[ CAS No. 2516-34-9 ]

Name: 2516-34-9|Cyclobutanamine|98%
Brand: Ambeed
SKU: A529599
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Quality Control of [ 2516-34-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 2516-34-9 ]

Product Details of [ 2516-34-9 ]

CAS No. :	2516-34-9	MDL No. :	MFCD00001328
Formula :	C₄H₉N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KZZKOVLJUKWSKX-UHFFFAOYSA-N
M.W :	71.12 g/mol	Pubchem ID :	75645
Synonyms :

Calculated chemistry of [ 2516-34-9 ]

Physicochemical Properties

Num. heavy atoms :	5
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	21.94
TPSA :	26.02 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) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.43
Log Po/w (XLOGP3) :	0.2
Log Po/w (WLOGP) :	0.5
Log Po/w (MLOGP) :	0.35
Log Po/w (SILICOS-IT) :	0.85
Consensus Log Po/w :	0.67

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	3.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.41
Solubility :	27.9 mg/ml ; 0.392 mol/l
Class :	Very soluble
Log S (Ali) :	-0.31
Solubility :	35.2 mg/ml ; 0.495 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.26
Solubility :	39.4 mg/ml ; 0.553 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 2516-34-9 ]

Signal Word:	Danger	Class:	3,8
Precautionary Statements:	P210-P280-P305+P351+P338-P310	UN#:	2733
Hazard Statements:	H225-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 2516-34-9 ]

* 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 [ 2516-34-9 ]
Downstream synthetic route of [ 2516-34-9 ]

[ 2516-34-9 ] Synthesis Path-Upstream 1~1

1
[ 2516-34-9 ]
[ 1616391-87-7 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 162 - 166

[ 2516-34-9 ] Synthesis Path-Downstream 1~58

1
[ 1503-98-6 ]
[ 2516-34-9 ]

Reference： [1]Chemische Berichte,1888,vol. 21,p. 2697
[2]Recueil des Travaux Chimiques des Pays-Bas,1918,vol. 37,p. 261

2
[ 2346-74-9 ]
[ 2516-34-9 ]
[ 109292-90-2 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2877 - 2882

3
[ 1503-98-6 ]
[ 7726-95-6 ]
KOH-solution [ No CAS ]
[ 2516-34-9 ]

Reference： [1]Chemische Berichte,1888,vol. 21,p. 2697

4
[ 3056-18-6 ]
[ 2516-34-9 ]
(2R,3R,4S,5R)-2-(2-Chloro-6-cyclobutylamino-purin-9-yl)-5-hydroxymethyl-tetrahydro-furan-3,4-diol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 250 - 260

5
[ 2516-34-9 ]
[ 111991-13-0 ]
2-cyclobutylamino-1-(3,4-difluoro-phenyl)-ethanol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2691 - 2696

6
[ 104-03-0 ]
[ 2516-34-9 ]
[ 136030-33-6 ]
[ 18637-83-7 ]
<i>N</i>-cyclobutyl-2-[4-(1,3,4-trioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-<i>b</i>]isoquinolin-2-yl)-phenyl]-acetamide [ No CAS ]

Reference： [1]Synlett,2003,p. 817 - 820

7
[ 2516-34-9 ]
[ 207557-35-5 ]
(S)-1-(2-Cyclobutylamino-acetyl)-pyrrolidine-2-carbonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 2774 - 2789

8
[ 515131-35-8 ]
[ 2516-34-9 ]
N-cyclobutyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 3-[(ethylimino)methylene]-amino}-N,N,N-trimethyl-1-propanaminium iodide; In chloroform; for 18h;	A mixture of 4-methyl-3-(4,4,5,5-tetramethyM,3,2-dioxaborolan-2-yl)benzoic acid(262mg) in chloroform (10ml) was stirred with 3-[(ethylimino)methylidene]amino}-/V,/V,A/-trimethyl-1-propanaminium iodide (450mg), 1-hydroxy-7-azabenzotriazole (13mg) and cyclobutylamine (102ul) for 18h. Water was added, the organic layer was separated using a20 hydrophobic filter tube and the solvent was removed under vacuum to give the title compound (210mg).NMR: [5H d6-DMSO] 8.59 (1H d, J=8Hz,), 8.08 (1H, d, J=1Hz), 7.81 (1H, dd,^8Hz J=1Hz), 7.26 (1H, d, J=8Hz), 4.47-4.37 (1H, m,), 2.50 (3H, s), 2.25-2.15 (2H, m), 2.14-2.03 (2H, m), 1.70-1.62 (2H,m), 1.32(12H,s).

Reference： [1]Patent: WO2005/73189,2005,A1 .Location in patent: Page/Page column 36

9
[ 2516-34-9 ]
[ 195609-18-8 ]
[ 875004-32-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: Preparation of 1-cyclobutyl-5-nitro-1,3-dihydro-indol-2-one (2-Fluoro-5-nitrophenyl)acetic acid (Step 1, Example 11, 2.00 g, 10.0 mmol) and cyclobutylamine (6 eq., 5.14 ml, 60.2 mmol) are mixed in dimethyl sulfoxide (10 ml) and stirred at 45 C. overnight. Excess cyclobutylamine is removed under vacuum and 2N hydrochloric acid (40 ml) added in one portion. The mixture is stirred for 1.5 hours at 45 C. and the resulting precipitate filtered, washed with water, and dried to give the title compound as a yellowish solid. HPLC r.t. 4.94 min; MS for C12H12N2O3 m/z 233.1 (M+H)+.

Reference： [1]Patent: US2006/30609,2006,A1 .Location in patent: Page/Page column 21

10
[ 97-08-5 ]
[ 2516-34-9 ]
[ 916050-77-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With pyridine; In dichloromethane; at 0 - 20℃; for 2.5h;	A solution of cyclobutylamine (0.552 mL, 6.44mmol) and pyridine (0.709 mL, 8.79 mmol) in dichloromethane (15 mL) was cooled at 0 0C. After the addition of 4-chloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.86 mmol), the mixture was warmed to room temperature and stirring was continued for 2.5 h. The solvent was evaporated at reduced pressure and the residue was partitioned between 1 N HCI and ethyl acetate. The organic was washed with water, brine, dried over Na2SO4 and evaporated to give the desired product as a yellow solid (1.21 g, 71%). 1H NMR (400 MHz, CDCI3) delta ppm 8.35 (d, J=2.3 Hz, 1 H), 7.99 (dd, J=8.5, 2.2, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 4.96 (d, J=8.5 Hz, 1 H), 3.87 (sext, J=8.2 Hz, 1 H), 2.26-2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.62 (m, 2H).
71%	With pyridine; In dichloromethane; at 0 - 20℃; for 2.5h;	A solution of cyclobutylamine (0.552 ml_, 6.44mmol) and pyridine (0.709 ml_, 8.79 mmol) in dichloromethane (15 ml.) was cooled at 0 0C. After the addition of 4-chloro-3- nitrobenzenesulfonyl chloride (1.5 g, 5.86 mmol), the mixture was warmed to room temperature and stirring was continued for 2.5 h. The solvent was evaporated at reduced pressure and the residue was partitioned between 1 N HCI and ethyl acetate. The organic was washed with water, brine, dried over Na2SO4 and evaporated to give the desired product as a yellow solid (1.21 g, 71 %). 1H NMR (400 MHz, CDCI3) delta ppm 8.35 (d, J=2.3 Hz, 1 H), 7.99 (dd, J=8.5, 2.2, 1 H), 7.72 (d, J=8.3 Hz, 1 H), 4.96 (d, J=8.5 Hz, 1 H), 3.87 (sext, J=8.2 Hz, 1 H), 2.26-2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.73-1.62 (m, 2H)

