-bottom flask were added 2-(hydroxymethyl)-2- (methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one (80.0 g, 401.5 mmol, 1.0 eq), CH3CN (800 mL) and (1R,3S)-(+)-camphoric acid (80.4 g, 401.5 mmol, 1.0 eq) at 25°C. The resulting mixture was stirred for 3 hours at 50°C and then stirred for 16 hours at 25°C. The precipitated solids were collected by filtration and washed with CH3CN (80 mL) and then dried under infrared light. This collected solid was dissolved in water (300 mL) and basified to pH=8 with saturated aq. Na2CO3, and then extracted with CH2Cl2 (5×400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced vacuum to give (S)-2- (hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one (assumed) as a white solid (33.5 g, ee>99%, 41.9%). LC-MS (ES, m/z) M+1: 200.1HNMR (300 MHz, Chloroform-d) 3.98 (d, J=11.7Hz, 1H), 3.83-3.79 (m, 3H), 3.39-3.28 (m, 5H), 3.02-2.89 (m, 2H), 2.43-2.38 (m, 1H), 2.11-2.02 (m, 4H).246-S, TR=0.822 min in CHIRAL-SFC, Column: CHIRALPACK IG-3 50*3.0mm,3.0um. mobile phase A: CO2; mobile phase B: MeOH (20mM NH3), Aq. Method Set: 10% to 50%_B2_2_2200, Oven Temperature: 35oC.

190 mg

With Lux Cellulose-4,100*4.6 mm,3 μm In ethanol; hexane Resolution of racemate;

13 Synthesis of (2S)-2-(hydroxymethyl)-2-(methoxymethyl)-1- azabicyclo[2.2.2]octan-3-one (Assumed) : 450 mg of 2-(hydroxymethyl)-2- (methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one was purified by Chiral-Prep-HPLC with the following conditions: Column, Lux Cellulose-4,100*4.6 mm,3 um H19-381245; mobile phase A:n-Hexane(0.1%DEA); mobile phase B: Ethanol; Flow rate: 1.0 ml/min; Gradient: 0%B to 15%B in 7 min; Detector, 220 nm. This resulted in 190 mg of (2S)-2- (hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo [2.2.2]octan -3-one(Assumed) as an off- white solid. LC-MS (ES, m/z): M+1: 200; ee = 100%.1HNMR (300 MHz, Methanol-d4) δ 3.86 (d, J = 4.8 Hz, 2H), 3.83 - 3.64 (m, 2H), 3.44 - 3.47 (m, 2H), 3.33 - 3.32 (m, 3H), 2.97 - 2.81 (m, 2H), 2.36-2.32 (m, 1H), 2.10-2.02 (m, 4H).

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 126-127
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 88-89
[3]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 126-127
[4]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1 Location in patent: Page/Page column 88-89

22
[ 5291-32-7 ]
[ 2682934-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: D-(+)-camphoric acid / acetonitrile / 19 h / 25 - 50 °C 2.1: triethylamine / dichloromethane / 4 h / 25 °C 2.2: 10 h / 80 °C
	Multi-step reaction with 2 steps 1: D-(+)-camphoric acid / acetonitrile / 19 h / 25 - 50 °C 2: ethyl acetate / 48 h / 60 °C

Reference： [1]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1
[2]Current Patent Assignee: NEWAVE PHARMACEUTICAL INC - WO2022/204109, 2022, A1

23
[ 5291-32-7 ]
[ 1612259-06-9 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
2.18 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	2 60 mg of crude compound VII-2 and APR-246 (30 mg, 0.10 mmol) from the previous step were sequentially added to 2 mL of DMF, EDC hydrochloride (30 mg, 0.156 mmol) and DMAP (3 mg) were added, and the reaction was stirred at room temperature for 12 h. After completion, the solvent was evaporated to dryness and purified by column chromatography to obtain the target compound 2, 18 mg of white solid, with a yield of 24%.

Reference： [1]Current Patent Assignee: AIR FORCE MEDICAL UNIVERSITY OF PLA - CN115746060, 2023, A Location in patent: Paragraph 0044; 0056-0057; 0060-0061

24
[ 5291-32-7 ]
[ 1613484-34-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
1.15 mg	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	1 Add 59mg of crude compound VII-1 and APR-246 (30mg, 0.10mmol) from the previous step to 2mL DMF in turn, add EDC hydrochloride (30mg, 0.156mmol) and DMAP (3mg), stir the reaction at room temperature for 12h, and react After completion, the solvent was evaporated to dryness, and purified by column chromatography to obtain the target compound 1, 15 mg of white solid, with a yield of 21%.

Reference： [1]Current Patent Assignee: AIR FORCE MEDICAL UNIVERSITY OF PLA - CN115746060, 2023, A Location in patent: Paragraph 0044; 0046-0047; 0054-0055

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 5291-32-7 ] {[proInfo.proName]}

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[ 5291-32-7 ] Synthesis Path-Downstream 1~24

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Ethers

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Quinuclidines

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