[ CAS No. 144282-37-1 ] {[proInfo.proName]}

Name: 144282-37-1|tert-Butyl (S)-(5-benzyl-5-azaspiro[2.4]heptan-7-yl)carbamate|97%
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SKU: A299963
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Quality Control of [ 144282-37-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 144282-37-1 ]

Product Details of [ 144282-37-1 ]

CAS No. :	144282-37-1	MDL No. :	MFCD17214772
Formula :	C₁₈H₂₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UCBLMUMETZZNIZ-OAHLLOKOSA-N
M.W :	302.41	Pubchem ID :	10709504
Synonyms :

Calculated chemistry of [ 144282-37-1 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.61
Num. rotatable bonds :	6
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	91.12
TPSA :	41.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.38
Log Po/w (XLOGP3) :	2.9
Log Po/w (WLOGP) :	2.58
Log Po/w (MLOGP) :	2.66
Log Po/w (SILICOS-IT) :	2.62
Consensus Log Po/w :	2.83

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.35
Solubility :	0.136 mg/ml ; 0.000449 mol/l
Class :	Soluble
Log S (Ali) :	-3.43
Solubility :	0.111 mg/ml ; 0.000369 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.5
Solubility :	0.00965 mg/ml ; 0.0000319 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.42

Safety of [ 144282-37-1 ]

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

Application In Synthesis of [ 144282-37-1 ]

* 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.

Downstream synthetic route of [ 144282-37-1 ]

[ 144282-37-1 ] Synthesis Path-Downstream 1~14

1
[ 129306-06-5 ]
[ 144282-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 5 h / Reflux; Large scale 1.2: 0.5 h / 20 °C / Large scale 2.1: (1S)-(+)-10-camphorsulfonic acid / toluene / 1 h / 20 °C / Large scale 3.1: dichloromethane / 2 h / 20 °C / Large scale

Reference： [1]Current Patent Assignee: SUZHOU CHUKAI PHARMACEUTICAL - CN103420896, 2016, B

2
[ 144282-35-9 ]
[ 24424-99-5 ]
5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.2%	With triethylamine In ethanol at 20℃;	1.6; 2.6 Step 6 3.75 g of Compound V was added to the reaction flask, followed by 35 mL of ethanol, 3.75 g of triethylamine and 6.5 g of Boc2O.Stir the reaction at room temperature for 12-14 hours, concentrate, add ethyl acetate, and then use aqueous lemon solution, sodium bicarbonate solution, and saturatedWashed with brine, dried, concentrated and dried to give compound VI5.25g.The yield was 98.2%
95.6%	In dichloromethane at 20℃; for 2h; Large scale;	1 Benzyl-7 [beta] -tert-butoxycarbonylamino-5-azaspiro [2,4] heptane I 5-benzyl -7 (S) - 5-azaspiro [2,4] heptane VIII (. 3kg, 14 9mol) to the 50L reaction vessel was added methylene chloride 20L, two tert-butyl dicarbonate (3. 9kg, 17. 9mol), after stirring for 2 hours at room temperature, water was added 20L, extract the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 5-benzyl -7 (S) - tert-butoxycarbonyl-amino-5-azaspiro [2,4] heptane-I (4 3kg, 95 6%..).

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A Location in patent: Paragraph 0026; 0038; 0039; 0047; 0059; 0060
[2]Current Patent Assignee: SUZHOU CHUKAI PHARMACEUTICAL - CN103420896, 2016, B Location in patent: Paragraph 0053-0054

3
[ 882-36-0 ]
[ 144282-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 - 35 °C / Large scale 2.1: N-Bromosuccinimide; chloro-trimethyl-silane / acetonitrile / 5 h / 0 °C / Large scale 3.1: tetrabutylammomium bromide; sodium hydroxide / 1,2-dichloro-ethane / 5 h / 50 - 70 °C / Large scale 4.1: hydroxylamine hydrochloride; pyridine / water / 2.5 h / 20 °C / Large scale 5.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 5 h / Reflux; Large scale 5.2: 0.5 h / 20 °C / Large scale 6.1: (1S)-(+)-10-camphorsulfonic acid / toluene / 1 h / 20 °C / Large scale 7.1: dichloromethane / 2 h / 20 °C / Large scale

