α-Cyclobutylglycine | Aliphatic Cyclic Hydrocarbons

CAS No. :	28024-69-3
Formula :	C₆H₁₁NO₂
M.W :	129.16
SMILES Code :	NC(C1CCC1)C(O)=O
MDL No. :	MFCD09264350
InChI Key :	FZENWFNLDOYYFB-UHFFFAOYSA-N
Pubchem ID :	14352283

Safety of [ 28024-69-3 ]

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

Computational Chemistry of [ 28024-69-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	0
Fraction Csp3	0.83
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	33.32
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	63.32 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.11
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-1.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.2
Log P_o/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.	-2.21
Log P_o/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	0.05
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.57

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	0.74
Solubility	708.0 mg/ml ; 5.48 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Highly soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	1.17
Solubility	1930.0 mg/ml ; 14.9 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Highly 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	0.22
Solubility	213.0 mg/ml ; 1.65 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	No
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.	-8.49 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 of [ 28024-69-3 ]

* 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 [ 28024-69-3 ]

[ 28024-69-3 ] Synthesis Path-Downstream 1~32

2
[ 28024-69-3 ]
cyclobutyl-2-hydroxyacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; sodium nitrite; In water; at 0 - 20℃; for 72.0h;	To <strong>[28024-69-3]2-amino-2-cyclobutylacetic acid</strong> (1 g, 6.04 mmol) in 1 M H2SO4(aq) (12 mL, 0.5 M) at0C was added 2 M NaNO2(aq) (15 mL, 30.19 mmol) slowly and the reaction was allowed to warm to rt slowly. After 3 days, 1H NMR showed no starting material and the reaction was extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to afford 64a (495.0 g, 44%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 53.78 (d, J= 8.5 Hz, 1H), 2.62 (m, 1H), 1.94 (m, 4H).
	With sulfuric acid; water; sodium nitrite; at 0 - 27℃; for 16.0h;	To a solution of <strong>[28024-69-3]2-amino-2-cyclobutylacetic acid</strong> (10.0 g, 77.5 mmol) in water (100 mL) and aqueous H2SO4 solution (0.5 M, 180 mL) at 0 C was added sodium nitrite (32 g, 465.1 mmol) and the reaction mixture warmed to RT and stirred for 16 hrs. The reaction mixture was partitioned between water and THF. The aqueous layer was four times further extracted with THF. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was washed with EtOAc and the filtrate concentrated to afford crude 2- cyclobutyl-2-hydroxyacetic acid (8.0 g, 61.5 mmol, 79 %) as a yellow liquid. This material was used without further purification.

References: [1]Patent: WO2013/185093,2013,A1 .Location in patent: Page/Page column 246.
[2]Patent: WO2021/69927,2021,A1 .Location in patent: Page/Page column 42; 59-60.

3
(S)-N-(2-benzoyl-4-chlorophenyl)-2-[3,5-dihydro-4H-dinaphth[2,1-c:1′,2′-e]azepin-4-yl]acetamide [ No CAS ]
[ 6018-89-9 ]
[ 28024-69-3 ]
C₄₃H₃₄ClN₃NiO₃ [ No CAS ]

References: [1]Journal of Organic Chemistry,2015,vol. 80,p. 9817 - 9830.

4
4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid [ No CAS ]
[ 28024-69-3 ]
2-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzamido)-2-cyclobutylacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 16.0h;	To a stirred solution of 4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.25 g, 0.50 mmol) in tetrahydrofuran (10 mL)was added <strong>[28024-69-3]2-amino-2-cyclobutylacetic acid</strong> (0.128 g, 1.0 mmol) 1,1 ‘-carbonyldiimidazole (CDI)(0.097 g, 0.60 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.379 g, 2.50 mmol). Thereaction mixture was stirred at ambient temperature for 16 h then diluted with dichloromethane (50mL), washed with saturated ammonium chloride solution, brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (gradient of acetonitrile in water) to afford the title compound as a colorless solid (0.054 g, 18%):‘H NMR (300 MHz, CDC13) 9.36-8.59 (br, s, 1H), 8.02 (s, 1H), 7.60-7.43 (m, 3H), 7.12 (dd, J 12.1, 7.5 Hz, 1H), 6.38 (d, J= 13.5Hz, IH), 4.56 (t, J= 7.0 Hz, 1H), 4.24-4.07 (m, 2H), 4.06-3.84(m, 2H), 3.19 (t,J= 12.8 Hz, 2H), 2.93-2.67 (m, 3H), 2.29-2.14 (m, 2H), 2.14-1.70(m, 9H),0.94-0.79 (m, 2H), 0.70-0.54 (m, 2H); MS (ES+) m/z 617.2, 615.2 (M + 1).

References: [1]Patent: WO2016/7534,2016,A1 .Location in patent: Page/Page column 219.

5
[ 28024-69-3 ]
methyl 2-(2-(diisopropylamino)-2-oxoacetamido)-2-(2-(4-methoxyphenyl)cyclobutyl)acetate [ No CAS ]

References: [1]Journal of Organic Chemistry,2016,vol. 81,p. 5681 - 5689.

6
[ 28024-69-3 ]
methyl 2-cyclobutyl-2-(2-(diisopropylamino)-2-oxoacetamido)acetate [ No CAS ]

References: [1]Journal of Organic Chemistry,2016,vol. 81,p. 5681 - 5689.

7
[ 67-56-1 ]
[ 28024-69-3 ]
C₇H₁₃NO₂ [ No CAS ]

References: [1]Journal of Organic Chemistry,2016,vol. 81,p. 5681 - 5689.