Reference： [1]Patent: WO2006/127458,2006,A2 .Location in patent: Page/Page column 50
[2]Patent: WO2007/103758,2007,A2 .Location in patent: Page/Page column 49

11
[ 885500-55-0 ]
[ 2516-34-9 ]
C₁₄H₁₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 6h;	Example 325A mixture of cyclobutanamine (6.4 mg) , ethyl 4-chloro- li-pyrrolo[2,3-jb]pyridine-5-carboxylate (0.030M solution in 1- methyl-2-pirrolidone, 1.00 mL) , and N,N-diisopropylethylamine (0.016 mL) was heated at 1500C for 6 days. The reaction mixture was cooled to ambient temperature, then solvent was removed in vacuo. To the residue was added 1,4-dioxane (ImL) and LiOH (0.090M solution in water, l.OOmL) . The mixture was heated at 1000C for 24 hours and it was cooled to ambient temperature, and the solvent was' removed in vacuo. To the residue was added 1,4-dioxane (1 mL) ,N,N-dimethylformamide (0.5mL) , N,N-diisoprorhoylethylamirie (O.OldeltamL), and diphenylphosphoryl azide (0.090M solution in 1,4-dioxane, l.OOmL) . The mixture was heated at 1000C for 24 hours and it was cooled to ambient temperature, and the solvent was removed in vacuo. To the residue was added chloroform (2 mL) , and IM NaOH solution (1 EPO <DP n="181"/>itiL) and was mixed with Bortex Mixer. The organic phase was separated with IPS Filter Tube (from Whatman) and evaporated. Purification by preparative high performance liquid chromatography gave l-cyclobutyl-3, 6-dihydroimidazo [4, 5-d]pyrrolo [2, 3-jb] pyridin- -2 (IH) -one (0.3mg) .

Reference： [1]Patent: WO2007/7919,2007,A2 .Location in patent: Page/Page column 178-179

12
[ 106157-91-9 ]
[ 2516-34-9 ]
[ 50607-30-2 ]
2-(2-Amino-pyrimidin-4-yl)-1-cyclobutyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 487 - 501

13
[ 2516-34-9 ]
[ 102-83-0 ]
[ 245421-04-9 ]
[ 1018478-82-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1308 - 1311

14
[ 900789-14-2 ]
[ 2516-34-9 ]
[ 1192711-67-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In butan-1-ol; at 70℃; for 18h;	A solution of <strong>[900789-14-2]5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine</strong> (142 mg, 0.530 mmol), cyclobutylamine (0.090 mL, 1.06 mmol) and TEA (0.150 mL, 1.08 mmol) in nBuOH (6 mL) was stirred at 70 C for 18 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with IN HCl, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154 mg).

Reference： [1]Patent: WO2009/131687,2009,A2 .Location in patent: Page/Page column 128

15
[ 1053228-29-7 ]
[ 2516-34-9 ]
[ 1192711-69-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In butan-1-ol; at 70℃; for 5h;	A solution of <strong>[1053228-29-7]2,4-dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine</strong> (50 mg, 0.24 mmol), cyclobutylaniine (0.041 mL, 0.48 mmol) and TEA (0.070 mL, 0.50 mmol) in nBuOH (2 mL) was stirred at 70 C for 5 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with IN HCl, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-cyclobutyl-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (54 mg).

Reference： [1]Patent: WO2009/131687,2009,A2 .Location in patent: Page/Page column 129

16
[ 1192711-71-9 ]
[ 2516-34-9 ]
[ 1192711-72-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In butan-1-ol; at 70℃;	A solution of <strong>[1192711-71-9]2,4-dichloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (190 mg, 0.94 mmol), cyclobutylamine (0.160 mL, 1.88 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was stirred at 70 0C overnight. It was then purified by HPLC to give 2- chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg).

Reference： [1]Patent: WO2009/131687,2009,A2 .Location in patent: Page/Page column 135

17
[ 2516-34-9 ]
[ 2105-96-6 ]
[ 1190631-52-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5191 - 5194

18
[ 2516-34-9 ]
[ 3006-96-0 ]
[ 1022171-45-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; chloroform; at 20℃; for 5h;	Stage 1: N-cyclobutyl-4-(hydroxymethyl)benzamide 1-hydroxybenzotriazole (HOBt) (888 mg, 1 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.26 g, 1 eq) in solution in chloroform (40 ml) then cyclobutylamine (470 mg) are successively added to 4-(hydroxymethyl)benzoic acid (1 g, 1 eq) in solution in anhydrous THF (30 ml). After stirring for 5 hours at a temperature of approximately 20 C., the reaction mixture is concentrated under reduced pressure at 40 C. The residue is taken up in dichloromethane (100 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with water, then with salt water, dried over Na2SO4 and concentrated under reduced pressure at 40 C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 40:60 to heptane/ethyl acetate 25:75) produces the expected compound in the form of a white powder (1.3 g; 67% yield). MS/LC: calculated MM=205.5; m/z=206.2 (MH+) NMR (1H, 400 MHz, DMSO-d6): delta 1.66 (m, 2H), 2.05 (m, 2H), 2.20 (m, 2H), 4.40 (m, 1H), 4.54 (d, 2H), 5.26 (t, 1H), 7.36 (AB, 2H), 2.01 (AB, 2H), 8.52 (d, 1H).

Reference： [1]Patent: US2010/56507,2010,A1 .Location in patent: Page/Page column 9

19
[ 51940-64-8 ]
[ 2516-34-9 ]
[ 1198306-28-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;	Dichloropyrimidine 1.4 (5.9g, 27 mmol) was dissolved in acetonitrile (50 mL) and treated sequentially with diisopropylamine (5.2 mL, 30 mmol) followed by cyclobutyl amine (1.9g, 27 mmol) and stirred at rt until all starting material had been consumed. The reaction mixture was then diluted with water to a total volume of 150 mL and the precipitate collected by filtration affording the desired product as a light yellow solid (6.02g, 87%). 1H NMR (DMSOd6, 400 MHz): delta 8.60 (S, IH), 8.48 (d, IH), 4.52 (m, IH), 4.29 (q, 2H), 2.30 (m, 2H), 2.04 (m, 2H), 1.73 (m, 2H), 1.30 (t, 3H).

