[ CAS No. 1159599-99-1 ]

Name: 1159599-99-1|2-Oxa-6-azaspiro[3.3]heptane oxalate|97%
Brand: Ambeed
SKU: A161934
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Quality Control of [ 1159599-99-1 ]

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Product Details of [ 1159599-99-1 ]

CAS No. :	1159599-99-1	MDL No. :	MFCD11976178
Formula :	C₇H₁₁NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	189.17 g/mol	Pubchem ID :	53308464
Synonyms :

Calculated chemistry of of [ 1159599-99-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.71
Num. rotatable bonds :	1
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	44.73
TPSA :	95.86 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) :	-9.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.71
Log Po/w (XLOGP3) :	-3.22
Log Po/w (WLOGP) :	-1.62
Log Po/w (MLOGP) :	-1.43
Log Po/w (SILICOS-IT) :	1.4
Consensus Log Po/w :	-0.83

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	1.08
Solubility :	2280.0 mg/ml ; 12.1 mol/l
Class :	Highly soluble
Log S (Ali) :	1.78
Solubility :	11300.0 mg/ml ; 59.9 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.96
Solubility :	20.7 mg/ml ; 0.109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 1159599-99-1 ]

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

Application In Synthesis of [ 1159599-99-1 ]

* 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 [ 1159599-99-1 ]
Downstream synthetic route of [ 1159599-99-1 ]

[ 1159599-99-1 ] Synthesis Path-Upstream 1~8

1
[ 13573-28-9 ]
[ 144-62-7 ]
[ 1159599-99-1 ]

Yield	Reaction Conditions	Operation in experiment
51.1%	Stage #1: With magnesium In methanolSonication; Inert atmosphere Stage #2: for 0.0833333 h; Inert atmosphere	To a solution of 9 (7.5 g, 29.6 mmol) in 500 mL MeOH, magnesium turnings (5.04 g, 207 mmol) were added and reaction mass was sonicated for 1 h. Then solvent was evaporated and 1 L of diethyl ether was added along with sodium sulphate decahydrate (4.21 g, 29.6 mmol) and stirred for 1 h at RT. The reaction mixture was filtered through celite and dried over anhyd. Na2SO4 and then oxalic acid (1.33 g, 14.80 mmol) dissolved in 2 mL EtOH added and stirred for 5 min to get oxalate salt of amine (10) (1.5 g). Yield: 51.1percent; off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 4.65 (s, 4H, 2CH_2, spiro morpholine), 4.16 (s, 4H, 2CH_2, spiro morpholine); LC-MS (ESI + ve) m/z 100.0 [M+H]⁺.

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[2] Patent: WO2017/15106, 2017, A1, . Location in patent: Page/Page column 138; 139

2
[ 174-78-7 ]
[ 144-62-7 ]
[ 1159599-99-1 ]

Reference： [1] Organic Process Research and Development, 2016, vol. 20, # 3, p. 675 - 682
[2] Fitoterapia, 2014, vol. 92, p. 111 - 115

3
[ 1522-92-5 ]
[ 1159599-99-1 ]

Reference： [1] Fitoterapia, 2014, vol. 92, p. 111 - 115
[2] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[3] Patent: WO2017/15106, 2017, A1,
[4] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

4
[ 144-62-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

5
[ 13573-28-9 ]
[ 1159599-99-1 ]

Reference： [1] Fitoterapia, 2014, vol. 92, p. 111 - 115

6
[ 78-71-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

7
[ 2402-83-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

8
[ 46246-91-7 ]
[ 1159599-99-1 ]

Reference： [1] Synthesis (Germany), 2017, vol. 49, # 11, p. 2394 - 2401

[ 1159599-99-1 ] Synthesis Path-Downstream 1~32

1
[ 1159599-99-1 ]
[ 1240402-76-9 ]
[ 1240402-44-1 ]

