[ CAS No. 832710-65-3 ] {[proInfo.proName]}

Name: 832710-65-3|2,8-Diazaspiro[4.5]decan-1-one hydrochloride|97%
Brand: Ambeed
SKU: A126135
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Quality Control of [ 832710-65-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 832710-65-3 ]

SDS Specification

Alternatived Products of [ 832710-65-3 ]

Product Details of [ 832710-65-3 ]

CAS No. :	832710-65-3	MDL No. :	MFCD02179151
Formula :	C₈H₁₅ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DLQSUWJKWQAKJH-UHFFFAOYSA-N
M.W :	190.67	Pubchem ID :	42614558
Synonyms :

Calculated chemistry of [ 832710-65-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.88
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	56.68
TPSA :	41.13 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.32
Log Po/w (WLOGP) :	-0.08
Log Po/w (MLOGP) :	0.6
Log Po/w (SILICOS-IT) :	1.31
Consensus Log Po/w :	0.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.22
Solubility :	11.4 mg/ml ; 0.0597 mol/l
Class :	Very soluble
Log S (Ali) :	-0.75
Solubility :	34.1 mg/ml ; 0.179 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.06
Solubility :	1.65 mg/ml ; 0.00865 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 832710-65-3 ]

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

Application In Synthesis of [ 832710-65-3 ]

* 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 [ 832710-65-3 ]
Downstream synthetic route of [ 832710-65-3 ]

[ 832710-65-3 ] Synthesis Path-Upstream 1~2

1
[ 832710-65-3 ]
[ 24424-99-5 ]
[ 268550-48-7 ]

Reference： [1] Patent: WO2005/84667, 2005, A1, . Location in patent: Page/Page column 78

2
[ 268550-48-7 ]
[ 832710-65-3 ]

Yield	Reaction Conditions	Operation in experiment
240 mg	With hydrogenchloride In ethanol; ethyl acetate at 60℃; for 2 h;	C) 2,8-diazaspiro[4.5]decan-1-one hydrochloride To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg), ethyl acetate (10 mL) and ethanol (2.0 mL) was added 4 M hydrogen chloride/ethyl acetate solution (5.0 mL) at room temperature, the mixture was stirred at 60°C for 2 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the obtained solid was collected by filtration to give the title compound (240 mg). ¹H NMR (300 MHz, CDCl₃) δ 1.47-1.64 (2H, m), 1.77-1.92 (2H, m), 1.93-2.03 (2H, m), 2.81-3.03 (2H, m), 3.11-3.34 (4H, m), 7.72 (1H, brs), 8.62-9.33 (2H, m).

Reference： [1] Patent: WO2015/17305, 2015, A1, . Location in patent: Page/Page column 106
[2] Patent: EP2933247, 2015, A1, . Location in patent: Paragraph 0335
[3] Patent: WO2016/60941, 2016, A1, . Location in patent: Page/Page column 56

[ 832710-65-3 ] Synthesis Path-Downstream 1~40

1
[ 625099-22-1 ]
[ 832710-65-3 ]
C₂₆H₃₅F₃N₄O₂ [ No CAS ]
C₂₆H₃₅F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 18; A mixture of the Intermediate 4 (176 mg, 0.5 mmol), the spiropiperidine (as HCl salt, 115 mg, 0.6 mmol), DIEA (100 mg, 0.8 mmol), molecular sieves (4 , 200 mg) and sodium triacetoxyborohydride (212 mg, 1.0 mmol) in dichloromethane (10 mL) was stirred overnight. The reaction was quenched with sat. aq. sodium carbonate. The solid was removed by filtration through celite. The crude product was extracted into dichloromethane and purified on preparative TLC (1000 micron, 10%[aq. NH4OH/MeOH 1/9]/DCM). The title compound was obtained as a mixture of cis and trans racemic isomers (155 mg, 63%). LC-MS calc. for C26H35F3N4O2: 492; Found: 493 (M+H).

Reference： [1]Patent: US2008/81803,2008,A1 .Location in patent: Page/Page column 52

2
[ 832710-65-3 ]
[ 20017-68-9 ]
[ 832710-62-0 ]

Yield	Reaction Conditions	Operation in experiment
44.9%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 8h;	To a mixture of 1. 49 g (7. 8 mmol) of 2, 8-diaza- spiro [4. 5] decan-l-one hydrochloride, 2. 39 g (8. 6 mmol) of 3, 3-diphenylpropyl bromide and 3. 23 g (23. 4 mmol) of potassium carbonate was added 40 mL of anhydrous DMF. The reaction mixture was stirred for 8 hours at 60C. Then 10 mL of water was added and the solution was extracted with DCM (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The yellow crude oil was purified by flash chromatography on silica gel (DCM/methanol 100 : 0 to 90 : 10) and 8- (3, 3-diphenylpropyl)-2, 8-diaza- spiro [4. 5] decan-l-one was isolated as a pale yellow solid (1. 22 g, 44. 9%). 1H NMR (400 MHZ, DMSO-D6) : o [PPM] 7. 49 (br s, 1H), 7. 3-7. 22 (m, 8H), 7. 13 (m, 2H), 3. 97 (t, 1H), 3. 09 (t, 2H), 2. 67 (m, 2H), 2. 13 (m, 4H), 1. 86 (m, 4H), 1. 63 (t x d, 2H), 1. 25 (br d, 2H).