Reference： [1]Patent: WO2010/129802,2010,A1 .Location in patent: Page/Page column 73-74

20
[ 27550-59-0 ]
[ 2516-34-9 ]
[ 1260225-29-3 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 342 - 353

21
[ 2516-34-9 ]
[ 1263868-24-1 ]
[ 1263868-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one at 20℃; for 3h;	Gg To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2- chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94 % yield), which was used for the next step without any purification. LC- MS (M+H)+ = 300.1.
	In 1-methyl-pyrrolidin-2-one at 20℃; for 3h;	Gg Preparation Gg2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amineTo a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (160 mg, 0.60 mmol) in NMP (2 mL) was added cyclobutanamine (129 mg, 1.81 mmol) dropwise. The mixture was stirred at RT for 3 hrs. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2- chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (177 mg, 0.57 mmol, 94 % yield), which was used for the next step without any purification. LC- MS (M+H)+ = 300.1

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2011/14535, 2011, A1 Location in patent: Page/Page column 57
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2012/103297, 2012, A1 Location in patent: Page/Page column 41

22
[ 2516-34-9 ]
[ 110104-60-4 ]
[ 1093951-30-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; acetonitrile; at 20℃;	Genera procedure: To a solution of the corresponding alkyl amine (1.2 equiv) in THF (2.0 M) was added simultaneously a solution of <strong>[110104-60-4](E)-4-chloro-3-methoxy-but-2-enoic acid methyl ester</strong> (1 equiv) in acetonitrile (1.5 M) and a solution of triethylamine (1 equiv) in acetonitrile (3.6 M) over 30 min at room temperature. After stirring overnight at room temperature or 3 h at 55 C, the resulting precipitate in the reaction mixture was removed by filtration. The mother liquor was concentrated and purified by flash chromatography on silica gel eluting with a gradient of 20-100% ethyl acetate in hexanes to afford the title compound in greater than 75% yield.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 2927 - 2938

23
[ 2516-34-9 ]
[ 149793-69-1 ]
[ 1333154-03-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃;	In a 50-mL,3Nround-bottomed flask equipped with nitrogen inlet and a rubber septum, 3-fluoro-5-trifluorobenzonitrile (1.5 g, 1.0 eq.) was dissolved in DMSO (30 mL) and cyclobutanamine (1.128 g, 2.0 eq.) and potassium carbonate(3.81 g, 3.5 eq.) was added. The reaction mixture was heated at 100 C for 4-5 h. The progress of reaction was followed by TLC analysis on silica gel with 20% Ethyl acetate- hexane as mobile phase. SM f=0.6 and Product Rf=0.4. eaction mixture was poured into ice water (150 mL) and extracted with EtOAc ( 3x50 mL). The combined organic layers were washed with brine solution(3x50mL) and dried over anhydrous MgS04, filtered, and concentrated by rotary evaporation (25C, 20mmHg) to afford 1.8g of crude compound which was used for next step without any purification. Yield (94.7%). Mass: 240.90.

Reference： [1]Patent: WO2011/109799,2011,A1 .Location in patent: Page/Page column 261-262

24
[ 2516-34-9 ]
[ 1196155-38-0 ]
[ 1333153-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	hydrogenchloride; In butan-1-ol; at 130℃; for 0.5h;Microwave;	Synthesis of Intermediate (1) 1.21[00654] In a25-mL microwave seal tube <strong>[1196155-38-0]2-chloro-6-trifluoromethylisonicotinonitrile</strong> (lg) Isopropyl amine(0.517g) was dissolved in n-butanol(lOmL) and one drop of con. HC1 was added. Reaction mixture was irradiated at 130°C for 30 min in Microwave. The Completion of the reaction was confirmed by TLC using 10percent EtOAc-n-hexane as mobile phase. Reaction mixture was quenched into ice water slurry. Extract compound in ethyl acetate, organic layer washed with water two times dried over Nu3/4804, filtered, and concentrated by rotary evaporation(40°C,20 mmHg) to afford 8g of a yellow oil. The resulting crude compound was purified by column chromatography. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate :n-hexane as mobile phase. The columnwas packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection(25 -mL fractions) from 1-3 percent ethyl acetate in hexane. Compound started eluting with 2 percent ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound(0.8 g).

Reference： [1]Patent: WO2011/109799,2011,A1 .Location in patent: Page/Page column 249-250

25
[ 2516-34-9 ]
[ 65515-28-8 ]
[ 1374215-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 48h;	Dichloro ester 1.2 (2.0 g, 9.7 mmol) was diluted with 20 mL of acetonitrile then treated with diisopropyl ethyl amine (1.9 mL, 10.7 mmol) followed by cyclobutyl amine (0.75 mL, 9.7 mmol). The reaction as then stirred at room temperature for two days during which time a precipitate formed. When the progress was checked by UPLC the reaction was found to be only 50% complete with an 4:1 ratio of the 2-amino to 6-amino isomers. The solids were removed by filtration affording 0.40 g of the desired product. The filtrate was then diluted with water to 100 mL total volume affording an additional 0.50 g of the desired product. MS found for C11H13ClN2O2 as (M+H)+ 241.0, 243.0. UV lambda=263 (major), 288 (minor).

Reference： [1]Patent: US2012/108566,2012,A1 .Location in patent: Page/Page column 43

26
[ 2516-34-9 ]
[ 362527-61-5 ]
[ 1398111-93-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5396 - 5404

27
[ 1187-59-3 ]
[ 2516-34-9 ]
[ 1001346-17-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 140℃; for 0.5h;Microwave irradiation;	General procedure: A solution of <strong>[1187-59-3]N-methylacrylamide</strong> (2) (1.88 g, 22.0 mmol) and cyclopentylamine (1.98 mL, 20.0 mmol) in MeOH (14 mL) was heated under microwave irradiation to 140 C for 30 min (Biotage Initiator). The volatiles were removed under reduced pressure, the residue diluted with MeOH (20 mL) and purified by strong cation exchange filtration (50 g SCX-2 cartridge) washing with MeOH (100 mL) and eluting with 7 M methanolic NH3 (100 mL). The eluted product was concentrated under reduced pressure to afford the title compound 3 as a brown oil (3.09 g, 18.2 mmol, 91%). This was used directly with no further purification.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 5049 - 5055

28
[ 2516-34-9 ]
[ 77284-64-1 ]
[ 1284249-39-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;	Example 611-cyclobutyl-4-[6-cyclopropyM-methyl-4-(trifluoromethyl)-1H-benztoyl]carbonyl}-5-ethyl-2-piperazinoneStep A1, 1 -dimethyl ethyl {1-[(cyclobutylamino)carbonyl ]propyl}carbamate[00284] To a solution of 2-([(1 ,1-dimethylethyl)oxy]carbonyl}amino)butanoic acid (4.0 g, 20 mmol) in N,N-dimethylformamide (100 mL) was added cyclobutylamine (1.9 mL, 22 mmol), N,N-diisopropylethylamine (10.3 mL, 59.0 mmol), and N-[(dimethylamino)(3H-[1 ,2,3]triazolo[4,5- b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (8.23 g, 21.7 mmol). The mixture was stirred for 2 hours, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate and concentrated. The residue was slurried in ethyl ether, stirred for 30 minutes, and the solids collected by filtration. The product was purified by passing through a silica gel plug, eluting with 25% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (3.1 g; 62%). 1H NMR (400 MHz, CHLOROFORM- d) 5 ppm 6.00 - 6.39 (m, 1 H), 4.85 - 5.19 (m, 1 H), 4.27 - 4.53 (m, 1 H), 3.78 - 4.03 (m, 1 H), 2.26 - 2.46 (m, 2 H), 1.78 - 1.96 (m, 3 H), 1.52 - 1.78 (m, 3 H), 1.45 (s, 9 H), 0.94 (t, 3 H).

