[ CAS No. 1148048-39-8 ] {[proInfo.proName]}

Name: 1148048-39-8|(1R,3R,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid|98%
Brand: Ambeed
SKU: A693924
Price: 39.0 USD
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Quality Control of [ 1148048-39-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1148048-39-8 ]

SDS Specification

Alternatived Products of [ 1148048-39-8 ]

Product Details of [ 1148048-39-8 ]

CAS No. :	1148048-39-8	MDL No. :	MFCD16621713
Formula :	C₁₁H₁₇NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VXIIZQXOIDYWBS-BWZBUEFSSA-N
M.W :	227.26	Pubchem ID :	25266991
Synonyms :

Calculated chemistry of [ 1148048-39-8 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	61.06
TPSA :	66.84 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) :	-6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.1
Log Po/w (XLOGP3) :	1.33
Log Po/w (WLOGP) :	1.09
Log Po/w (MLOGP) :	1.03
Log Po/w (SILICOS-IT) :	0.09
Consensus Log Po/w :	1.13

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.82
Solubility :	3.42 mg/ml ; 0.015 mol/l
Class :	Very soluble
Log S (Ali) :	-2.33
Solubility :	1.05 mg/ml ; 0.00462 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.19
Solubility :	148.0 mg/ml ; 0.65 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.14

Safety of [ 1148048-39-8 ]

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 [ 1148048-39-8 ]

* 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 [ 1148048-39-8 ]

[ 1148048-39-8 ] Synthesis Path-Downstream 1~21

1
[ 1148048-39-8 ]
[ 1148048-41-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 1.75h; Stage #2: With methanol In tetrahydrofuran at 0 - 20℃; for 0.583333h;	5 Example 5 tert-Butyl (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate; To the title compound of Example 4 (9.60 g, 42,2 mmol) in anhydrous THF (210 mL) at ambient temperature was added a 2 M solution of borane-dimethylsulfide-complex in THF (23.2 mL, 46.5 mmol) dropwise over 15 minutes. The reaction was heated at reflux for 1.5 h and was then cooled by an ice-bath. Methanol (40 mL) was added dropwise during 30 min while the temperature was maintained between 4-15° C. The ice-bath was removed and the reaction was allowed to reach ambient temperature over 35 min. The reaction mixture was concentrated under reduced pressure at 25° C. and the residue was partitioned between DCM and water. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. The aqueous layer from the final wash was extracted with a small portion of DCM and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title product (9.15 g, quantitative yield).1H NMR (400 MHz, CDCl3): δ 4.82 (bd, 1H), 4.33 (m, 1H), 3.52-3.40 (m, 3H), 2.45 (m, 1H), 1.53-1.43 (m, 11H), 0.78 (m, 1H), 0.39 (m, 1H).
	Stage #1: (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid With dimethylsulfide borane complex In tetrahydrofuran for 1.5h; Heating / reflux; Stage #2: With methanol In tetrahydrofuran at 4 - 20℃; for 1.08333h;	2 tert-Butyl(1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate Example 2 tert-Butyl(1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate To the title compound of Example 1 (9.60 g, 42.2 mmol) in anhydrous THF (210 mL) at ambient temperature was added a 2 M solution of borane-dimethylsulfide-complex in THF (23.2 mL, 46.5 mmol) dropwise over 15 minutes. The reaction was heated at reflux for 1.5 h and was then cooled by an ice-bath. Methanol (40 mL) was added dropwise during 30 min while the temperature was maintained between 4-15° C. The ice-bath was removed and the reaction was allowed to reach ambient temperature over 35 min. The reaction mixture was concentrated under reduced pressure at 25° C. and the residue was partitioned between DCM and water. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. The aqueous layer from the final wash was extracted with a small portion of DCM and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude title product (9.15 g, quantitative yield). 1H NMR (400 MHz, CDCl3): δ 4.82 (bd, 1H), 4.33 (m, 1H), 3.52-3.40 (m, 3H), 2.45 (m, 1H), 1.53-1.43 (m, 11H), 0.78 (m, 1H), 0.39 (m, 1H).
	With borane-THF In tetrahydrofuran at 0 - 70℃; for 1h; Inert atmosphere;	120.1 120.1. Synthesis of tert-butyl (1R,3R,5R)-3-(hydroxymethyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate To a stirred solution of (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (1.0 g, 4.40 mmol, 1.00 equiv) in THF (20.00 mL) was added BH3 (1M in THF, 6.6 mL, 6.60 mmol, 1.50 equiv) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred for 1 h at 70 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of MeOH (3 mL) at 0°C. The resulting mixture was concentrated under reduced pressure to obtain tert-butyl (1R,3R,5R)-3-(hydroxymethyl)- 2-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g, crude) as a colorless oil. LC-MS: (M+H)+ found:157.95.