Reference： [1]Patent: WO2005/7656,2005,A1 .Location in patent: Page 251

3
[ 832710-65-3 ]
[ 841200-43-9 ]
[ 841200-68-8 ]

Yield	Reaction Conditions	Operation in experiment
49%	With Silicycle dimethylamine resin; In acetonitrile; at 80℃; for 18h;	A suspension of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (EXAMPLE 9; 257 mg, 0.73 mmol), <strong>[832710-65-3]2,8-diaza-spiro[4.5]decan-1-one hydrochloride</strong> (153 mg, 0.80 mmol) and Silicycle dimethylamine resin (1.7 g, 2.4 mmol) in CH3CN was heated to 80 C. for 18 h. The reaction mixture was filtered, and the collected resin was rinsed with CH3CN. The combined filtrates were concentrated under reduced pressure to a crude solid, which was purified on SiO2 (10 g; 0-100% 10% [2 M NH3 in CH3OH] in CH2Cl2/CH2Cl2) to provide an off-white solid (152 mg, 49% yield). MS (ESI): mass calculated for C23H25N3O3S, 423.16; m/z found, 424.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.78 (dd, J=8.1, 0.6, 1H), 7.69 (dd, J=8.0, 0.8, 1H), 7.41 (dt, J=7.5, 1.3, 1H), 7.32-7.27 (m, 3H), 7.00 (m, 2H), 6.36 (br s, 1H), 4.15 (t, J=5.9, 2H), 3.36 (t, J=7.0, 2H), 3.00, (dt, J=11.9, 3.9, 2H), 2.87 (t, J=5.8, 2H), 2.32 (dt, J=11.5, 2.4, 2H), 2.10-1.98 (m, 2H), 2.07 (t, J=7.0, 2H), 1.50 (br d, J=13.3, 2H).
49%	With Silicycle dimethylamine resin; In acetonitrile; at 80℃; for 18h;	EXAMPLE 25; 8-F2- [4- (BENZOTHIAZOL-2-YLOXY)-PHENOXY]-ETHYL}-2, 8-diaza-spiro [4.5] decan-1-one; A suspension of 2- [4- (2-BROMO-ETHOXY)-PHENOXY]-BENZOTHIAZOLE (EXAMPLE 9; 257 mg, 0.73 MMOL), 2,8-diaza-spiro [4.5] DECAN-1-ONE hydrochloride (153 mg, 0.80 MMOL) and SILICYCLEE DIMETHYLAMINE resin (1.7 g, 2.4 MMOL) in CH3CN was heated to 80 C for 18 h. The reaction mixture was filtered, and the collected resin was rinsed with CH3CN. The combined filtrates were concentrated under reduced pressure to a crude solid, which was purified on Si02 (10 g ; 0-100% 10% [2 M NH3 in CH30H] in CH2CI2/CH2CI2) to provide an off-white solid (152 mg, 49% yield). MS (ESI) : mass calculated for C23H25N303S, 423.16 ; m/z found, 424.2 [M+H] +. 1H NMR (400 MHz, CDC13) : 7.78 (dd, J = 8.1, 0.6, 1 H), 7.69 (dd, J = 8.0, 0.8, 1H), 7.41 (dt, J = 7.5, 1.3, 1 H), 7.32-7. 27 (m, 3H), 7.00 (m, 2H), 6. 36 (BR S, 1 H), 4.15 (t, J = 5.9, 2H), 3.36 (t, J = 7.0, 2H), 3.00, (dt, J = 11.9, 3.9, 2H), 2.87 (t, J = 5. 8, 2H), 2.32 (dt, J = 11.5, 2.4, 2H), 2.10-1. 98 (m, 2H), 2.07 (t, J = 7.0, 2H), 1.50 (br d, J = 13.3, 2H)

Reference： [1]Patent: US2008/194630,2008,A1 .Location in patent: Page/Page column 35
[2]Patent: WO2005/12296,2005,A1 .Location in patent: Page/Page column 94-95

4
[ 832710-65-3 ]
[ 24424-99-5 ]
[ 268550-48-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; water;pH ~ 10;	To a solution of 2, 8-diaza-spiro [4.5] decan-l-one hydrochloride (763 mg, 4 mmol, 1 equiv) in 10 mL of 1 : 1 THF and water was added (Boc) 20 (960 mg, 1.1 equiv). The pH of the solution was adjusted to-10 by addition of K2CO3. Upon completion, the mixture was extraction with EtOAc. Organic layer was dried over sodium sulfate, filtered, and evaporated to givel-oxo-2, 8-diaza-spiro [4,5] decane-8-carboxylic acid tert-butyl ester.

Reference： [1]Patent: WO2005/84667,2005,A1 .Location in patent: Page/Page column 78

5
[ 832710-65-3 ]
[ 928149-24-0 ]
[ 928195-99-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 0.0833333h;Microwave irradiation;	Example 3 7-Chloro-3-[(5-{4-spiro[(2-pyrrolidinone)-3-yl1piperidin-1-yl)methyl)-([1 ,2,41-thiadiazol- 3-vDI-i -(tetrahydropyran-4-yl)methyl-1 /-/-indole, hydrochloride salt Methanesulfonic acid 3-(1-{tetrahydropyran-4-yl}methyl-7-chloro-1 H-indol-3- yl)-[1 ,2,4]thiadiazol-5-ylmethyl ester (Example 1 ; Step 1G; 0.10 g, 0.23 mmol) was dissolved in 1-methyl-2-pyrrolidinone (1 ml) and <strong>[832710-65-3]4-spiro-[3-(2-pyrrolidinone)]piperidine hydrochloride</strong> (0.21 g, 1.1 mmol) and potassium carbonate (0.30 g, 2.3 mmol) was added and the mixture was subjected to microwave irradiation for 5 min at 100 C. The mixture was filtered through a 5 g Strata SCX giga tube. The tube was washed with methanol and then eluted with 2 M ammonia in methanol. Purified by semi-prep HPLC (Method ii) to afford the title compound, (0.03 g, 0.062 mmol), as the free base. EsIMS: m/z 500.0 [M+H]+.