Reference： [1]Patent: WO2011/97491,2011,A1 .Location in patent: Page/Page column 144

29
[ 2516-34-9 ]
[ 72130-97-3 ]
[ 1402446-99-4 ]

Yield	Reaction Conditions	Operation in experiment
	at 70℃; for 2.5h;	Step AK4: 1-Cvclobutyl-1 H-imidazole-4-carboxylic acid ethyl ester The stirred mixture of <strong>[72130-97-3](Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester</strong> (17.0 g, 100 mmol) and cyclobutaneamine (21.79 g, 300 mmol) was heated for 2.5 h at 70 C. The reaction mixture was cooled to rt and concentrated. The residue was purified by flash chromatography (EtOAc/hexane, 5:1 ) to afford the title compound as an orange oil. tR: 0.70 min (LC-MS 2); ESI-MS: 195.2 [M+H]+ (LC-MS 2); H-NMR (DMSO-c 6, 400 MHz) delta ppm 8.03 (s, 1 H), 7.83 (s, 1 H), 4.73 (m, 1 H), 4.18 (q, 2H), 2.36 (m, 4H), 1.74 (m, 2H), 1.24 (t, 3H).

Reference： [1]Patent: WO2013/111105,2013,A1 .Location in patent: Page/Page column 141

30
[ 2516-34-9 ]
[ 175358-02-8 ]
[ 1400668-19-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium t-butanolate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; for 4h;Reflux;	A mixture of <strong>[175358-02-8]4,6-dichloropyrido[3,2-d]pyrimidine</strong> (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclobutanamine (0.047 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 mmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (0.098 g, 84%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.79-1.89 (2H, m), 2.06-2.17 (2H, m), 2.48-2.56 (2H, m), 4.71-4.82 (1H, m), 7.11 (1H, brs), 7.61 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=8.8 Hz), 8.61 (1H, s).

Reference： [1]Patent: US2012/238587,2012,A1 .Location in patent: Page/Page column 25

31
[ 2516-34-9 ]
[ 33089-15-5 ]
[ 1192132-93-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 60℃; for 2h;	To a stirring solution of <strong>[33089-15-5]4-chloro-2-(methylthio)pyrimidine-5-carbonitrile</strong> (2 g, 10.8 mmol) in DMF (10 mL) was added DIEA (4.2 g, 32.4 mmol) and cyclobutanamine (2.3 g, 32.4 mmol) at 0 C. The resulting mixture was stirred at 60 C for 2 h. The reaction mixture was poured into saturated sodium chloride, and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. The crude product was purified via silica gel column chromatography (10% ethyl acetate in petroleum ether) to get the desired product as a white solid (1.7 g, 7.7 mmol, 71% yield). MS (ESI) m/z = 221.2[M+H] +.

Reference： [1]Patent: WO2012/145569,2012,A1 .Location in patent: Page/Page column 145

32
[ 17973-86-3 ]
[ 2516-34-9 ]
[ 1542265-47-3 ]

Yield	Reaction Conditions	Operation in experiment
55.3%	With triethylamine; In 1,4-dioxane; hexane; at 90℃; for 0.45h;Microwave irradiation;	Step 1. 6-Bromo-N-cyclobutylpyridazin-3-amine Into a solution of <strong>[17973-86-3]3,6-dibromopyridazine</strong> (1.19 g, 5 mmol) in dioxane (5 mL) was added cyclobutylamine (0.39 g, 5.5 mmol), and Et3N (0.60 g, 6 mmol). The reaction was microwave at 90 C., 150W for 0.45 h. The reaction was monitored by TLC and the crude product was purified by silica gel chromatography (eluent: 30% Ethyl acetate in n-hexane), to give the desired product (0.63 g, 55.3%). 1H NMR (300 MHz, CDCl3) delta: 7.25-7.28 (1H, d, J=9.0 Hz), 6.49-6.52 (1H, d, J=9.0 Hz), 5.27 (1H, s), 4.16-4.24 (1H, m), 2.40-4.49 (2H, m), 1.87-1.95 (2H, m), 1.75-1.84 (2H, m).

Reference： [1]Patent: US2014/31354,2014,A1 .Location in patent: Paragraph 0301; 0302

33
[ 2516-34-9 ]
[ 369-25-5 ]
[ 1563216-16-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 60℃; for 12h;	Step 1: A mixture of 33-1 (Ri, R2 = H) (2.4 g, 14 mmol) and cyclobutanamine (2 g, 28 mmol) in DMSO (30 mL) was stirred at 60 C for 12 hrs. The reaction was poured into ice water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL) and dried over Na2S04. After being concentrated, the crude product was purified by flash column chromatography eluting with PE/EA = 10/1 to give 33- 2 as a white solid, *H NMR (300 MHz, CDC13) delta 7.72 - 7.68 (m, 1H), 7.63 - 7.58 (m, 1H), 6.60 - 6.54 (m, 1H), 4.01 - 3.96 (m, 1H), 3.85 (s, 3H), 2.48 - 2.42 (m, 2H), 1.97 - 1.83 (m, 4H). LC-MS: m/z = 224.1 [M+H]+.

Reference： [1]Patent: WO2014/28669,2014,A1 .Location in patent: Paragraph 00614

34
[ 2516-34-9 ]
[ 50488-42-1 ]
N-cyclobutyl-5-(trifluoromethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16h;Sealed tube;	To a solution of <strong>[50488-42-1]2-bromo-5-(trifluoromethyl)pyridine</strong> (10.0 g, 44.24 mmol), K2003 (8.3 g, 60.05 mmol) in DMSO (50 mL) was added cyclobutylamine (4.51 mL, 52.82 mmol) and maintained at 100 C for 16 h in sealed tube. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with water, brine solution, dried over an hydrous Na2SO4 and concentrated. The crude product was purified by column chromatography over silica gel (100 - 200 mesh) using a solvent gradient of 20 % ethyl acetate in pet-ether to afford 8.0 g (84 %) of N-cyclobutyl-5- (trifluoromethyl)pyridin-2-amine 160-1 as a white solid. 1H-NMR (400 MHz, DMSO-d6): c5 8.26 (5, 1H), 7.55-7.63 (m, 2H), 6.50 (d, J= 11.6 Hz, 1H), 4.30-4.33 (m, 1H), 2.23-2.31 (m, 2H), 1.82-1.93 (m, 2H), 1.64-1.72 (m, 2H). ESI-LC/MS: m/z217.06 (M+H); R = 2.85 mm [Waters Acquity UPLC with SOD; Waters Acquity UPLC BEH 018, 1.7 pm, 2.1 X 50 mm column; gradient of 98:02 H20 (0.1% H000H): CH3CN (0.1% H000H) hold for 0.8 mm and to 45:55 H2Q (0.1% H000H):CH3CN (0.1% H000H) in 2.0 mm and hold for 1.0 mm and to 0:100 H2Q (0.1% H000H):CH3CN (0.1% H000H) in 0.5 mm and hold for 1.5 mm with flow rate of 0.4 mLlmin].