Reference： [1]Current Patent Assignee: SUZHOU CHUKAI PHARMACEUTICAL - CN103420896, 2016, B

4
[ 147011-39-0 ]
[ 144282-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide; chloro-trimethyl-silane / acetonitrile / 5 h / 0 °C / Large scale 2.1: tetrabutylammomium bromide; sodium hydroxide / 1,2-dichloro-ethane / 5 h / 50 - 70 °C / Large scale 3.1: hydroxylamine hydrochloride; pyridine / water / 2.5 h / 20 °C / Large scale 4.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 5 h / Reflux; Large scale 4.2: 0.5 h / 20 °C / Large scale 5.1: (1S)-(+)-10-camphorsulfonic acid / toluene / 1 h / 20 °C / Large scale 6.1: dichloromethane / 2 h / 20 °C / Large scale

Reference： [1]Current Patent Assignee: SUZHOU CHUKAI PHARMACEUTICAL - CN103420896, 2016, B

5
[ 331443-52-8 ]
[ 144282-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; sodium hydroxide / 1,2-dichloro-ethane / 5 h / 50 - 70 °C / Large scale 2.1: hydroxylamine hydrochloride; pyridine / water / 2.5 h / 20 °C / Large scale 3.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 5 h / Reflux; Large scale 3.2: 0.5 h / 20 °C / Large scale 4.1: (1S)-(+)-10-camphorsulfonic acid / toluene / 1 h / 20 °C / Large scale 5.1: dichloromethane / 2 h / 20 °C / Large scale

Reference： [1]Current Patent Assignee: SUZHOU CHUKAI PHARMACEUTICAL - CN103420896, 2016, B

6
[ 129306-04-3 ]
5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; pyridine / water / 2.5 h / 20 °C / Large scale 2.1: sodium tetrahydroborate; boron trifluoride diethyl etherate / tetrahydrofuran / 5 h / Reflux; Large scale 2.2: 0.5 h / 20 °C / Large scale 3.1: (1S)-(+)-10-camphorsulfonic acid / toluene / 1 h / 20 °C / Large scale 4.1: dichloromethane / 2 h / 20 °C / Large scale

Reference： [1]Current Patent Assignee: SUZHOU CHUKAI PHARMACEUTICAL - CN103420896, 2016, B

7
[ 24424-99-5 ]
[ 2155805-89-1 ]
[ 144282-37-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	In tetrahydrofuran at 0 - 20℃; for 18h;	265.1 Step 1. Preparation of te/f-butyl (S)-(5-benzyl-5-azaspiro[2.4]heptan-7-yl)carbamate EXAMPLE 265 Synthesis of (S)-4-((5-benzyl-5-azaspiro[2.4]heptan-7-yl)(methyl)amino)-5-chloro-2- fluoro-/V-(thiazol-4-yl)benzenesulfonamide 2,2,2-trifluoroacetate Step 1. Preparation of te/f-butyl (S)-(5-benzyl-5-azaspiro[2.4]heptan-7-yl)carbamate To a mixture of (S)-5-benzyl-5-azaspiro[2.4]heptan-7-amine hydrochloride (0.70 g, 2.55 mmol) and 2 M sodium hydroxide (25.5 mmol, 12.75 mL) in tetrahydrofuran (30 mL) was added di-terf-butyl dicarbonate (1.11 g, 5.10 mmol) at 0 °C. The mixture was allowed to warm to ambient temperature, stirred for 18 h, and then diluted with ethyl acetate (85 mL). The mixture was washed with water (50 mL), brine (2 χ 50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% of ethyl acetate (containing 20% of ethanol and 0.1 % of ammonium hydroxide) in hexanes, afforded the title compound as a colorless oil (0.74 g, 96% yield): H NMR (300 MHz, CDCI3) δ 7.35-7.31 (m, 5H), 4.98-4.92 (m, 1 H), 3.83 (ddd, J = 9.1 , 6.0, 3.1 Hz, 1 H), 3.69-3.55 (m, 2H), 2.92 (dd, J = 9.6, 5.9 Hz, 1 H), 2.71-2.65 (m, 2H), 2.35 (d, J = 9.0 Hz, 1 H), 1.44 (s, 9H), 0.82-0.73 (m, 2H), 0.60 (ddd, J = 9.3, 5.6, 3.7 Hz, 1 H), 0.46 (ddd, J = 9.5, 5.7, 3.9 Hz, 1 H); MS (ES+) m/z 303.4 (M + 1).