Reference： [1]Patent: WO2007/23143,2007,A1 .Location in patent: Page/Page column 19

6
[ 832710-65-3 ]
[ 928149-24-0 ]
7-chloro-3-[(5-{4-spiro-[(2-pyrrolidinone)-3-yl]piperidin-1-yl}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydronyran-4-yl)methyl-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 0.0833333h;Microwave irradiation;	EXAMPLE 3 7-Chloro-3-[(5-{4-spirol[(2-pyrrolidinone)-3-yltaupiperidin-1-yl}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydronyran-4-yl)methyl-1H-indole, hydrochloride salt Methanesulfonic acid 3-(1-{tetrahydropyran-4-yl}methyl-7-chloro-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (Example 1; Step 1G; 0.10 g, 0.23 mmol) was dissolved in 1-methyl-2-pyrrolidinone (1 ml) and <strong>[832710-65-3]4-spiro-[3-(2-pyrrolidinone)]piperidine hydrochloride</strong> (0.21 g, 1.1 mmol) and potassium carbonate (0.30 g, 2.3 mmol) was added and the mixture was subjected to microwave irradiation for 5 min at 100 C. The mixture was filtered through a 5 g Strata SCX giga tube. The tube was washed with methanol and then eluted with 2 M ammonia in methanol. Purified by semi-prep HPLC (Method ii) to afford the title compound, (0.03 g, 0.062 mmol), as the free base. EsIMS: m/z 500.0 [M+H]+.

Reference： [1]Patent: US2007/82931,2007,A1 .Location in patent: Page/Page column 9

7
[ 832710-65-3 ]
[ 1189852-16-1 ]
[ 76-05-1 ]
4-(2-hydroxypropan-2-yl)-N-(2-methyl-7-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		N-(7-Chloro-2-methylpyrazolo[ 1 ,5-alpha]pyrimidin-5-yl)-4-(2-hydroxypropan-2- yl)benzamide (2F, 0.05g, 1.0 equivalent) and 2,8-diazaspiro[4.5]decan-l-one hydrochloride (2.0 equivalents) in DMF (0.1M) was added Et3N (6.0 equivalents). The mixture was heated to 80 0C for 2.5h. Then the solvent was removed in vacuo and the crude mixture was purified by preparatory HPLC (20-35% ACN/water, TFA mode) to afford the TFA salt of the titled compound 241 (85%) as a white solid. 1H NMR (400 MHz, DMSO-J6) delta ppm 1.45 (s, 6 H) 1.56 (d, J=13.64 Hz, 2 H) 1.84 - 1.94 (m, 2 H) 2.08 (t, J=6.82 Hz, 2 H) 2.38 (s, 3H) 3.23 (t, J=6.82 Hz, 2 H) 3.31 (t, J=12.00 Hz, 2 H) 4.34 (ddd, J=12.76, 3.54, 3.41 Hz, 2 H) 6.16 (s, 1 H) 7.35 (s, 1 H) 7.57 - 7.62 (m, 2 H) 7.67 (s, 1 H) 7.96 - 8.01 (m, 2 H) 10.85 (s, 1 H); ESI-MS: m/z 463.2 (M+H)+.

Reference： [1]Patent: WO2009/123986,2009,A1 .Location in patent: Page/Page column 305

8
[ 832710-65-3 ]
[ 27064-94-4 ]
[ 1257999-90-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6375 - 6378

9
[ 832710-65-3 ]
[ 94108-56-2 ]
[ 1349632-86-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In dichloromethane; for 3h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (200 mg, 1.049 mmol) was dissolved in a mixture of dichloromethane (10 mL) and triethylamine (0.439 mL, 3.15 mmol), and 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (328 mg, 1 .259 mmol) was added. After 3 h, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica column chromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM) to give 8-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-2,8- diazaspiro[4.5]decan-1 -one (300 mg, 0.769 mmol, 73% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .45 (ddd, J=13.47, 3.49, 3.32 Hz, 2 H) 1.62 - 1.71 (m, 2 H) 1.76 (t, J=6.77 Hz, 2 H) 2.57 - 2.65 (m, 2 H) 3.09 (t, J=6.77 Hz, 2 H) 3.43 - 3.51 (m, 2 H) 7.60 (s, 1 H) 7.64 (dd, J=8.91 , 0.90 Hz, 2 H) 7.87 - 7.92 (m, 2 H). MS ES+ve m/z 379 (M+H

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 22-23

10
[ 832710-65-3 ]
[ 777-44-6 ]
[ 1349632-83-2 ]

Yield	Reaction Conditions	Operation in experiment
22%	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (200 mg, 1.049 mmol) was dissolved in a mixture of dichloromethane (10 mL) and triethylamine (0.439 mL, 3.15 mmol), and 3-(trifluoromethyl)benzenesulfonyl chloride (308 mg, 1.259 mmol) was added. After 16 h, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by silica column chromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM) to give two batches of the desired product as white solids: 8-[3- (trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (204 mg, 0.557 mmol, 53% yield) and 8-[3-(trifluoromethyl)phenyl]sulfonyl}-2,8- diazaspiro[4.5]decan-1 -one (83 mg, 0.227 mmol, 22% yield). 1 H NMR (400 MHz, DMSO-de) delta ppm 1 .45 (ddd, J=13.47, 3.55, 3.43 Hz, 2 H) 1.62 - 1 .71 (m, 2 H) 1 .76 (t, J=6.80 Hz, 2 H) 2.59 - 2.69 (m, 2 H) 3.08 (t, J=6.82 Hz, 2 H) 3.47 - 3.56 (m, 2 H) 7.60 (s, 1 H) 7.92 (t, J=7.87 Hz, 1 H) 7.98 (br. s., 1 H) 8.08 (d, J=8.00 Hz, 1 H) 8.14 (d, J=7.78 Hz, 1 H). MS ES+ve m/z 363 (M+H).