Reference： [1]Patent: WO2014/78802,2014,A1 .Location in patent: Page/Page column 247

35
[ 53180-76-0 ]
[ 2516-34-9 ]
[ 1614246-97-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	In water at 125℃; for 4h; Microwave irradiation;	98 5-Chloro-N3-cyclobutylpyridazine-3,4-diamine A mixture of 3,5-dichloro-4-aminopyridazine (Preparation 4, 200 mg, 1.22 mmol), cyclobutyl amine (0.56 mL) and water (1.12 mL) was heated under microwave irradiation at 125° C. for 4 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 98:2 to afford the title compound as a brown solid in 58% yield, 140 mg. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.68-1.75 (m, 2H), 1.84-1.92 (m, 2H), 2.30-2.37 (m, 2H), 4.40-4.46 (m, 1H), 6.15 (br s, 2H), 6.33 (br s, 1H), 8.10 (s, 1H). LCMS (System 7): Rt=2.17 minutes MS m/z 199 [M+H]+

Reference： [1]Current Patent Assignee: PFIZER INC - US2014/171435, 2014, A1 Location in patent: Paragraph 0739; 0740; 0741

36
[ 2516-34-9 ]
[ 148625-35-8 ]
2-cyclobutyl-2H-indazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(Step 1) [0308] Toluene (30 mL) and cyclobutylamine (2.25 mL) were added to <strong>[148625-35-8]methyl 3-formyl-4-nitrobenzoate</strong> (5.00 g), and the reaction solution was stirred at room temperature for 5 minutes. The solvent was evaporated under vacuum, then triethyl phosphite (11.3 mL) was added to the residue, and the reaction solution was stirred at 100°C for 7 hours. The solvent was evaporated under vacuum, the resultant residue was purified by column chromatography on silica gel [0309] (developing solvent: hexane/ethyl acetate). Ethanol (2 mL) and a 5 N aqueous sodium hydroxide solution (5.0 mL) were added to the resultant crude product, and the reaction solution was stirred at room temperature for 1 hour. A 10percent aqueous phosphoric acid solution was added to acidify the reaction solution. Furthermore, water was added, and the deposited precipitate was filtrated to obtain 2-cyclobutyl-2H-indazole-5-carboxylate as a white solid.

Reference： [1]Patent: EP2762476,2014,A1 .Location in patent: Paragraph 0308; 0309

37
[ 2516-34-9 ]
[ 82437-64-7 ]
[ 122-51-0 ]
[ 1621967-99-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With acetic acid; at 160℃;Inert atmosphere; Autoclave;	General procedure: To a pressure bottle containing <strong>[82437-64-7]methyl 3-amino-4-phenylthiophene-2-carboxylate</strong> (100 mg, 0.43 mmol), CH(OEt)3 (1 mL) was added, followed by allylamine hydrochloride (93 mg, 0.99 mmol) and AcOH (0.1 mL). The reaction mixture was stirred and refluxed at 160 C overnight. After the reaction, the mixture was evaporated then solidified with ether. The produced white crystals were filtered and dried in vacuo to give the title compound 4-1 (66 mg, 0.25 mmol, 58 % yield): 1HNMR (300 MHz, CDCl3) delta 8.11 (s, 1H), 7.84-7.79 (m, 3H), 7.50-7.44 (m, 2H), 7.41-7.36 (m, 1H), 6.08-5.95 (m, 1H), 5.34-5.24 (m, 2H), 4.72-4.67 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 157.3, 154.3, 147.3, 138.1, 133.7, 131.9, 130.5,128.7, 128.3, 128.0, 124.9, 119.1, 48.0; LC/MS (ESI+): m/z: calcd for C15H12N2OS: 268.34, [M + H]+; found: 269.05

Reference： [1]Bulletin of the Korean Chemical Society,2015,vol. 36,p. 1439 - 1451

38
[ 77317-97-6 ]
[ 2516-34-9 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a mixture of N-hydroxy-3-phenylpropanamide (1j) (0.198 g, 1.2 mmol), K2CO3 (0.166 g, 1.2 mmol), and DMSO (0.5 mL) was added acetic anhydride (1.1 mL, 0.012 mmol) and heated to 50 C. After stirring at that temperature for 10 min,the reaction mixture was cooled to 0 C and then treated with 2 M HCl (ca. 1mL). After the mixture became the clear solution, 2 M NaOH (ca. 2 mL) and di-t-butyl dicarbonate (0.55 mL, 2.4 mmol) was added successively. After stirring for 12 h, the mixture was extracted with Et2O (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et2O,1:1) to yield t-butyl 3-phenylpropylcarbamate (2j) (0.122 g, 46%) as a colorless liquid.
		General procedure: A 10 mL test tube was charged with 3-phenylpropanoic acid (1l) (0.300 g, 2.00 mmol) and anhydrous DMSO (2 mL) and placed under an argon atmosphere. CDI (0.486 g, 3.00 mmol) was added and the resulting mixture was stirred at rt for 1 h. DMAP (24.0 mg, 0.200 mmol) and NH2OTMS (0.420 g, 4.00 mmol) was added at rt and stirred at ambient temperature for 18 h. After addition of anhydrous K2CO3 (0.696 g, 5.04 mmol), the resulting mixture was heated to 90 C and stirred at that temperature for 3 h. After cooling of the reaction mixture to rt, 2 M HCl (2 mL) was added and stirred for 1 h. 2 M NaOH (3 mL) was added to the reaction mixture at 0 C and then Z-chloride (0.51 mL, 3.6 mmol) was added. After stirred for 16 h, the mixture was extracted with CH2Cl2 (15 mL× 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et2O = 2:1) to yield the pure N-Boc-(2-phenylethyl)amine (3a) (0.180 g, 41%)

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 710 - 712
[2]Tetrahedron Letters,2016,vol. 57,p. 5304 - 5307

39
[ 4359-87-9 ]
[ 2516-34-9 ]
2,6-dichloro-N-cyclobutyl-5-nitropyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: Preparation of 2,6-dichloro-N-cyclobutyl-5-nitropyrimidin-4-amine Cyclobutanamine (0.485 mL, 5.68 mmol) in iPrOH (20 mL) was added to a solution of <strong>[4359-87-9]2,4,6-trichloro-5-nitropyrimidine</strong> (1.29 g, 5.65 mmol) in iPrOH (40 mL) at -78 C. dropwise via addition funnel. After complete addition, the mixture was allowed to warm to rt over 30 min, then DIEA (0.940 mL, 5.66 mmol) was added and the mixture stirred at rt for 10 min. The solvent was removed under reduced pressure and dried to give the title compound as a pale yellow oil which was used without purification.

