[ CAS No. 1234616-51-3 ] {[proInfo.proName]}

Name: 1234616-51-3|tert-Butyl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate|95%
Brand: Ambeed
SKU: A180310
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Quality Control of [ 1234616-51-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1234616-51-3 ]

Product Details of [ 1234616-51-3 ]

CAS No. :	1234616-51-3	MDL No. :	MFCD18325190
Formula :	C₁₁H₁₈N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IRALTYPUIGPWFA-UHFFFAOYSA-N
M.W :	226.27	Pubchem ID :	56777107
Synonyms :

Calculated chemistry of [ 1234616-51-3 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	65.94
TPSA :	58.64 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) :	-7.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.21
Log Po/w (XLOGP3) :	0.02
Log Po/w (WLOGP) :	-0.02
Log Po/w (MLOGP) :	0.62
Log Po/w (SILICOS-IT) :	0.75
Consensus Log Po/w :	0.72

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.06
Solubility :	19.8 mg/ml ; 0.0876 mol/l
Class :	Very soluble
Log S (Ali) :	-0.8
Solubility :	35.6 mg/ml ; 0.157 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.71
Solubility :	4.38 mg/ml ; 0.0194 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.66

Safety of [ 1234616-51-3 ]

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

Application In Synthesis of [ 1234616-51-3 ]

* 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 [ 1234616-51-3 ]

[ 1234616-51-3 ] Synthesis Path-Downstream 1~20

1
[ 1967004-42-7 ]
[ 1234616-51-3 ]
[ 1967004-43-8 ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With potassium phosphate; copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane In 1,4-dioxane at 20℃; for 12h; Inert atmosphere;	53.1 preparation of tert-butyl 6-[(6S)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-3-yl]-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (compound 53b) To a solution of tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate (271.5 mg, 1.2 mmol) in dioxane (15 mL) were added (6S)-3-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine(Intermediate I-1-1, 263.0 mg, 1.0 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (14.2 mg, 0.1 mmol), K3PO4 (637.0 mg, 3.0 mmol) and CuI (19.0 mg, 0.1 mmol) under N2, and the mixture was stirred at room temperature for 12 hours and then filtered and concentrated under reduced pressure, the residue was purified by column chromatograph on silica gel (DCM/MeOH=50/1 to 20/1) to give compound 53b (200 mg) as a white oil. LCMS (M+H+): 362.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2018/11160, 2018, A1 Location in patent: Page/Page column 103

2
[ 1181816-12-5 ]
tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With hydrogenchloride; mesitylenesulfonylhydroxylamine; In dichloromethane; water; at 20℃; for 12h;	General procedure: To a solution of 5-fluoro-1,2a,7,7a-tetrahydrocyclobuta[a]inden-2-one 1a (100 mg, 0.45 mmol) in dichloromethane (3.8 mL) at room temperature was added hydrogen chloride (2 M, 1.4 mL). Then, O-mesitylene sulfonylhydroxylamine (2.00 equiv., 2.0000) was then added and the resulting mixture was stirred for 3 h. Saturated NaHCO3 solution was added and the organic layer was extracted with dichloromethane. The organic layer was then dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography over silica gel to give 6-fluoro-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one 5f (87 mg, 0.802 mmol, 80percent) as a white solid.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 1896 - 1901

3
[ 1092953-04-2 ]
[ 1234616-51-3 ]
[ 2677040-95-6 ]