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 21-22

11
[ 832710-65-3 ]
[ 2991-42-6 ]
[ 1349632-78-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (280 mg, 1.469 mmol) was dissolved in dichloromethane (40 mL) and triethylamine (0.614 mL, 4.41 mmol), and 4-(trifluoromethyl)benzenesulfonyl chloride (467 mg, 1 .909 mmol) was added. After 16 h, the reaction mixture was washed with aqueous 2 M HCI followed by aqueous 2 M NaOH, and the organic layer was passed through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by silica columnchromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM) to give 8-[4- (trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (532 mg, 1 .453 mmol, 99% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.45 (ddd, J=13.29, 3.51 , 3.32 Hz, 2 H) 1.61 - 1 .72 (m, 2 H) 1 .77 (t, J=6.80 Hz, 2 H) 2.60 - 2.70 (m, 2 H) 3.09 (t, J=6.82 Hz, 2 H) 3.49 (ddd, J=1 1 .96, 4.65, 4.38 Hz, 2 H) 7.60 (s, 1 H) 7.97 (d, J=8.28 Hz, 2 H) 8.04 (d, J=8.39 Hz, 2 H). MS ES+ve m/z 363 (M+H).

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 18-19

12
[ 832710-65-3 ]
[ 2991-42-6 ]
[ 1349633-04-0 ]

Reference： [1]Patent: WO2011/141729,2011,A1

13
[ 832710-65-3 ]
[ 705-21-5 ]
[ 1349633-00-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In dichloromethane; for 17h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (1 1 1 mg, 0.584 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.244 mL, 1 .751 mmol), and 3,5-dichlorobenzenesulfonyl chloride (158 mg, 0.642 mmol) was added. After stirring for 17 h the reaction mixture was concentrated in vacuo and the resulting residue was purified by MDAP to give two batches of products: 8-[(3,5-dichlorophenyl)- sulfonyl]-2,8-diazaspiro[4.5]decan-1 -one (53.5 mg, 0.144 mmol, 25% yield) and 8- [(3,5-dichlorophenyl)sulfonyl]-2,8-diazaspiro[4.5]decan-1 -one (76.6 mg, 0.207 mmol, 35% yield) both as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.45 (ddd, J=13.33, 3.27, 3.01 Hz, 2 H) 1.60 - 1 .72 (m, 2 H) 1 .81 (t, J=6.80 Hz, 2 H) 2.61 - 2.74 (m, 2 H) 3.10 (t, J=6.80 Hz, 2 H) 3.52 (ddd, J=12.02, 4.48, 4.17 Hz, 2 H) 7.61 (s, 1 H) 7.76 (d, J=1.92 Hz, 2 H) 8.05 (t, J=1.86 Hz, 1 H). MS ES+ve m/z 363 (M+H)

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 29

14
[ 175205-54-6 ]
[ 832710-65-3 ]
[ 1349632-73-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (240 mg, 1.259 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.526 mL, 3.78 mmol), and 2-chloro-4-(trifluoromethyl)benzenesulfonyl chloride (457 mg, 1.636 mmol) was added. After stirring for 16 h, the reaction mixture was washed sequentially with aqueous 0.5 M HCI and 0.5 M NaOH, the organic layer was passed through a hydrophobic frit, and concentrated in vacuo. The resulting residue was recrystallised from methanol to give 8-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-2,8- diazaspiro[4.5]decan-1 -one (300 mg, 0.718 mmol, 57% yield) as a white solid. 1 H NMR (250 MHz, DMSO-d6) delta ppm 1 .38 - 1.49 (m, 2 H) 1.65 (ddd, J=13.38, 10.87, 4.22 Hz, 2 H) 1 .91 (t, J=6.83 Hz, 2 H) 2.96 - 3.09 (m, 2 H) 3.14 (t, J=6.81 Hz, 2 H) 3.65 (dt, J=12.99, 4.21 Hz, 2 H) 7.61 (s, 1 H) 7.94 (ddd, J=8.27, 1 .82, 0.62 Hz, 1 H) 8.14 - 8.22 (m, 2 H). MS ES+ve m/z 397 (M+H).

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 16-17

15
[ 220227-84-9 ]
[ 832710-65-3 ]
[ 1349632-98-9 ]

Yield	Reaction Conditions	Operation in experiment
49%	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (100 mg, 0.524 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.146 mL, 1.047 mmol). Then 3-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.098 mL, 0.577 mmol) was added and stirred for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by MDAP to give 8-({3-[(trifluoromethyl)oxy]phenyl}- sulfonyl)-2,8-diazaspiro[4.5]decan-1 -one (99 mg, 0.259 mmol, 49% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .44 (ddd, J=13.41 , 3.55, 3.32 Hz, 2 H) 1 .60 - 1 .71 (m, 2 H) 1 .76 (t, J=6.80 Hz, 2 H) 2.57 - 2.69 (m, 2 H) 3.09 (t, J=6.82 Hz, 2 H) 3.45 - 3.54 (m, 2 H) 7.60 (s, 1 H) 7.68 (dd, J=1.67, 0.79 Hz, 1 H) 7.74 - 7.83 (m, 3 H). MS ES+ve m/z 379 (M+H)

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 27-28

16
2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride [ No CAS ]
[ 832710-65-3 ]
[ 1349633-18-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (200 mg, 1.049 mmol) was dissolved in a mixture of triethylamine (0.439 mL, 3.15 mmol) and dichloromethane (10 mL), and 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (407 mg, 1 .259 mmol) was added. The reaction mixture was stirred for 16 h and the reaction mixture was concentrated in vacuo. The resulting yellow solid 8-[2-bromo-4- (trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (820 mg, impure) was used in the next reaction without further purification. MS ES+ve m/z 443 (M+H). 8-[2-Bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (820 mg, impure) and potassium carbonate (217 mg, 1 .574 mmol) was suspended in 1 ,4- dioxane (10 mL). Trimethylboroxine (0.219 mL, 1.574 mmol) and Pd(PPh3)4 (121 mg, 0.105 mmol) were then added and the reaction mixture was heated to 100 C. After 20 h, the reaction was cooled, filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by silica column chromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM). The resulting brown residue was further purified on MDAP to give 8-[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}-2,8- diazaspiro[4.5]decan-1 -one (61 mg, 0.160 mmol, 15% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .39 - 1.49 (m, 2 H) 1.59 - 1 .69 (m, 2 H) 1 .89 (t, J=6.80 Hz, 2 H) 2.64 (s, 3 H) 2.85 - 2.96 (m, 2 H) 3.13 (t, J=6.82 Hz, 2 H) 3.54 (ddd, J=12.48, 4.01 , 3.84 Hz, 2 H) 7.63 (s, 1 H) 7.79 (d, J=7.67 Hz, 1 H) 7.89 (s, 1 H) 8.01 (d, J=8.22 Hz, 1 H). MS ES+ve m/z 377 (M+H).