Reference： [1]Patent: US2015/141402,2015,A1 .Location in patent: Paragraph 0674; 0675

40
[ 2516-34-9 ]
[ 351-32-6 ]
N-[4-(cyclobutylamino)-3-nitrophenyl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 140℃; for 1.5h;Microwave irradiation;	1.00 g (5.04 mmol) <strong>[351-32-6]N-(4-fluoro-3-nitrophenyl)acetamide</strong> (for preparation see: WO2005/72741 page 26, Example 117A) and 0.86 ml (10.09 mmol) of cyclobutylamine were initially charged in 40 ml of ethanol, then 1.40 ml (10.09 mmol) of triethylamine were added and the reaction mixture was stirred in a microwave at 140 C. for 1.5 h. For workup, the mixture was concentrated under reduced pressure, the residue was stirred with MTBE, and the solid formed was filtered off and dried under high vacuum. This gave 185 mg (69% purity, 10% of theory) of the target compound. The remaining filtrate was concentrated, and the residue was taken up in ethyl acetate, washed once each with water and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. After drying under high vacuum, this gave a further 1.01 g (78% of theory) of the target compound. LC-MS (Method 3): Rt=1.31 min; MS (ESIpos): m/z=250 (M+H)+. 1H NMR (400 MHz, DMSO-d6): delta [ppm]=1.70-1.85 (m, 2H), 1.93-2.04 (m, 5H), 2.39-2.47 (m, 2H), 4.12 (sxt, 1H), 6.92 (d, 1H), 7.65 (dd, 1H), 7.93 (d, 1H), 8.46 (d, 1H), 9.97 (s, 1H).

Reference： [1]Patent: US2015/148340,2015,A1 .Location in patent: Paragraph 0662; 0663; 0664; 0665

41
[ 679406-03-2 ]
[ 2516-34-9 ]
C₁₁H₁₄ClN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 3.0h;	[0184j To compound 5-6 (220 mg, 1 mmol) in acetonitrile (2 ml) was added cyclobutamine (102 iL, 1.2 mmol) and DIEA (213 iL, 1.2 mmol) and the reaction mixture stirred at room temperature for 3 hr. After work up and extraction with ethyl acetate the crude compound 6-2 was isolated. To the THF solution of crude 6-2 added LiOH (84 mg) and stirred for 4hr. The reaction mixture was acidified and extracted the desired product 6-3 as white solid

Reference： [1]Patent: WO2015/123453,2015,A1 .Location in patent: Paragraph 0184

42
[ 779345-37-8 ]
[ 2516-34-9 ]
C₉H₁₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.2%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 1h;	Synthesis of compound 222.1. To a solution of 220.1 (0.275g, 1.936mmol, l .Oeq) in DMSO (5ml) was added cyclobutyl amine (0.165 g, 2.323 mmol, 1.2 eq.) and DIPEA (2.5 g, 19.4 mmol, 10 eq.). Reaction mixture was heated at 100 C for lh. After completion of reaction, mixture was poured in water, quenched with ammonium chloride solution and product was extracted with EtOAc. Organic layers were combined,dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 222.1 (0.3 g, 80.2 %). MS(ES): m/z 193.21 [M+H]+.

Reference： [1]Patent: WO2015/131080,2015,A1 .Location in patent: Paragraph 001162; 001163

43
[ 2516-34-9 ]
[ 72587-15-6 ]
N-cyclobutyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydrogencarbonate; In ethanol; for 0.666667h;	Step A. Alternative preparation of N-cyclobutyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine To a mixture of <strong>[72587-15-6]2-chloro-3-nitro-5-(trifluoromethyl)pyridine</strong> (1.00 g, 4.41 mmol) and NaHCO3 (1.12 g, 13.2 mmol) in EtOH (10 mL) was added cyclobutylamine (0.94 g, 13.2 mmol) drop-wise over 10 minutes. The mixture was stirred for 30 min, absorbed onto silica and purified on a 40 g ISCO gold silica gel column, eluting with a hexanes (100%) to hexanes (95%)/EtOAc (5%) gradient, to provide the desired compound (1.05 g, 91%) as a bright yellow solid.

Reference： [1]Patent: US2016/31875,2016,A1 .Location in patent: Paragraph 0288

44
[ 2516-34-9 ]
[ 3939-14-8 ]
2-(cyclobutylamino)isonicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	In tetrahydrofuran; at 20 - 50℃; for 32h;Sealed tube;	Intermediate 1-10-4A solution of <strong>[3939-14-8]2-fluoro-4-cyanopyridine</strong> (1.1 g, 9.1 mmol) and cyclobutylamine (1.89 g, 18.1 mmol) in THF (10 mL) was stirred at RT for 16h, then heated in a sealed tube at 50C for 16h. Allowed to cooled, diluted with water and extracted with EtOAc, the organics were combined, washed with water, sat. NaCI, dried over Na2S04 and concentrated. Purified by silica chromatography to give Intermediate 1 -10-4 2-(cyclobutylamino)isonicotinonitrile (1 .047 g, 67%).1 H-NMR (400 MHz ,DMSO-d6), Shift [ppm]= 1 .57-1 .74 (2H), 1 .79-1 .92 (2H), 2.21 -2.33 (2H), 4.24 (1 H), 6.68-6.78 (2H), 7.34 (1 H), 8.13 (1 H).

Reference： [1]Patent: WO2015/193339,2015,A1 .Location in patent: Page/Page column 391

45
[ 2516-34-9 ]
[ 7697-28-1 ]
4-bromo-N-cyclobutyl-3-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	A solution of <strong>[7697-28-1]4-bromo-3-methylbenzoic acid</strong> (2.0 g, 9.3 mmol) and cyclobutylamine (0.87 ml, 10.2 mmol) in DMF (60 ml) was treated with N, N-diisopropylamine (3.6 ml, 20.5 mmol) and a solution of HATU (4.24 g, 11.2 mmol) in DMF (30 ml) was added thereto.The reaction mixture was stirred at RT overnight (ca. 16 h).The solvent was removed at high vacuum and the residue was added, stirred and sucked with water.The residue was washed thoroughly with water and dried under high vacuum.This gave 2:35 g (94% d. Th.) Of the title compound.

Reference： [1]Patent: TW2016/5810,2016,A .Location in patent: Paragraph 0441

46
[ 82413-63-6 ]
[ 2516-34-9 ]
N-(4-(morpholinomethyl)benzyl)cyclobutanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; In methanol; at 20℃;Inert atmosphere;	General procedure: Typical procedure for reductive amination with cyclobutyl or cyclopentyl amine: Aldehyde (1 equiv) was dissolved in anhydrous MeOH under N2. Cyclobutyl amine (1.05 equiv) was added and the reaction stirred overnight at room temperature. NaBH4 (1.6 equiv) was added and the reaction stirred for 1 hour. The reaction was quenched with saturated NH4Cl, taken up in ethyl acetate, washed with brine, dried over MgSO4, concentrated, and taken directly to the next step without further purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1731 - 1736
[2]Journal of Enzyme Inhibition and Medicinal Chemistry,2017,vol. 32,p. 992 - 1001

47
[ 2516-34-9 ]
[ 1422772-78-8 ]
2-bromo-N-cyclobutyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		Ice bath,(COCl) 2 (7.5 mL) and DMF (0.4 mL)Was slowly added dropwise to a solution of 2-bromo-5H-pyrrolo [2,3-b] pyrazine-7-carboxylic acid (60%, 4.00 g, 8.26 mmol) in dichloromethane (150 mL)Reaction at room temperature for 2 h. Concentrated under reduced pressure,The residue was dissolved in dichloromethane (120 mL)Cyclobutylamine (2.2 mL, 26 mmol) and triethylamine were added(2.4 mL) was added and the reaction was carried out overnight. The reaction was quenched with water (150 mL)Dichloromethane (150 mL x 3), and the organic layer was dried over anhydrous Na2SO4, (Eluent: Cl2CH2 / MeOH (v / v) = 30/1) to give 1.20 g of a tan solid Rate: 49.0%.