Reference： [1]Current Patent Assignee: XENON PHARMACEUTICALS INC - WO2017/201468, 2017, A1 Location in patent: Page/Page column 326-327

8
5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane [ No CAS ]
[ 127199-45-5 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	With palladium on activated charcoal; hydrogen In ethanol at 20℃;	1.7; 2.7 Step 7 5.00 g of Compound VI was added to the reaction flask, then 0.5 g of Pd/C and 50 mL of ethanol were added, and the hydrogen was replaced three times.Stir at room temperature for 10-12 hours under hydrogen atmosphere, and filter.Concentrated and dried to give 3.25 g of Compound VII, yield 99.3%.
94.7%	With palladium 10% on activated carbon; ammonium formate In ethanol; water at 5 - 10℃;	2 Example 2 (1) Will (7S)-tert-butoxycarbonylamino-5-N-benzylazaspiro[2.4]heptane(raw material) 20 g and 10% by weight of palladium carbon (containing water, dry weight)2.3g added to ethanol 250g,Added 12g ammonium formate,After adding 5~10°C reaction,TLC detected the end of the reaction.The mixture was suction filtered, and the filtrate was concentrated under reduced pressure at 40 to 45°C and concentrated until no condensation occurred.(2) Add 180 g of methylene chloride and 70 g of purified water to the concentrate and dissolve it with 15% sodium hydroxide at 0 to 5°C.The liquid was adjusted to a pH of about 13 (pH paper), and the layers were separated. The aqueous layer was extracted three times with dichloromethane (25 g each) and the organic layers were combined. The organic layer was washed twice with saturated sodium chloride solution (30 g each), the brine layers were combined, the brine layer was extracted with dichloromethane three times (12 g each time), and the organic layers were combined.The organic layer was dried over anhydrous sodium sulfate (9 g) for 1 h, suction filtered, and the filtrate was concentrated under reduced pressure at 30-35[deg.] C. and concentrated until no condensation occurred.(3) 60 g of n-hexane was added to the concentrated residue, stirred at 510° C. for 3 h, suction-filtered, and the filter cake was vacuum dried at 35 4040° C. for 3 h to obtain 13.3 g of a white solid, ie, (7S)-tert-butoxycarbonylamino-. 5-Azaspiro[2.4]heptane (Compound 1), yield 94.7%, GC purity 99.4%.

Reference： [1]Current Patent Assignee: SUZHOU DAWNRAYS PHARMACEUTICAL - CN109232530, 2019, A Location in patent: Paragraph 0026; 0040; 0041; 0047; 0061; 0062
[2]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - CN107879966, 2018, A Location in patent: Paragraph 0061-0066; 0070

9
[ 180506-32-5 ]
[ 144282-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triphenylphosphine; diphenyl phosphoryl azide; diethylazodicarboxylate / tetrahydrofuran / 20 °C / Inert atmosphere; Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / Cooling with ice; Reflux 3: triethylamine / ethanol / 20 °C