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 32-33

17
2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride [ No CAS ]
[ 832710-65-3 ]
[ 1349633-06-2 ]

Reference： [1]Patent: WO2011/141729,2011,A1

18
3-bromo-5-(trifluoromethyl)benzene-1-sulphonyl chloride [ No CAS ]
[ 832710-65-3 ]
[ 1349633-16-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (200 mg, 1.049 mmol) was dissolved in a mixture of triethylamine (0.439 mL, 3.15 mmol) and dichloromethane (10 mL), and 3-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (407 mg, 1 .259 mmol) was added. The reaction mixture was stirred for 16 h and the reaction mixture was concentrated in vacuo. The resulting yellow solid 8-[3-bromo-5- (trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (819 mg, impure) was used in the next reaction without further purification. MS ES+ve m/z 443 (M+H). 8-[3-Bromo-5-(trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (819 mg, impure) and potassium carbonate (217 mg, 1.574 mmol) was suspended in 1 ,4- dioxane (10 mL). Trimethylboroxine (0.219 mL, 1.574 mmol) and Pd(PPh3)4 (121 mg, 0.105 mmol) were then added and the reaction mixture was heated to 100 C. After 20 h, the reaction was cooled, filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by silica column chromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM). The resulting brown residue was further purified on MDAP to give 8-[3-methyl-5-(trifluoromethyl)phenyl]sulfonyl}-2,8- diazaspiro[4.5]decan-1 -one (126 mg, 0.331 mmol, 32% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .46 (dt, J=13.41 , 3.46 Hz, 2 H) 1.61 - 1 .72 (m, 2 H) 1 .77 (t, J=6.80 Hz, 2 H) 2.52 (s, 3 H) 2.57 - 2.66 (m, 2 H) 3.09 (t, J=6.80 Hz, 2 H) 3.46 - 3.54 (m, 2 H) 7.55 - 7.63 (m, 1 H) 7.76 (s, 1 H) 7.89 (s, 1 H) 7.96 (s, 1 H). MS ES+ve m/z 377 (M+H).

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 31-32

19
3-bromo-5-(trifluoromethyl)benzene-1-sulphonyl chloride [ No CAS ]
[ 832710-65-3 ]
[ 1349633-05-1 ]

Reference： [1]Patent: WO2011/141729,2011,A1

20
[ 832710-65-3 ]
[ 176225-08-4 ]
[ 1349633-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (200 mg, 1.049 mmol) was dissolved in a mixture of triethylamine (0.439 ml, 3.15 mmol) and dichloromethane (10 ml), and 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (407 mg, 1 .259 mmol) was added. The reaction mixture was stirred for 16 h and the reaction mixture was concentrated in vacuo. The resulting yellow solid 8-[2-bromo-5- (trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (825 mg, impure) was used in the next reaction without further purification. MS ES+ve m/z 443 (M+H). 8-[2-bromo-5-(trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (825 mg, impure) and potassium carbonate (217 mg, 1.574 mmol) was suspended in 1 ,4- dioxane (10 ml_). Trimethylboroxine (0.219 ml_, 1.574 mmol) and Pd(PPh3)4 (121 mg, 0.105 mmol) were then added and the reaction mixture was heated to 100 C. After 20 h, the reaction was cooled, filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by silica column chromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM). The resulting brown residue was further purified on MDAP twice to give 8-[2-methyl-5-(trifluoromethyl)phenyl]sulfonyl}-2,8- diazaspiro[4.5]decan-1 -one (41 mg, 0.107 mmol) as a white solid. 1 H N MR (400 MHz, DMSO-de) delta ppm 1.39 - 1.49 (m, 2 H) 1.58 - 1 .70 (m, 2 H) 1 .89 (t, J=6.80 Hz, 2 H) 2.65 (s, 3 H) 2.84 - 2.95 (m, 2 H) 3.13 (t, J=6.80 Hz, 2 H) 3.54 (ddd, J=12.63, 4.08, 3.95 Hz, 2 H) 7.63 (s, 1 H) 7.74 (d, J=7.95 Hz, 1 H) 7.98 (dd, J=8.03, 1 .40 Hz, 1 H) 8.03 (d, J=1 .21 Hz, 1 H). MS ES+ve m/z 377 (M+H).

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 33-34

21
[ 832710-65-3 ]
[ 886499-99-6 ]
[ 1349632-94-5 ]

Yield	Reaction Conditions	Operation in experiment
42%	With triethylamine; In dichloromethane; for 17h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (100 mg, 0.524 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.219 mL, 1 .573 mmol). Then 3-fluoro-5-(trifluoromethyl)benzenesulfonyl chloride (165 mg, 0.629 mmol) was added and stirred for 17 h. The mixture was concentrated in vacuo and the resulting residue was purified by MDAP to give two batches of product: 8-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonyl}-2,8-diazaspiro[4.5]decan-1 -one (33.74 mg, 0.087 mmol, 17% yield) and 8-[3-fluoro-5-(trifluoromethyl)phenyl]sulfonyl}-2,8- diazaspiro[4.5]decan-1 -one (51 mg, 0.131 mmol, 25% yield) both as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .41 - 1.48 (m, 2 H) 1.61 - 1 .70 (m, 2 H) 1 .80 (t, J=6.80 Hz, 2 H) 2.64 - 2.73 (m, 2 H) 3.10 (t, J=6.80 Hz, 2 H) 3.55 (ddd, J=12.15, 4.34, 4.1 1 Hz, 2 H) 7.61 (s, 1 H) 7.84 (s, 1 H) 8.00 (d, J=7.73 Hz, 1 H) 8.18 (d, J=8.50 Hz, 1 H). MS ES+ve m/z 381 (M+H)