Yield	Reaction Conditions	Operation in experiment
8%		b) {3-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazol-5-yl}-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-methanone Trimethylaluminum (1.0 mL of a 2 M solution in hexane, 2 mmol) was slowly added to a solution of 2-oxa-6-azonia-spiro[3.3]heptane oxalate salt (100 mg, 0.53 mmol) in toluene (2 mL) at 0 C. and the resulting mixture stirred for 2 h at room temperature. Then a solution of 3-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-isoxazole-5-carboxylic acid methyl ester (200 mg, 0.6 mmol) in toluene (8 mL) was added dropwise and the resulting mixture heated at 110 C. for 3 h. After cooling to room temperature and extractive workup (ethyl acetate/aqueous saturated Seignette's salt solution) the organic phase was dried (Na2SO4) and filtered. Purification by chromatography (silica, dichloromethane:methanol=95:5 to 7:3) afforded the title compound (19 mg, 8%) as a colourless oil. MS: m/e=400.1 [M+H]+.

Reference： [1]Patent: US2010/210651,2010,A1 .Location in patent: Page/Page column 28

2
[ 1159599-99-1 ]
[ 1323407-86-8 ]
[ 1323403-80-0 ]

Yield	Reaction Conditions	Operation in experiment
10%		5.98 3-{4-[4-(2-OXA-6-AZA-SPIRO[3.3]HEPT-6-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE To the dichloromethane (10 ml) suspension of 2-oxa-6-azaspiro[3.3]heptane oxalate (0.124 g, 0.857 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.425 ml, 2.57 mmol). The mixture was stirred at room temperature for 5 min. Then 3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.380 g, 0.857 mmol) was added, which was still a suspension. About 3 ml of acetonitrile was added and the mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC (MeCN/water in 0.1% HCOOH) to give 3-{4-[4-(2-Oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione (39 mg, 10% yield); mp, not determined. HPLC: Waters Symmetry C-18, 3.9*150 mm, 5 mum, 1 mL/min, 240 nm, gradient from 10/90 to 90/10 in 5 min, isocratic at 90/10 in 5 min (CH3CN/0.1% H3PO4), 4.32 min (95.2%). 1H NMR (DMSO-d6) delta 1.93-2.04 (m, 1H, CHH), 2.36-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.30 (s, 3H, CH2CH2), 3.51 (s, 1H, CH2), 4.20-4.47 (m, 2H, CH2), 4.59 (s, 3H, CH2CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 1H, CH2), 7.23-7.36 (m, 4H, Ar), 7.38-7.53 (m, 31-1, Ar), 10.97 (br. s., 1H, NH). 13C NMR (DMSO-d6) delta 22.39, 31.21, 38.54, 45.13, 51.66, 61.97, 62.85, 69.47, 79.96, 115.05, 115.26, 127.62, 128.35, 129.79, 130.00, 133.35, 135.23, 137.96, 153.51, 167.99, 170.92, 172.76. LC/MS m/e=462.

Reference： [1]Patent: US2011/196150,2011,A1 .Location in patent: Page/Page column 114

3
[ 1159599-99-1 ]
[ 7697-28-1 ]
[ 1352621-28-3 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate Example Int23.014-bromo-3-methylphenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanoneTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.5 g) in DMF (55 mL) was added molecular sives (1.9 g) and the mixture was stirred for 1 h. TBTU (4.0 g) was added and the mixture was stirred for 30 minutes. Potassium carbonate (4.8 g) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane ethanedioate</strong> (2:1 ) (1.5 g) were added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.77 g of the title compound.
	In N,N-dimethyl-formamide; at 20℃; for 17.5h;	Intermediate Example Int23.014-bromo-3-methylphenyl)(2-oxa-6-azaspiro[3.3]hept-6-yl)methanoneTo a stirred solution of 4-bromo-3-methylbenzoic acid (1.5 g) in DMF (55 mL) was added molecular sives (1.9 g) and the mixture was stirred for 1 h. TBTU (4.0 g) was added and the mixture was stirred for 30 min. Potassium carbonate (4.8 g) and <strong>[1159599-99-1]2-oxa-6-azaspiro[3.3]heptane ethanedioate</strong> (2:1 ) (1.5 g) were added and the mixture was stirred at r.t. for 16 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 1.77 g of the title compound.