Yield	Reaction Conditions	Operation in experiment
65.6%	With sodium hydride In tetrahydrofuran at 20℃; for 0.5h;	4.1.5 General procedure for the synthesis of 4(a-c) General procedure: To a stirring mixture of NaH (60%, 1.33mmol) and different N-Boc substituted spiro rings (0.442mmol) in 20mL of THF was added 3 (220mg, 0.440mmol) in THF, and the reaction mixture was stirred at room temperature for 0.5h. After completion of the reaction, the solvent was removed under reduced pressure. Water (50mL) and ethyl acetate (25mL×3) were added to the crude and extracted. The organic phases were collected and combined and extracted once more with saturated sodium chloride solution (25mL). The organic phases were dried with anhydrous magnesium sulfate. After filtering, it was separated by flash column chromatography with developing solvent PE: EA=4:1. The obtained solid was recrystallized by using a dichloromethane-n-hexane system to achieve the desired products. 4.1.5.1 Tert-butyl 6-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (4a) Yield: 65.6%; mp: 92-93°C; 1H NMR (400MHz, DMSO-d6): δ 9.36 (d, J=241.0Hz, 1H, dihydropyrimidine-H), 8.08-7.83 (m, 2H, thiazole-H), 7.57 (d, J=8.6Hz, 1H, Ph-H), 7.43 (ddd, J=11.4, 8.7, 6.2Hz, 1H, Ph-H), 7.30-7.19 (m, 1H, Ph-H), 6.12-5.85 (m, 1H, dihydropyrimidine-CH), 4.68-4.53 (d, J=2.1Hz, 2H, dihydropyrimidine-CH2), 4.00 (q, J=7.1Hz, 2H, CH2CH3), 3.94-3.77 (m, 4H, CCH2N), 3.76-3.64 (m, 2H, NCH2), 2.67 (d, J=9.5Hz, 2H, COCH2), 1.37 (d, J=1.3Hz, 9H, Boc), 1.08 (dt, J=9.0, 7.1Hz, 3H, CH3); 13C NMR (100MHz, DMSO-d6): δ 174.82, 173.12, 165.58, 161.65 (d, J=252.5Hz), 155.94, 150.48, 144.81, 143.84, 140.67 (d, J=3.4Hz), 131.96 (d, J=8.3Hz), 126.48, 123.02 (d, J=9.6Hz), 120.08 (d, J=29.5Hz), 116.30 (d, J=21.2Hz), 105.11, 99.60, 79.09, 60.21, 58.94, 58.34, 58.00, 52.07, 44.87, 34.26, 28.49, 14.52; EI-MS: 648.18 [M+H]+; C28H31BrFN5O5S [647.12].
65.6%	Stage #1: tert-butyl 6-oxo-2,7-diazaspiro[3.4]octane-2-carboxylate With sodium hydride In tetrahydrofuran at 20℃; Stage #2: ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydro-pyrimidine-5-carboxylate In tetrahydrofuran at 20℃; for 0.5h;	3 Example 3. Preparation of compound 4(a-c) General procedure: Different substituted spiro rings (0.442 mmol) and NaH (54 mg, 1.33 mmol) were dissolved in a dry tetrahydrofuran solution and stirred at room temperature for 0.5-1 h until the substituted spiro rings were dissolved.A solution of Intermediate 3 (220 mg, 0.440 mmol) in tetrahydrofuran was added dropwise. Stir at room temperature for 0.5h.After the reaction was completed, tetrahydrofuran was removed under reduced pressure, water (25mL) was added, and it was extracted with ethyl acetate (20mL×3).Collect and combine the organic phases, extract once with saturated sodium chloride (25 mL), and dry the organic phase with anhydrous magnesium sulfate. Filtration, flash column chromatography.The target compound 4(a-c) was obtained by recrystallization using dichloromethane-n-hexane system.

Reference： [1]Ma, Yue; Zhao, Shujie; Ren, Yujie; Cherukupalli, Srinivasulu; Li, Qilan; Woodson, Molly E.; Bradley, Daniel P.; Tavis, John E.; Liu, Xinyong; Zhan, Peng [European Journal of Medicinal Chemistry, 2021, vol. 225]
[2]Current Patent Assignee: SHANDONG UNIVERSITY - CN113135921, 2021, A Location in patent: Paragraph 0064-0066

4
[ 1092579-89-9 ]
[ 1234616-51-3 ]
[ 2648453-60-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine In 1-methyl-pyrrolidin-2-one at 200℃; for 2h; Microwave irradiation; Sealed tube;

Reference： [1]Hatcher, John M.; Vatsan, Prasanna S.; Wang, Eric; Jiang, Jie; Gray, Nathanael S. [ACS Medicinal Chemistry Letters, 2021, vol. 12, # 11, p. 1689 - 1693]

5
[ 1234616-51-3 ]
[ 2385255-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil / 18 h / 0 - 60 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.75 h / -15 °C 2.2: 0.75 h
	Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 18 h / 60 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 0.75 h / -15 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2022/93856, 2022, A1
[2]Current Patent Assignee: AMGEN INC - WO2022/83569, 2022, A1

6
[ 1234616-51-3 ]
[ 2386763-17-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / mineral oil / 18 h / 0 - 60 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.75 h / -15 °C 2.2: 0.75 h 3.1: borane-THF / tetrahydrofuran / 4 h / 0 - 65 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 18 h / 60 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 0.75 h / -15 °C 3: borane-THF / tetrahydrofuran / 4 h / 0 - 65 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2022/93856, 2022, A1
[2]Current Patent Assignee: AMGEN INC - WO2022/83569, 2022, A1