8
aminocyclobutylacetonitrile [ No CAS ]
[ 28024-69-3 ]

Yield	Reaction Conditions	Operation in experiment
75.9%	With hydrogenchloride; water; at 80℃; for 6.0h;	In a three-necked flask, 300 mL of 6M hydrochloric acid and 30. 0 g of aminocyclobutylacetonitrile were added and the temperature was increased to 100 C for 6 hours. Into the sodium carbonate to adjust the pH of 8, filtered temperature, the filter cake dried to amino cyclobutylacetic acid 26. 7g (75.9%).

References: [1]Patent: CN103880768,2016,B .Location in patent: Paragraph 0028-0029.

9
[ 2987-17-9 ]
[ 28024-69-3 ]

References: [1]Patent: CN103880768,2016,B .

10
[ 28024-69-3 ]
N-(1-cyclobutyl-2-hydroxyethyl)chloropropionamide [ No CAS ]

References: [1]Patent: CN103880768,2016,B .

11
[ 28024-69-3 ]
5-cyclobutylmorpholin-3-one [ No CAS ]

References: [1]Patent: CN103880768,2016,B .

12
[ 28024-69-3 ]
3-cyclobutylmorpholine [ No CAS ]

References: [1]Patent: CN103880768,2016,B .

13
[ 28024-69-3 ]
ethyl 2-cyclobutyl-2-chloropropionamidoacetate [ No CAS ]

References: [1]Patent: CN103880768,2016,B .

14
[ 64-17-5 ]
[ 28024-69-3 ]
aminocyclobutylacetic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.8%	With hydrogenchloride;Reflux;	250 mL of an ethanolic solution of hydrochloric acid and 25. 0 g of aminocyclobutylacetic acid were added to a three-necked flask and reacted in a reflux state. After completion of the reaction, the reaction mixture was concentrated, and 200 mL of dichloromethane was added. The mixture was washed with saturated sodium hydrogencarbonate and washed with brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to give 17.6 g (57.8%) of ethylcyclobutylacetic acid ethyl ester.

References: [1]Patent: CN103880768,2016,B .Location in patent: Paragraph 0030-0031.

15
[ 28024-69-3 ]
2-cyclobutyl-2-phthalimido-2-fluoro-N-(pyridin-2-yl)acetamide [ No CAS ]

References: [1]Organic Letters,2018,vol. 20,p. 7100 - 7103.

16
[ 28024-69-3 ]
2-cyclobutyl-2-phthalimido-N-(pyridin-2-yl)acetamide [ No CAS ]

References: [1]Organic Letters,2018,vol. 20,p. 7100 - 7103.

17
[ 85-44-9 ]
[ 28024-69-3 ]
C₁₄H₁₃NO₄ [ No CAS ]

References: [1]Organic Letters,2018,vol. 20,p. 7100 - 7103.

18
(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidin-2-carboxamide [ No CAS ]
nickel diacetate [ No CAS ]
[ 28024-69-3 ]
nickel(II)-(R)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(R)-2-cyclobutylglycine Schiff base complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In methanol; at 60℃; for 16.0h;	General procedure: A suspension of (S)-4 or (R)-4 (100.3 mg, 0.2 mmol, 1 equiv.), rac-phenylalanine 5a (33 mg, 0.2mmol, 1 equiv.), Ni(OAc)2 (35.3 mg, 0.2 mmol, 1 equiv.), and K2CO3 (138.1 mg, 1.0 mmol, 5 equiv.) were refluxed in methanol (4 mL) at 60 C for 8 h. After cooling to room temperature, the mixture was diluted with 5% aqueous acetic acid (15 mL) and extracted three times with dichloromethane.The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (PE/EA = 4:1 to DCM/MeOH =20:1) to afford two diastereomers (S,2S)-6a and (S,2R)-6a (138 mg, yield 98%) for analysis (dr > 99:1). The mixture was purified again by column chromatography on silica gel (DCM/MeOH = 40:1) to givethe pure diastereomer (S,2S)-6a as a red solid.

References: [1]Molecules,2019,vol. 24.

19
(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide [ No CAS ]
nickel diacetate [ No CAS ]
[ 28024-69-3 ]
nickel(II)-(S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-2-methylpyrrolidine-2-carboxamide/(S)-2-cyclobutylglycine Schiff base complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In methanol; at 60℃; for 16.0h;	General procedure: A suspension of (S)-4 or (R)-4 (100.3 mg, 0.2 mmol, 1 equiv.), rac-phenylalanine 5a (33 mg, 0.2mmol, 1 equiv.), Ni(OAc)2 (35.3 mg, 0.2 mmol, 1 equiv.), and K2CO3 (138.1 mg, 1.0 mmol, 5 equiv.) were refluxed in methanol (4 mL) at 60 C for 8 h. After cooling to room temperature, the mixture was diluted with 5% aqueous acetic acid (15 mL) and extracted three times with dichloromethane.The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (PE/EA = 4:1 to DCM/MeOH =20:1) to afford two diastereomers (S,2S)-6a and (S,2R)-6a (138 mg, yield 98%) for analysis (dr > 99:1). The mixture was purified again by column chromatography on silica gel (DCM/MeOH = 40:1) to givethe pure diastereomer (S,2S)-6a as a red solid.

References: [1]Molecules,2019,vol. 24.

20
[ 28024-69-3 ]
methyl 4-(1-(2-cyclobutyl-2-((3-(methylsulfonyl)benzyl)oxy)acetamido)cyclopropyl)benzoate [ No CAS ]