Reference： [1]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 140-141
[2]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 114-115

4
[ 1159599-99-1 ]
[ 1008769-87-6 ]
[ 1352621-31-8 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate Example Int24.05[4-bromo-3-(trifluoromethoxy)phenyl](2-oxa-6-azaspiro[3.3]hept-6- yl)methanone To a stirred solution of Int24.03 (900 mg) in DMF (24 mL) was added molecular sives ( 1 .0 g) and the mixture was stirred for 1 h. TBTU (1 .32 g) was added and the mixture was stirred for 30 minutes. Potassium carbonate (2.18 g) and 2- oxa-6-azaspiro[3.3]heptane ethanedioate (2: 1 ) (454 mg) were added and the mixture was stirred at r. t. for 1 6 h . Further TBTU (500 mg) and 2-oxa-6- azaspiro[3.3]heptane ethanedioate (2: 1 ) (225 mg) were added and the mixture was stirred at r.t. for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 386 mg of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 4.18 (s, 2H), 4.46 (s, 2H), 4.63 (s, 4H), 7.53 (dd, 1 H), 7.61 - 7.67 (m, 1 H), 7.89 (d, 1 H).
	With potassium carbonate; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 18.5h;	Intermediate Example Int24.05[4-bromo-3-(trifluoromethoxy)phenyl](2-oxa-6-azaspiro[3.3]hept-6-yl)- methanoneTo a stirred solution of Int24.03 (900 mg) in DMF (24 mL) was added molecular sives ( 1.0 g) and the mixture was stirred for 1 h. TBTU (1.32 g) was added and the mixture was stirred for 30 min. Potassium carbonate (2.18 g) and 2-oxa-6- azaspiro[3.3]heptane ethanedioate (2:1 ) (454 mg) were added and the mixture was stirred at r.t. for 16 h. Further TBTU (500 mg) and 2-oxa-6- azaspiro[3.3]heptane ethanedioate (2:1 ) (225 mg) were added and the mixture was stirred at r.t. for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave 386 mg of the title compound.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 4.18 (s, 2H), 4.46 (s, 2H), 4.63 (s, 4H), 7.53 (dd, 1 H), 7.61 - 7.67 (m, 1 H), 7.89 (d, 1 H).

Reference： [1]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 143-144
[2]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 117-118

5
[ 893761-44-9 ]
[ 1159599-99-1 ]
[ 1394241-82-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 7746 - 7758

6
[ 1159599-99-1 ]
C₃₀H₃₈ClNO₃ [ No CAS ]
C₃₅H₄₆N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With triethylamine; In dichloromethane; at 20℃; for 5h;	Compound TX64007: Compound 11 (0.3 mmol) and 2-oxa-6- azaspiro[3,3]heptanes oxalate (124.7 mg, 0.66 mmol) were taken up in CH2CI2 (5 mL). Et3N (418 mu, 3 mmol) was added and the mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with HC1 (5 mL) and extracted with CH2CI2 (2x 10 mL). The combined organic phase was washed by NaCl (Sat.), dried over Na2S04, then directly loaded on a silica gel column and purified by column chromatography (silica gel, 0-75% EtOAc in Hexanes) to give the compound TX64007 as a white foam (56.8 mg, 34%>) (only the pure fractions were collected, purification was not optimized). 1H NMR (500 MHz, CDC13) delta 8.01 (s, 1H), 6.01 (s, 1H), 4.79 (s, 4H), 4.33 (s, br, 4H), 2.90-3.01 (m, 2H), 2.41-2.51 (m, 1H), 1.83-1.96 (m, 2H), 1.13-1.82 (m, 13H), 1.44 (s, 3H), 1.32 (s, 3H), 1.25 (d, 3H, J= 6.4 Hz), 1.01 (s, 3H), 1.01 (s, 3H), 0.91 (s, 3H); m/z 559 (M+l).