7
[ 1234616-51-3 ]
[ 2768872-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil / 18 h / 0 - 60 °C 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.75 h / -15 °C 2.2: 0.75 h 3.1: borane-THF / tetrahydrofuran / 4 h / 0 - 65 °C / Inert atmosphere 4.1: hydrogen; palladium on activated charcoal / methanol / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: sodium hydride / tetrahydrofuran; mineral oil / 18 h / 60 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 0.75 h / -15 °C 3: borane-THF / tetrahydrofuran / 4 h / 0 - 65 °C 4: hydrogen; palladium on activated charcoal / methanol / 2 h / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - WO2022/93856, 2022, A1
[2]Current Patent Assignee: AMGEN INC - WO2022/83569, 2022, A1

8
[ 1234616-51-3 ]
[ 100-39-0 ]
[ 2081079-67-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydride In mineral oil at 0 - 60℃; for 18h;	Step 1: tert- Butyl 6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate To a solution of tert-butyl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (500 mg, 2.21 mmol) and benzyl bromide (397 mg, 2.32 mmol) in THF (10 mL) at 0 °C was added NaH (60% dispersion, 97 mg, 2.43 mmol). The reaction mixture was stirred at 60 °C for 18 h. Upon completion, the reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was stirred in Et20 (15 mL) and filtered to provide tert-butyl 6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2 -carboxylate (500 mg, 1.58 mmol, 72 % yield) as a white solid, m/z (ESI): 317.0 (M+H)+.
72%	With sodium hydride In mineral oil at 0 - 60℃; for 18h;	Step 1: tert- Butyl 6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate To a solution of tert-butyl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (500 mg, 2.21 mmol) and benzyl bromide (397 mg, 2.32 mmol) in THF (10 mL) at 0 °C was added NaH (60% dispersion, 97 mg, 2.43 mmol). The reaction mixture was stirred at 60 °C for 18 h. Upon completion, the reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was stirred in Et20 (15 mL) and filtered to provide tert-butyl 6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2 -carboxylate (500 mg, 1.58 mmol, 72 % yield) as a white solid, m/z (ESI): 317.0 (M+H)+.
72%	With sodium hydride In mineral oil at 0 - 60℃; for 18h;	Step 1: tert- Butyl 6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate To a solution of tert-butyl 7-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (500 mg, 2.21 mmol) and benzyl bromide (397 mg, 2.32 mmol) in THF (10 mL) at 0 °C was added NaH (60% dispersion, 97 mg, 2.43 mmol). The reaction mixture was stirred at 60 °C for 18 h. Upon completion, the reaction was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was stirred in Et20 (15 mL) and filtered to provide tert-butyl 6-benzyl-7-oxo-2,6-diazaspiro[3.4]octane-2 -carboxylate (500 mg, 1.58 mmol, 72 % yield) as a white solid, m/z (ESI): 317.0 (M+H)+.

72%

With sodium hydride In tetrahydrofuran; mineral oil at 60℃; for 18h;

Reference： [1]Current Patent Assignee: AMGEN INC - WO2022/93856, 2022, A1 Location in patent: Page/Page column 100
[2]Current Patent Assignee: AMGEN INC - WO2022/93856, 2022, A1 Location in patent: Page/Page column 100
[3]Current Patent Assignee: AMGEN INC - WO2022/93856, 2022, A1 Location in patent: Page/Page column 100
[4]Current Patent Assignee: AMGEN INC - WO2022/83569, 2022, A1 Location in patent: Page/Page column 636-637

9
[ 1234616-51-3 ]
[ 76-05-1 ]
[ 2228784-02-7 ]

Yield	Reaction Conditions	Operation in experiment
0.78 g	In dichloromethane at 0 - 20℃;	33.A Step A: Preparation of Compound 33A 0°C,Trifluoroacetic acid (2 mL)Slowly added dropwise to tert-butyl 7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate (0.5g) in dichloromethane(10 mL) in the reaction solution.After the addition was completed, the mixture was stirred at room temperature.After the reaction is complete,The reaction solution was concentrated to obtain compound 33A (0.78 g).

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - WO2022/68917, 2022, A1 Location in patent: Page/Page column 82

10
[ 1234616-51-3 ]
[ 2765379-49-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dichloromethane / 0 - 20 °C 2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium tertiary butoxide / 1,4-dioxane / 100 °C / Inert atmosphere