With borane-THF In tetrahydrofuran at 0 - 70℃; for 1h; Inert atmosphere;

120.1 120.1. Synthesis of tert-butyl (1R,3R,5R)-3-(hydroxymethyl)-2- azabicyclo[3.1.0]hexane-2-carboxylate To a stirred solution of (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (1.0 g, 4.40 mmol, 1.00 equiv) in THF (20.00 mL) was added BH3 (1M in THF, 6.6 mL, 6.60 mmol, 1.50 equiv) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred for 1 h at 70 °C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of MeOH (3 mL) at 0°C. The resulting mixture was concentrated under reduced pressure to obtain tert-butyl (1R,3R,5R)-3-(hydroxymethyl)- 2-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g, crude) as a colorless oil. LC-MS: (M+H)+ found:157.95.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2009/111820, 2009, A1 Location in patent: Page/Page column 13
[2]Current Patent Assignee: ASTRAZENECA PLC - US2009/111825, 2009, A1 Location in patent: Page/Page column 13
[3]Current Patent Assignee: SCORPION THERAPEUTICS - WO2022/66734, 2022, A1 Location in patent: Page/Page column 598-599
[4]Current Patent Assignee: SCORPION THERAPEUTICS - WO2022/66734, 2022, A1 Location in patent: Page/Page column 598-599

2
[ 871727-37-6 ]
[ 1148048-39-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 2-tert-butyl 3-ethyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate With lithium hydroxide; ethanol; water at 17 - 23℃; Stage #2: With hydrogenchloride; water In ethanol	4 Example 4 (1R,3R,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid; To a stirred solution 2-tert-butyl 3-ethyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (11.7 g, 45.8 mmol) in EtOH (40 mL) was added a solution of lithium hydroxide monohydrate (2.31 g, 55.0 mmol) in water (20 mL) during 5 minutes while maintaining the temperature between 17-23° C. After stirring overnight under a nitrogen atmosphere the reaction mixture was concentrated under reduced pressure at 40° C. The residue was partitioned between water and MTBE and the aqueous layer was washed with a second portion of MTBE. The organic layers were discarded. MTBE was added to the aqueous layer and pH was adjusted to 2 by dropwise addition of 1 M aqueous HCl. The aqueous layer was extracted with a second portion of MTBE and the combined organic layers were concentrated under reduced pressure at 30-35° C. to give the title product as a waxy solid (9.76 g, 94%).1H NMR (400 MHz, CDCl3): δ 4.69-4.49 (m, 1H), 3.60-3.46 (m, 1H), 2.72-2.05 (m, 2H), 1.60-1.32 (m, 10H), 0.95-0.60 (m, 2H).
94%	Stage #1: 2-tert-butyl 3-ethyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate With lithium hydroxide; water In ethanol at 17 - 23℃; Stage #2: With hydrogenchloride In water	1 To a stirred solution 2-tert-butyl 3-ethyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (11.7 g, 45.8 mmol) in EtOH (40 mL) was added a solution of lithium hydroxide monohydrate (2.31 g, 55.0 mmol) in water (20 mL) during 5 minutes while maintaining the temperature between 17-23° C. After stirring overnight under a nitrogen atmosphere the reaction mixture was concentrated under reduced pressure at 40° C. The residue was partitioned between water and MTBE and the aqueous layer was washed with a second portion of MTBE. The organic layers were discarded. MTBE was added to the aqueous layer and pH was adjusted to 2 by dropwise addition of 1 M aqueous HCl. The aqueous layer was extracted with a second portion of MTBE and the combined organic layers were concentrated under reduced pressure at 30-35° C. to give the title product as a waxy solid (9.76 g, 94%).1H NMR (400 MHz, CDCl3): δ 4.69-4.49 (m, 1H), 3.60-3.46 (m, 1H), 2.72-2.05 (m, 2H), 1.60-1.32 (m, 10H), 0.95-0.60 (m, 2H).

3
[ 1313517-64-4 ]
[ 1148048-39-8 ]
[ 1417743-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide monohydrate In 1,4-dioxane; water at 20℃; for 18h; Overall yield = 2.75 g;	27 Description 27: (3fi)-2-(ferf-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxylic acid (diastereoisomer mixture) (D27) To a mixture of (3R)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1 .0]hexane-2,3- dicarboxylate (D26) (diastereoisomer mixture) (3.4 g, 13.3 mmol) in dioxane (15 ml) and water (15 ml), LiOH H20 (2.2 g, 53 mmol). The mixture was stirret at RT for 18h. Dioxane was evaporated off and water was washed with Et20 (2x40 ml) then the pH was adjusted to ~4 by addition of citric acid and the resulting aqueous phase was extacted with DCM (200 ml), washed with water (20 ml), dried over Na2S04 and evaporated in vacuo to afford the title compound (D27) (2.75 g) as diastereoisomer mixture with syn-anti ratio 10/2. MS: (ES/+) m/z: 226 [M"] C1 1 H17N04 requires 227.12 1 H NMR (400MHz ,DMSO-d6) δ (ppm): 12.69 - 12.41 (m, 2 H), 4.45 - 4.32 (m, 1 H), 3.89 (br.s. 1 H), 3.42 - 3.32 (m, 2 H), 2.65 - 2.54 (m, 1 H), 2.35 - 2.24 (m, 1 H), 2.09 (m, 1 H), 1 .95 - 1 .73 (m, 1 H), 1 .60 - 1 .46 (m, 2 H), 1 .44 - 1 .30 (m, 18 H), 0.76 - 0.60 (m, 3 H), 0.46 (dt, J = 2.4, 4.9 Hz, 1 H).

