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Chemical Structure| 832710-65-3

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2,8-Diazaspiro[4.5]decan-1-one hydrochloride

CAS No.: 832710-65-3

4.5 *For Research Use Only !

Cat. No.: A126135 Purity: 97%

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Product Details of [ 832710-65-3 ]

CAS No. :832710-65-3
Formula : C8H15ClN2O
M.W : 190.67
SMILES Code : Cl.O=C1NCCC11CCNCC1
MDL No. :MFCD02179151
Boiling Point : No data available
InChI Key :DLQSUWJKWQAKJH-UHFFFAOYSA-N
Pubchem ID :42614558

Safety of [ 832710-65-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Calculated chemistry of [ 832710-65-3 ] Show Less

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 ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

41.13 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.32
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

-0.08
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.6
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.31
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.43

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.22
Solubility 11.4 mg/ml ; 0.0597 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.75
Solubility 34.1 mg/ml ; 0.179 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-2.06
Solubility 1.65 mg/ml ; 0.00865 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

No
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.24 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.77

Application In Synthesis [ 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.

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

[ 832710-65-3 ] Synthesis Path-Downstream   1~25

  • 1
  • [ 625099-22-1 ]
  • [ 832710-65-3 ]
  • C26H35F3N4O2 [ No CAS ]
  • C26H35F3N4O2 [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 2
  • [ 832710-65-3 ]
  • [ 20017-68-9 ]
  • [ 832710-62-0 ]
YieldReaction ConditionsOperation 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).
  • 3
  • [ 832710-65-3 ]
  • [ 841200-43-9 ]
  • [ 841200-68-8 ]
YieldReaction ConditionsOperation 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)
  • 4
  • [ 832710-65-3 ]
  • [ 24424-99-5 ]
  • [ 268550-48-7 ]
YieldReaction ConditionsOperation 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.
  • 5
  • [ 832710-65-3 ]
  • [ 928149-24-0 ]
  • [ 928195-99-7 ]
YieldReaction ConditionsOperation 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]+.
  • 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 ]
YieldReaction ConditionsOperation 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]+.
  • 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 ]
YieldReaction ConditionsOperation 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)+.
  • 8
  • [ 832710-65-3 ]
  • [ 27064-94-4 ]
  • [ 1257999-90-8 ]
  • 9
  • [ 832710-65-3 ]
  • [ 94108-56-2 ]
  • [ 1349632-86-5 ]
YieldReaction ConditionsOperation 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
  • 10
  • [ 832710-65-3 ]
  • [ 777-44-6 ]
  • [ 1349632-83-2 ]
YieldReaction ConditionsOperation 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).
  • 11
  • [ 832710-65-3 ]
  • [ 2991-42-6 ]
  • [ 1349632-78-5 ]
YieldReaction ConditionsOperation 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).
  • 12
  • [ 832710-65-3 ]
  • [ 2991-42-6 ]
  • [ 1349633-04-0 ]
  • 13
  • [ 832710-65-3 ]
  • [ 705-21-5 ]
  • [ 1349633-00-6 ]
YieldReaction ConditionsOperation 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)
  • 14
  • [ 175205-54-6 ]
  • [ 832710-65-3 ]
  • [ 1349632-73-0 ]
YieldReaction ConditionsOperation 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).
  • 15
  • [ 220227-84-9 ]
  • [ 832710-65-3 ]
  • [ 1349632-98-9 ]
YieldReaction ConditionsOperation 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)
  • 16
  • 2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride [ No CAS ]
  • [ 832710-65-3 ]
  • [ 1349633-18-6 ]
YieldReaction ConditionsOperation 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).
  • 17
  • 2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride [ No CAS ]
  • [ 832710-65-3 ]
  • [ 1349633-06-2 ]
  • 18
  • 3-bromo-5-(trifluoromethyl)benzene-1-sulphonyl chloride [ No CAS ]
  • [ 832710-65-3 ]
  • [ 1349633-16-4 ]
YieldReaction ConditionsOperation 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).
  • 19
  • 3-bromo-5-(trifluoromethyl)benzene-1-sulphonyl chloride [ No CAS ]
  • [ 832710-65-3 ]
  • [ 1349633-05-1 ]
  • 20
  • [ 832710-65-3 ]
  • [ 176225-08-4 ]
  • [ 1349633-20-0 ]
YieldReaction ConditionsOperation 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).
  • 21
  • [ 832710-65-3 ]
  • [ 886499-99-6 ]
  • [ 1349632-94-5 ]
YieldReaction ConditionsOperation 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)
  • 22
  • [ 832710-65-3 ]
  • [ 886762-48-7 ]
  • [ 1349633-02-8 ]
YieldReaction ConditionsOperation 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)
  • 23
  • [ 832710-65-3 ]
  • [ 890095-46-2 ]
  • [ 1354946-05-6 ]
YieldReaction ConditionsOperation 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)
  • 24
  • [ 832710-65-3 ]
  • [ 35748-36-8 ]
  • [ 1383453-27-7 ]
YieldReaction ConditionsOperation 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)
  • 25
  • [ 832710-65-3 ]
  • [ 1383453-29-9 ]
  • [ 1383452-70-7 ]
YieldReaction ConditionsOperation 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).
 

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