Reference： [1]Patent: WO2012/125488,2012,A1 .Location in patent: Page/Page column 164

7
[ 1159599-99-1 ]
[ 1370447-63-4 ]
[ 1370444-27-1 ]

Yield	Reaction Conditions	Operation in experiment
13 mg	With sodium tris(acetoxy)borohydride; acetic acid; In chloroform; at 20℃; for 72h;	A suspension of the compound (150 mg) prepared in Reference Example P-J1, 2-oxa-6-azaspiro[3.3]heptane oxalate (2:1) (157 mg), and acetic acid (0.1 mL) in CHCl3 (3 mL) was stirred at room temperature for a while, and then sodium triacetoxyborohydride (231 mg) was added thereto, followed by stirring for 3 days. A saturated NaHCO3 solution was added to the reaction solution, followed by extraction with CHCl3. The organic layer was filtered through a phase separator, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (PTLC) (1.0 mm silica gel 60F254 plate, mobile phase: CHCl3/MeOH=90/10 (v/v)) and column chromatography (SNAP Cartridge KP-NH: 11 g, mobile phase: EtOAc/MeOH=100/0 to 95/5 (v/v)). The resulting crude product was washed with a solvent mixture of EtOAc and n-hexane (EtOAc/n-hexane=1/6 (v/v)) with stirring to yield the title compound (13 mg, colorless solid). MS (ESI pos.) m/z: 496 ([M+H]+). 1H-NMR (600 MHz, CDCl3) delta (ppm); 1.19 (6H, d, J=6.9 Hz), 2.59-2.72 (4H, m), 3.36 (4H, br. s.), 4.06-4.13 (1H, m), 4.35 (2H, s), 4.74 (4H, s), 6.36-6.43 (1H, m), 7.23-7.29 (2H, m), 7.49 (1H, d, J=7.8 Hz), 7.51-7.54 (1H, m), 7.75 (1H, d, J=9.2 Hz), 7.85-7.88 (1H, m), 7.93 (2H, d, J=8.3 Hz).

Reference： [1]Patent: US2013/197217,2013,A1 .Location in patent: Paragraph 0604; 0605; 0606; 0607

8
[ 1159599-99-1 ]
[ 1449712-49-5 ]
[ 1449710-19-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; 1-hydroxy-1H-benzotriazol hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dimethyl sulfoxide; at 20℃; for 16h;	General procedure: 4-{7-[3-Cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}-benzoic acid (100 mg, 0.23 mmol) and N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (47.5 mg, 0.27 mmol) are dissolved in DMSO (2 ml). N-(3-Dimethylamino- propyl)-N'-ethylcarbodiimidhydrochloride (DAPECI) (87.0 mg, 0.45 mmol), 1- hydroxybenzotriazole hydrate (HOBt) (34.8 mg, 0.15 mmol) and N-methyl- morpholine (49.9 muIota, 0.45 mmol) are added to the solution. The mixture is stirred at room temperature for 16 h. DMSO is evaporated and the product is isolated by chromatography; yield: 61 mg [2-(4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)- phenyl]-furo[3,2-b]pyridin-2-yl}-benzoylamino)-ethyl]-methyl-carbamic acid tert-butyl ester; HPLC/MS: 2.37 min, [M+H] = 597; 1H NMR (500 MHz, DMSO-d6/TFA-di) delta [ppm] 8.84 (d, J = 6.5 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.55 (dd, J = 9.0, 2.3 Hz, 1H), 8.25 - 8.17 (m, 3H), 8.11 - 7.97 (m, 3H), 7.62 (d, J = 9.2 Hz, 1 H), 5.02 - 4.87 (m, 1 H), 3.96 - 3.81 (m, 2H), 3.65 - 3.49 (m, 3H), 3.47 - 3.29 (m, 4H), 2.80 (s, 3H), 2.10 - 2.02 (m, 2H), 1.79 - 1.70 (m, 2H), 1.28 (s, 9H).

Reference： [1]Patent: WO2013/117285,2013,A1 .Location in patent: Page/Page column 69; 77; 78

9
[ 1159599-99-1 ]
[ 1537168-68-5 ]

Reference： [1]Patent: WO2014/9296,2014,A1

10
[ 1003845-06-4 ]
[ 1159599-99-1 ]
C₉H₁₂BN₃O₃ [ No CAS ]