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 26

22
[ 832710-65-3 ]
[ 886762-48-7 ]
[ 1349633-02-8 ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine; In dichloromethane; for 16h;	2,8-Diazaspiro[4.5]decan-1 -one hydrogen chloride (185 mg, 0.973 mmol) was dissolved in a mixture of triethylamine (0.542 ml_, 3.89 mmol) and dichloromethane (10 ml_), and 3-chloro-4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (344 mg, 1 .167 mmol) was added. After 16 h the reaction mixture was concentrated in vacuo and the resulting residue was purified by silica column chromatography on SP4 (gradient elution: 0 - 20% MeOH - DCM) to give a yellow solid. The yellow solid was further purified on MDAP to give 8-({3-chloro-4-[(trifluoromethyl)oxy]phenyl}sulfonyl)- 2,8-diazaspiro[4.5]decan-1 -one (269 mg, 0.645 mmol, 66% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1 .40 - 1.51 (m, 2 H) 1.61 - 1 .72 (m, 2 H) 1 .80 (t, J=6.80 Hz, 2 H) 2.62 - 2.73 (m, 2 H) 3.10 (t, J=6.82 Hz, 2 H) 3.51 (ddd, J=12.00, 4.38, 4.17 Hz, 2 H) 7.61 (s, 1 H) 7.80 - 7.89 (m, 2 H) 8.02 - 8.07 (m, 1 H). MS ES+ve m/z 413 (M+H)

Reference： [1]Patent: WO2011/141729,2011,A1 .Location in patent: Page/Page column 29-30

23
[ 832710-65-3 ]
[ 890095-46-2 ]
[ 1354946-05-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 120℃; for 0.333333h;Microwave irradiation;	Compound 12: 8-({1-[3-(Trifluoromet yl)phenyl]-1W-tetrazol-5-yl}methyl)-2,8- diazaspiro[4.5]f. e can-1-one; To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1 H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added 2,8-diazaspiro[4.5]decan-1 -one hydrochloride (290 mg, 1.52 mmol, Tyger Scientic, Ewing, USA) and triethylamine (0.318 mL, 2.29 mmol). The reaction mixture was heated at 120C for 20 minutes in a microwave reactor. The reaction mixture was then cooled and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The product was partitioned between DC (6mL) and saturated aqueous NaHC03 (3mL) and the organic layer collected via a hydrophobic frit. The solvent was removed under a stream of argon to yield the title compound as a solid (0.161g).MS ES+ve m/z 381 (M+H)1H NMR (400 MHz, Chloroform-d) d ppm 1.48 (d, 2 H) 1.88 - 1.97 (m, 2 H) 2.06 (t, J=6.9 Hz, 2 H) 2.37 (td, J=11 .4, 2.6 Hz, 2 H) 2.92 (dt, J=1 1 .8, 3.8 Hz, 2 H) 3.35 (t, J=6.9 Hz, 2 H) 3.78 (s, 2 H) 5.95 (br. s., 1 H) 7.74 (t, J=7.9 Hz, 1 H) 7.83 (d, J=7.9 Hz, 1 H) 8.1 1 (d, J=8.1 Hz, 1 H) 8.33 (s, 1 H)

Reference： [1]Patent: WO2012/4604,2012,A1 .Location in patent: Page/Page column 90-91

24
[ 832710-65-3 ]
[ 35748-36-8 ]
[ 1383453-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃;	1-1To a solution of 3-nitrosalicyclic acid (500 mg, 2.73 mmol) in dichloromethane (10 mL) is added oxalylchloride (2 M in dichloromethane, 1.50 ml, 3 mmol) and three drops ofN,N- dimethylformamide. The mixture is stirred at room temperature overnight. The solvent is evaporated under vacuum to leave a crude residue, a portion of which (127 mg, 0.63 mmol) is dissolved in dichloromethane (5 mL) and the solution cooled to 0 C. Triethylamine (0.22 mL, 1.57 mmol) is added followed by 2,8-diaza-spiro[4.5]decan-l-one hydrochloride (100 mg, 0.52 mmol). The mixture is allowed to warm to room temperature and stirred overnight. Water is added, the phases separated, the organic layer dried over MgS04 and evaporated under reduced pressure to give compound 1-1.Yield: 200 mgES mass spectrum: [M+H]+ = 320Retention time: 0.69 min (UPLC method 2)

Reference： [1]Patent: WO2012/80456,2012,A1 .Location in patent: Page/Page column 34

25
[ 832710-65-3 ]
[ 1383453-29-9 ]
[ 1383452-70-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4Compound 4-2 (50 mg, 0.15 mmol) and PyBOP (160 mg, 0.31 mmol) are dissolved in DMF (1.5 mL) and stirred for 20 minutes. 2,8-Diaza-spiro[4.5]decan-l-one hydrochloride (41 mg, 0.22 mmol) and triethylamine (86 mu, 0.62 mmol) are added and the mixture stirred overnight. The solvent is removed under reduced pressure, the residue dissolved in DCM and washed with 5% aqueous NaHC03 solution, dried and the solvent removed. The residue is purified by flash chromatography (Silica Gel, gradient: DCM/methanol from 98:2 to 90: 10) to give Example 4.Yield: 14 mgES mass spectrum: [M+H]+ = 461Retention time: 9.95 min (Method 6)'H NMR (Varian 400 MHz. DMSO-d6; 28 C) 9.57 (IH, br); 9.17 (IH, s); 9.08 (IH, s); 7.97 (2H, m); 7.57 (IH, s); 7.31 (IH, m); 7.05 (IH, m); 6.84 (2H, m); 3.91 (IH, br); 3.09 (5H, m); 1.99 (2H, m); 1.67 (2H, m); 1.39 (2H, m).
		Compound 4-2 (50 mg, 0.15 mmol) and PyBOP (160 mg, 0.31 mmol) are dissolved in DMF (1.5 mL) and stirred for 20 minutes. 2,8-Diaza-spiro[4.5]decan-1-one hydrochloride (41 mg, 0.22 mmol) and triethylamine (86 muL, 0.62 mmol) are added and the mixture stirred overnight. The solvent is removed under reduced pressure, the residue dissolved in DCM and washed with 5% aqueous NaHCO3 solution, dried and the solvent removed. The residue is purified by flash chromatography (Silica Gel, gradient: DCM/methanol from 98:2 to 90:10) to give Example 4.Yield: 14 mgES mass spectrum: [M+H]+=461Retention time: 9.95 min (Method 6)1H NMR (Varian 400 MHz. DMSO-d6; 28 C.) 9.57 (1H, br); 9.17 (1H, s); 9.08 (1H, s); 7.97 (2H, m); 7.57 (1H, s); 7.31 (1H, m); 7.05 (1H, m); 6.84 (2H, m); 3.91 (1H, br); 3.09 (5H, m); 1.99 (2H, m); 1.67 (2H, m); 1.39 (2H, m).