Reference： [1]Patent: CN106432246,2017,A .Location in patent: Paragraph 0453; 0609; 0610; 0611

48
[ 2516-34-9 ]
[ 152120-55-3 ]
C₂₁H₂₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	In tetrahydrofuran; at 25℃; for 12h;	To a solution of compound N,N-di-CBZ- 1H-pyrazole- 1 -carbamidine (5.0 g, 13.2 mmol) in THF (20 mL) was added cyclobutylamine (1.1 g, 15.8 mmol) at 25 C. The reaction was stirred for 12 hrs at 25 C. The mixture was concentrated in vacuo to get a residue. The residue was purified by silica gel column to obtain compound 64 (2.5 g, 44% yield) as a white solid.

Reference： [1]Patent: WO2017/160569,2017,A1 .Location in patent: Paragraph 00444; 00445

49
[ 23806-24-8 ]
[ 2516-34-9 ]
N-cyclobutyl-3-methylthiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With oxygen; potassium carbonate; eosin y; In toluene; at 20℃;Irradiation; Green chemistry;	General procedure: A flame-dried 10 mL flask was charged with amine 2 (0.5 mmol), potassium acetic acid 1 (1.5 mmol), potassium carbonate (2.0 mmol) and toluene (3 mL). Eosin Y (0.01 mmol) was added to the mixture. The mixture was allowed to stir at room temperature opening in air, and be irradiated with a Luxeon Rebel high power green LEDs [2.50 W, lambda = 535 nm] for 60-180 min. at room temperature, until all of the starting material disappeared. Then, the mixture was poured into water (10 mL), extracted with EtOAc (4 * 10 mL), washed with brine (15 mL), and dried over Na2SO4. The crude organic phase was concentrated in vacuo and purified with a short flash column chromatography (silica gel, hexane/EtOAc = 5:1) to afford the corresponding product 3(a-n) in high yield (71-95%) in Table 2.

Reference： [1]Nature Chemistry,2017,vol. 9,p. 571 - 577
[2]Tetrahedron Letters,2019,vol. 60,p. 40 - 43

50
[ 2516-34-9 ]
[ 892-48-8 ]
C₁₄H₂₀N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In ethanol; at 120℃; for 48h;Inert atmosphere; Sealed tube;	In a sealed tube, compound 1[1] (500 mg, 1.75 mmol) was dissolved in a mixture of EtOH (2 mL) and cyclobutanamine (2 mL) and heated at 120C for 48 h. The resulting mixture was evaporated to dryness and the residue was purified with flash chromatography on silica gel (8 : 1 : 0.01, DCM - MeOH - sat. aq. NH3) to afford product 10 (brown amorphous solid, 449 mg, 80%). Compound 10: Rf 0.22 (8 : 1 : 0.01, DCM - MeOH - NH4OH); [alpha] D20 -10.86 (c 0.175 CH3OH); HPLC tR 0.60 min; 1H-NMR (500 MHz, CD3OD) delta 8.25 (s, 1H, Purine-H), 8.20 (s, 1H, Purine-H), 5.95 (d, J = 5.6 Hz, 1H, H-1?), 4.85 (d, J = 5.6 Hz, 1H, H-2?), 4.27 (dd, J = 5.3, 4.1 Hz, 1H, H-3?), 4.16 (dt, J = 7.6, 3.9 Hz, 1H, H-4?), 3.34 - 3.31 (m, 1H, cyclobutyl-CH), 2.92 (dd, J = 12.6, 7.4 Hz, 1H, H-5?a), 2.86 (dd, J = 12.6, 3.8 Hz, 1H, H-5?b), 2.22 (dtd, J = 14.0, 7.0, 2.8 Hz, 2H, cyclobutyl-CH2), 1.85 - 1.77 (m, 2H, cyclobutyl-CH2), 1.76 - 1.68 (m, 2H, cyclobutyl-CH2), NH, OH and NH2 are missing; 13C-NMR (126 MHz, CD3OD) delta 157.40 (Purine-C), 153.75 (Purine-C), 150.56 (Purine-C), 142.11 (Purine-C), 120.94 (Purine-C), 90.86 (C-1?), 84.95 (C-4?), 74.50 (C-2?), 73.39 (C-3?), 54.96 (cyclobutyl-CH), 49.68 (C-5?), 30.96 (cyclobutyl-CH2), 30.88 (cyclobutyl-CH2), 15.51 (cyclobutyl-CH2); HRMS (ESI+) calcd. For C14H21N6O3+ 321.1670, found 321.1660.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 415 - 417

51
[ 2516-34-9 ]
[ 2016-99-1 ]
2,6-dibromo-N-cyclobutylisonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;	HATU (3.25 g, 8.54 mmol), cyclobutanamine (0.506 g, 7.12 mmol) and Et3N (1.191 mL, 8.54 mmol) were added to a solution of <strong>[2016-99-1]2,6-dibromoisonicotinic acid</strong> (2 g, 7.12 mmol, commercially available from, for example, Fluorochem) in DCM (20 mL) at rt. The mixture was stirred overnight, then washed with water (2 x 20 mL), dried and evaporated in vacuo to give a brown solid. The product was dissolvedin DCM (10 mL) and loaded onto a 50 g silica column, then eluted with O-5O% EtOAc/cycohexane and the product-containing fractions were evaporated in vacuo to give 2,6-dibromo-N- cyclobutylisonicotinamide (2.10 g, 6.29 mmol, 88 % yield) as a colourless solid.LCMS (2 mm High pH): Rt = 1.10 mi [MH]+ = 335.1

Reference： [1]Patent: WO2017/202742,2017,A1 .Location in patent: Page/Page column 43

52
[ 2516-34-9 ]
[ 23688-89-3 ]
6-chloro-N-cyclobutylpyrazine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	6-Chloro-N-cyclobutylpyrazine-2-carboxamide: To a suspension of <strong>[23688-89-3]<strong>[23688-89-3]6-chloropyrazine-2-carboxylic</strong> acid</strong> (100 mg, 0.631 mmol), HATU (288 mg, 0.757 mmol), and cyclobutanamine (49 mg, 0.69 mmol) in DMF (1.26 mL) at 0 C was added DIEA (220 pi, 1.26 mmol) and the resulting mixture was stirred at rt for 2 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (0 - 100 % EtOAc in hexanes) to give the title compound (84 mg, 63%) as an off-white solid. MS (ES+) C9H,0C1N30 requires: 211, found: 212 [M+Hf?. ?H NMR (600 MI-Tz, Chloroform-d) oe 9.28 (s, 1H), 8.75 (s, 1H), 7.72 (s, 1H), 4.66 - 4.53 (m, 1H), 2.50 - 2.38 (m, 2H), 2.13 - 1.98 (m, 2H), 1.87- 1.73 (m, 2H)