Reference： [1]Current Patent Assignee: ROTTAPHARM BIOTECH S.R.L. - WO2013/4290, 2013, A1 Location in patent: Page/Page column 54; 55

4
[ 1148048-39-8 ]
[ 100-51-6 ]
3-benzyl 2-(tert-butyl) (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	5.1 Step 1. A suspension of (1R,3R,5R)-2-(tert-butoxycarbonyl)-2- azabicyclo[3. 1. Ojhexane-3 -carboxylic acid (500 mg, 2.20 mmol), 4-(dimethylamino)pyridine(592 mg, 4.85 mmol), and N,N’-dicyclohexylcarbodiimide (918 mg, 4.45 mmol) in dichloromethane (7 mL) was stirred at ambient temperature as benzyl alcohol (0.27 mL, 2.61 mmol) was added. The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with diethyl ether (30 mL), and stirred at ambient temperature for 30 mm before filtering off the solids. After the filtrate was concentrated, the residue was dissolved in diethyl ether again and filtered off the insoluble solids. (repeated 4 times) The residue was purified by silica gel column chromatography eluting 0-25% ethyl acetate in hexanes to give 3-benzyl 2-(tert-butyl) (1 R, 3R,5R)-2-azabicyclo [3.1. Ojhexane-2,3 - dicarboxylate: ‘H NMR (400 MHz, Chloroform-d) δ 7.34 (m, 5H), 5.25 - 5.03 (m, 2H), 4.68 (dd, J 11.6, 3.0 Hz, 0.4H), 4.55 (dd, J 11.5, 3.3 Hz, 0.6H), 3.55 (td, J= 6.3, 2.5 Hz, 0.6H), 3.46 (td, J = 6.3, 2.4 Hz, 0.4H), 2.70- 2.42 (m, 1H), 2.05 (q, J = 2.8, 2.0 Hz, 0.6H), 2.01 (t, J = 3.6 Hz, 0.4H), 1.45 - 1.55 (m, 1H), 1.49 (s, 3.6H), 1.34 (s, 5.4H), 0.90 (td, J = 5.5, 5.1, 2.4 Hz, 0.6H), 0.87 - 0.80 (m, 0.4H), 0.77 - 0.69 (m, 0.6H), 0.65 (q, J = 6.7 Hz, 0.4H): LCMSESL’ (m/z): [M-C4H8+Hj calculated for C,4H,6N04: 262.11; found: 261.81.

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2018/39531, 2018, A1 Location in patent: Paragraph 0233

5
[ 1148048-39-8 ]
[ 100-51-6 ]
benzyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 20 °C 2: dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - WO2018/39531, 2018, A1

6
[ 1148048-39-8 ]
[ 100-39-0 ]
3-benzyl 2-(tert-butyl) (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.08 g	With potassium carbonate In N,N-dimethyl-formamide at 0 - 22℃;	31.1 Step 1: Step 1: Preparation of 3-benzyl 2-(tert-butyl) (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate To a solution of (1R,3R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (1.52 g, 6.70 mmol) in DMF (5.0 mL) was added potassium carbonate (1.03 g, 7.37 mmol). The resulting mixture was cooled to 0° C. and then benzyl bromide (0.96 mL, 8.05 mmol) was added dropwise over five minutes. The resulting mixture was allowed to warm to 22° C. and stirred overnight. It was diluted with EtOAc (70 mL) and washed 4 times with water (200 mL total volume). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by MPLC using silica gel and eluted with a gradient of 0-15% EtOAc/hexanes to provide 3-benzyl 2-(tert-butyl) (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (2.08 g, 6.56 mmol) as a colorless, viscous oil. LCMS-APCI (POS.) m/z: 218.1 (M+H-Boc)+.

Reference： [1]Current Patent Assignee: CYTOKINETICS INC; AMGEN INC - US2019/77793, 2019, A1 Location in patent: Paragraph 0310

7
[ 1148048-39-8 ]
benzyl (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 0 - 22 °C 2: trifluoroacetic acid / dichloromethane / 0.5 h / 22 °C