Reference： [1]Patent: WO2012/80456,2012,A1 .Location in patent: Page/Page column 38
[2]Patent: US2012/329773,2012,A1 .Location in patent: Page/Page column 17-18

26
[ 832710-65-3 ]
[ 1400797-17-2 ]
[ 1400795-10-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example of General Method A: Preparation of 8-[(S)-4-(2,3-Dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)-benzyl]-2,8- diaza-spiro[4.5]decan-l-one (Example 125)TEA (0.12mL, 0.83 mmol) is added to a mixture of C (100 mg, 0.42 mmol) and 2,8-Diaza-spiro[4.5]decan-l-one; hydrochloride (158 mg, 0.83 mmol) in 2 mL of DCM. One drop of acetic acid is added, and the mixture is stirred for 10 min,sodiumacetoxyborohydride (132mg, 0.83 mmol) is added, and the resulting mixture is stirred for 24 h. The solvent is evaporated and the crude mixture is dissolved in 2 ml of MeCN/H20 (1:1). The mixture is purified on a reverse phase CI 8 semi-preparative HPLC column eluting with a gradient of 0-95% MeCN/H20 to give the title product.
		General procedure: Synthesis of Compounds of Formula I General Method A through N (protocols for reductive amination). Example of General Method A: TEA (0.12mL, 0.83 mmol) is added to a mixture of C (100 mg, 0.42 mmol) and 2,8-Diaza-spiro[4.5]decan-l-one; hydrochloride (158 mg, 0.83 mmol) in 2 mL of DCM. One drop of acetic acid is added, and the mixture is stirred for 10 min, sodiumacetoxyborohydride (132mg, 0.83 mmol) is added, and the resulting mixture is stirred for 24 h. The solvent is evaporated and the crude mixture is dissolved in 2 ml of MeCN/H20 (1:1). The mixture is purified on a reverse phase CI 8 semi-preparative HPLC column eluting with a gradient of 0-95% MeCN/H20 to give the title product.

Reference： [1]Patent: WO2012/125598,2012,A1 .Location in patent: Page/Page column 63
[2]Patent: WO2013/134226,2013,A1 .Location in patent: Page/Page column 103; 104

27
[ 832710-65-3 ]
[ 85-38-1 ]
[ 1383453-27-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 3-nitrosalicyclic acid (500 mg, 2.73 mmol) in dichloromethane (10 mL) is added oxalylchloride (2 M in dichloromethane, 1.50 ml, 3 mmol) and three drops of N,N-dimethylformamide. The mixture is stirred at room temperature overnight. The solvent is evaporated under vacuum to leave a crude residue, a portion of which (127 mg, 0.63 mmol) is dissolved in dichloromethane (5 mL) and the solution cooled to 0 C. Triethylamine (0.22 mL, 1.57 mmol) is added followed by <strong>[832710-65-3]2,8-diaza-spiro[4.5]decan-1-one hydrochloride</strong> (100 mg, 0.52 mmol). The mixture is allowed to warm to room temperature and stirred overnight. Water is added, the phases separated, the organic layer dried over MgSO4 and evaporated under reduced pressure to give compound 1-1.Yield: 200 mgES mass spectrum: [M+H]+=320Retention time: 0.69 min (HPLC method 2)

Reference： [1]Patent: US2012/329773,2012,A1 .Location in patent: Page/Page column 16

28
[ 832710-65-3 ]
[ 1383452-98-9 ]

Reference： [1]Patent: US2012/329773,2012,A1

29
[ 832710-65-3 ]
[ 1383452-66-1 ]

Reference： [1]Patent: US2012/329773,2012,A1

30
[ 832710-65-3 ]
[ 1383453-28-8 ]