Reference： [1]Patent: WO2018/81276,2018,A1 .Location in patent: Page/Page column 129; 130

53
[ 2516-34-9 ]
[ 40106-58-9 ]
N-cyclobutyl-6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃;Microwave irradiation;	General procedure: In a suitable microwave reaction vessel the required chloropyrimidine (1 equiv.) was taken up in i-PrOH. To this was added the required amine (1.1 equiv.) and the mixture irradiated under stirring at 120C for 1-2h. Upon completion of the reaction, the mixture was directly purified using FCC to afford the compound. Similarly, any precipitate could be collected under vacuum and washed several time with cold i-PrOH to afford the desired compound.6.2.1.1 100 N-Phenyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (9a) (0026) General procedure A. Purification by FCC (eluent, 1:1 EtOAc/PE) afforded 105mg of a white amorphous solid (84%). LCMS (m/z): 281.9 [M+H]+. HPLC: tR 6.244min, >95% purity (214 & 254nm). HRMS (m/z): C16H15N3S requires 282.1071 [M+H]+; found 282.1059. 1H NMR (CDCl3) δ 8.48 (s, 1H), 7.64 (dt, J=8.8, 1.7Hz, 2H), 7.41-7.34 (m, 2H), 7.17-7.10 (m, 2H), 3.06 (dd, J=8.1, 3.9Hz, 2H), 2.85 (dd, J=8.0, 3.9Hz, 2H), 2.03-1.89 (m, 4H). 13C NMR (CDCl3) δ 166.3, 155.0, 152.6, 138.5, 134.7, 129.1, 124.8, 124.0, 121.3, 116.6, 26.5, 25.5, 22.5, 22.4.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 168,p. 474 - 490

54
[ 2516-34-9 ]
[ 69812-51-7 ]
methyl 4-(N-cyclobutylsulfamoyl)-benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;	[1269] Methyl 4-(N-cyclobutylsulfamoyl)-benzoate : To a stirred solution of cyclobutanamine (0.303 g, 4.26 mmol, 1.0 eq) in THF (15 mL) was added triethyl amine (1.78 mL, 12.78 mmol, 3.0 eq) followed by methyl 4-(chlorosulfonyl)benzoate (1.0 g, 4.26 mmol, 1.0 eq) at 0C. The reaction was stirred at room temperature for 2 h. TLC (50% EtOAc in n-Hexane) showed the reaction was completed. After the consumption of starting material, solvent was evaporated under reduced pressure, to get the crude. The crude product was purified by silica gel chromatography (eluting with: Hexane/EtOAc=50:50) to give methyl 4-(N-cyclobutylsulfamoyl)benzoate. LC-MS (m/z)=268.1 [M+H]+. 1H NMR (400 MHz, CDCl3) delta: 1.56-1.67 (m, 2H), 1.71-1.78 (m, 2H), 2.13-2.15 (m, 2H), 3.96 (s, 3H), 3.80-3.88 (m, 1H), 4.65 (d, J=4.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 8.16 (d, J=7.6 Hz, 2H).

Reference： [1]Patent: US2019/263802,2019,A1 .Location in patent: Paragraph 1269

55
[ 728034-12-6 ]
[ 2516-34-9 ]
[ 165806-95-1 ]
4-(1-cyclobutyl-4-(4-fluorophenyl)-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%		General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were used

Reference： [1]Patent: WO2019/185631,2019,A1 .Location in patent: Page/Page column 14; 25

56
[ 24424-99-5 ]
[ 2516-34-9 ]
[ 74733-27-0 ]
C₁₉H₂₇NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.82 g		A mixture of <strong>[74733-27-0]methyl 4-(bromomethyl)-2-methoxybenzoate</strong> 5 (1 g, 3.86 mmol) and cyclobutanamine 5a (0.659 mL, 7.72 mmol) in DMF (2 mL) was heated at 70 C. over 30 min at which point LCMS showed the formation of an amine product. The excess base was evaporated and Hunig's Base (1.348 mL, 7.72 mmol) was added, followed by addition of Boc-anhydride (0.896 mL, 3.86 mmol). LCMS showed the completion of reaction. The solvent was evaporated and the crude product was purified by COMBIFLASH apparatus using EtOAc/hexanes to provide 0.82 g desired product 6 as a colorless oil. LCMS ESI: calculated for C19H27NO5=350.42 (M+H+), found 350.1 (M+H+).

Reference： [1]Patent: US2020/38403,2020,A1 .Location in patent: Paragraph 0186; 0189

57
[ 723280-98-6 ]
[ 2516-34-9 ]
7-bromo-N-cyclobutyl-3-nitroquinolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃;	To a stirred mixture of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (2 g, 6.96 mmol, 1 equiv) and TEA (1.06 g, 10.43 mmol, 1.5 equiv) in DCM (80 mL) was added cyclobutanamine (0.59 g, 8.35 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-N-cyclobutyl-3- nitroquinolin-4-amine (1.8 g, 80.32%) as a yellow crude solid. LC-MS: (ES, m/z): [M+H]+ =322.0.
	With triethylamine; In dichloromethane; at 20℃;	To a stirred mixture of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (2 g, 6.96 mmol, 1 equiv) and TEA (1.06 g, 10.44 mmol, 1.5 equiv) in DCM (80 mL) was added cyclobutanamine (0.59 g, 8.35 mmol, 1.2 equiv) dropwise at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-N-cyclobutyl-3-nitroquinolin-4-amine (1.8 g, 80.32%) as a yellow crude solid. LC-MS: (ES, m/z): [M+H]+ =322.0.

Reference： [1]Patent: WO2020/37091,2020,A1 .Location in patent: Page/Page column 50-52
[2]Patent: WO2020/37092,2020,A1 .Location in patent: Page/Page column 51-52

58
[ 2516-34-9 ]
[ 136818-50-3 ]
N-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.51 g	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h;

Reference： [1]Vadukoot, Anish K.; Sharma, Swagat; Aretz, Christopher D.; Kumar, Sushil; Gautam, Nagsen; Alnouti, Yazen; Aldrich, Amy L.; Heim, Cortney E.; Kielian, Tammy; Hopkins, Corey R. [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 10, p. 1848 - 1854]

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H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 2516-34-9 ]

Quality Control of [ 2516-34-9 ]

Related Doc. of [ 2516-34-9 ]

Product Details of [ 2516-34-9 ]

Calculated chemistry of [ 2516-34-9 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 2516-34-9 ]

Application In Synthesis of [ 2516-34-9 ]

[ 2516-34-9 ] Synthesis Path-Upstream 1~1

[ 2516-34-9 ] Synthesis Path-Downstream 1~58

Related Functional Groups of [ 2516-34-9 ]

Aliphatic Cyclic Hydrocarbons

Amines

Precautionary Statements-General

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Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

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[ 2516-34-9 ]