Reference： [1]Patent: US2012/329773,2012,A1

31
[ 268550-48-7 ]
[ 832710-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; water; at 20℃; for 8h;	Step A: 2,8-diazaspiro[4.Sldecan-1-one hydrochloride: To a solution of tert-butyl 1-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (Inermediate 14, 92 g, 0.36 mol) in CH2C12 (1 L) was slowly added a 4 M HC1 solution (500 mL). The mixture was stirred for 8 h at RT. The mixture was concentrated under vacuum to afford the title compound. ?H NMR (400 MHz, DMSO-d6) oe 9.35 (s, 1H), 9.02 (s, 1H), 7.72 (s, 1H), 3.30-3.20 (m, 2H), 3.16 (m,J= 6.8Hz, 2H), 2.98-2.85(m, 2H), 1.96 (m,J= 6.8Hz, 2H), 1.90-1.80 (m, 2H), 1.55 (d,J 14Hz, 2H).
240 mg	With hydrogenchloride; In ethanol; ethyl acetate; at 60℃; for 2h;	C) 2,8-diazaspiro[4.5]decan-1-one hydrochloride To a mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (400 mg), ethyl acetate (10 mL) and ethanol (2.0 mL) was added 4 M hydrogen chloride/ethyl acetate solution (5.0 mL) at room temperature, the mixture was stirred at 60C for 2 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the obtained solid was collected by filtration to give the title compound (240 mg). 1H NMR (300 MHz, CDCl3) delta 1.47-1.64 (2H, m), 1.77-1.92 (2H, m), 1.93-2.03 (2H, m), 2.81-3.03 (2H, m), 3.11-3.34 (4H, m), 7.72 (1H, brs), 8.62-9.33 (2H, m).
	With hydrogenchloride; In dichloromethane; ethyl acetate; at 20℃; for 8h;	To a solution of tert-butyl l-oxo-2,8- diazaspiro[4.5]decane-8-carboxylate (INTERMEDIATE 14) (92 g, 0.36 mol) in CH2C12 (1 L) was slowly added a 4 M HC1 solution in EtOAc (500 mL). The mixture was stirred for 8 h at rt. The mixture was concentrated under vacuum to afford the title compound. 1H-NMR (400 MHz, DMSO-d6): delta 9.35 (s, 1H), 9.02 (s, 1H), 7.72 (s, 1H), 3.30-3.20 (m, 2H), 3.16 (m, J = 6.8Hz, 2H), 2.98-2.85 (m, 2H), 1.96 (m, J = 6.8Hz, 2H), 1.90-1.80 (m, 2H), 1.55 (d, J = 14 Hz, 2H).

Reference： [1]Patent: WO2015/17305,2015,A1 .Location in patent: Page/Page column 106
[2]Patent: EP2933247,2015,A1 .Location in patent: Paragraph 0335
[3]Patent: WO2016/60941,2016,A1 .Location in patent: Page/Page column 56

32
[ 832710-65-3 ]
[ 1255206-70-2 ]
(R)-8-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2,8-diazaspiro[4.5]decan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step B: (R)-8-(2-hydroxy-2-(4-methyl- 1 -oxo- 1 ,3-dihydroisobenzofuran-5-yl)ethyl)-2,8- diazaspiro [4.51 decan- 1-one: To a solution of 2, 8-diazaspiro [4.5 ]decan- 1-one hydrochloride (68 g, 0.35 mol) in ethanol (1.5 L) was added Et3N (55 mL). The mixture was stirred for 2 hours. Then (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-1(3H)-one (Intermediate 3B, 65 g, 0.34 mol)was added. The mixture was heated to reflux for 40 h. After filtration, the solid was collected toprovide the title compound. The filtrate was concentrated and purified by SFC separation toprovide additional title compound. ?H NMR (400 Hz, CDC13) oe 7.82-7.75 (m, 2H), 6.00 (s, 1H),5.24 (s, 2H), 5.08 (dd, J= 2.1 Hz and 10.4 Hz, 1H), 4.21 (s, 1H), 3.35 (t, J= 6.8 Hz, 2H), 3.17-3.14 (m, 1H), 2.85-2.82 (m, 1H), 2.57 (dd, J 2.1 Hz and 10.4 Hz, 1H), 2.49 (t, J= 8.8 Hz, 1H),2.37 (t, J= 10.8 Hz, 1H), 2.27 (s, 3H), 2.23 (J 6.8 Hz, 1H), 2.09-1.98 (m, 4H), 1.52 (t, J 12.8 Hz, 2H).
	With triethylamine; In ethanol; for 40h;Reflux;	To a solution of 2,8-diazaspiro[4.5]decan-l-one hydrochloride (68 g, 0.35 mol) in ethanol (1.5 L) was added Et3N (55 mL). The mixture was stirred for 2 hours. Next, (R)-4-methyl-5-(oxiran-2-yl)isobenzofuran-l(3H)-one (65 g, 0.34 mol) was added. The mixture was heated to reflux for 40 h. After filtration, the solid was collected to provide the title compound. The filtrate was concentrated and purified by SFC separation to provide additional (R)-8-(2-hydroxy-2-(4-methyl-l-oxo-l,3-dihydroisobenzofuran-5-yl)ethyl)-2,8- diazaspiro[4.5]decan-l-one. 1H-NMR (400 Hz, CDC13): delta 7.82-7.75 (m, 2H), 6.00 (s, 1H), 5.24 (s, 2H), 5.08 (dd, J = 2.1 Hz and 10.4 Hz, 1H), 4.21 (s, 1H), 3.35 (t, J = 6.8 Hz, 2H), 3.17-3.14 (m, 1H), 2.85-2.82 (m, 1H), 2.57 (dd, J = 2.1 Hz and 10.4 Hz, 1H), 2.49 (t, J = 8.8 Hz, 1H), 2.37 (t, J = 10.8 Hz, 1H), 2.27 (s, 3H), 2.23 (J = 6.8 Hz, 1H), 2.09-1.98 (m, 4H), 1.52 (t, J = 12.8 Hz, 2H).

Reference： [1]Patent: WO2015/17305,2015,A1 .Location in patent: Page/Page column 106
[2]Patent: WO2016/60941,2016,A1 .Location in patent: Page/Page column 57

33
[ 832710-65-3 ]
3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine [ No CAS ]
8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36 mg	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 160 - 180℃; for 31h;	D) 8-(4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)-2,8-diazaspiro[4.5]decan-1-one A mixture of 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (50 mg), <strong>[832710-65-3]2,8-diazaspiro[4.5]decan-1-one hydrochloride</strong> (54 mg), potassium carbonate (120 mg) and NMP (0.20 mL) was stirred at 160C for 1 day, and then at 180C for 7 hr. The mixture was allowed to be cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (36 mg). MS (API+): [M+H]+312.2.

Reference： [1]Patent: EP2933247,2015,A1 .Location in patent: Paragraph 0336

34
[ 832710-65-3 ]
3-bromo-4-chloro-5-methylpyridine [ No CAS ]
8-(3-bromo-5-methylpyridin-4-yl)-2,8-diazaspiro[4.5]decan-1-one [ No CAS ]