[ CAS No. 37828-19-6 ] {[proInfo.proName]}

Name: 37828-19-6|1-Phenylcyclobutanecarboxylic acid|95%
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Quality Control of [ 37828-19-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 37828-19-6 ]

CAS No. :	37828-19-6	MDL No. :	MFCD00019262
Formula :	C₁₁H₁₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JHZRNLRTNIDFKG-UHFFFAOYSA-N
M.W :	176.21	Pubchem ID :	277171
Synonyms :

Calculated chemistry of [ 37828-19-6 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.36
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.18
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	2.27
Log Po/w (WLOGP) :	2.19
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	2.5
Consensus Log Po/w :	2.19

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.57
Solubility :	0.472 mg/ml ; 0.00268 mol/l
Class :	Soluble
Log S (Ali) :	-2.69
Solubility :	0.36 mg/ml ; 0.00204 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.87
Solubility :	0.24 mg/ml ; 0.00136 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.42

Safety of [ 37828-19-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 37828-19-6 ]

* 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 [ 37828-19-6 ]
Downstream synthetic route of [ 37828-19-6 ]

[ 37828-19-6 ] Synthesis Path-Upstream 1~6

1
[ 14377-68-5 ]
[ 37828-19-6 ]

Yield	Reaction Conditions	Operation in experiment
79.2%	With potassium hydroxide In ethylene glycol at 185 - 190℃; for 6 h;	Part A. 1-Phenyl-l-cyclobutylcarbonitrile(5. 0 g, 31.83 mmol) and KOH (85percent, 6.29 g, 95.49 mmol, 3 eq) were heated in ethylene glycol (10 mL) at185-190 C for 6h underN2. LC-MS showed completion of the reaction.H20 was added to the cooled mixture. It was extracted with Et2O (3x). The aqueous layer was acidified with conc. HC1, and then extracted with CHC13 (2x). The chloroform layer was washed withH20, brine, dried overMgSO4, filtered, and concentrated to dryness to give 1-phenyl-l-cyclobutyl carboxylic acid (4.43 g, yield: 79.2percent). LC/MS(ESI+) 177.4 (M+H) +, tR = 2.56 min(10-90percentCH3CN/H2O in a 6-min run).
55%	With potassium hydroxide In diethylene glycol at 190℃; for 16 h;	To a stirred solution of 1-phenylcyclobutanecarbonitrile (1.6 g, 10.19 mmol) in diethylene glycol (10 mL) was added KOH (5.7 g, 101.9 mmol). The reaction was heated to reflux (190° C.) for 16 h, then cooled to 0° C. and poured onto crushed ice (50 g). The aqueous layer was washed with Et₂O (2*50 mL) and acidified slowly with 6N HCl maintaining the temperature below 25° C. The solid was filtered and washed with water (50 mL) and dried under vacuum to yield the title compound (1.0 g, 55percent) as an off white solid.

Reference： [1] Chemische Berichte, 1984, vol. 117, # 11, p. 3303 - 3319
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7341 - 7348
[3] Patent: WO2003/99276, 2003, A1, . Location in patent: Page 316-317
[4] Journal of Organometallic Chemistry, 1993, vol. 448, # 1-2, p. 9 - 14
[5] Pharmaceutical Chemistry Journal, 1980, vol. 14, # 2, p. 114 - 118[6] Khimiko-Farmatsevticheskii Zhurnal, 1980, vol. 14, # 2, p. 40 - 45
[7] Patent: US2015/57443, 2015, A1, . Location in patent: Paragraph 0247; 0249
[8] Journal of Organic Chemistry, 1978, vol. 43, p. 700 - 710
[9] Chemische Berichte, 1973, vol. 106, p. 2890 - 2903
[10] Patent: WO2008/70707, 2008, A1, . Location in patent: Page/Page column 52
[11] Patent: WO2006/41797, 2006, A2, . Location in patent: Page/Page column 49
[12] Patent: WO2011/42797, 2011, A1, . Location in patent: Page/Page column 71

2
[ 50921-39-6 ]
[ 37828-19-6 ]

Reference： [1] Patent: US2004/6056, 2004, A1, . Location in patent: Page 39

3
[ 140-29-4 ]
[ 37828-19-6 ]

Reference： [1] Patent: WO2011/42797, 2011, A1,
[2] Patent: US2015/57443, 2015, A1,
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7341 - 7348

4
[ 1469-83-6 ]
[ 37828-19-6 ]

Reference： [1] Journal of the Chemical Society [Section] C: Organic, 1966, p. 655 - 660

5
[ 6940-76-7 ]
[ 28744-77-6 ]
[ 37828-19-6 ]

Reference： [1] Journal of the American Chemical Society, 1933, vol. 55, p. 2927,2930

6
[ 37828-19-6 ]
[ 1469-83-6 ]

Reference： [1] Organic Letters, 2017, vol. 19, # 10, p. 2626 - 2629

[ 37828-19-6 ] Synthesis Path-Downstream 1~72

1
[ 6940-76-7 ]
[ 28744-77-6 ]
[ 37828-19-6 ]

Reference： [1]Journal of the American Chemical Society,1933,vol. 55,p. 2927,2930

2
[ 37828-19-6 ]
[ 124-41-4 ]
[ 4392-30-7 ]

Reference： [1]Journal of the American Chemical Society,1934,vol. 56,p. 715

3
[ 37828-19-6 ]
(+/-)-1-phenyl-cyclobutanecarboxylic acid-(<i>trans</i>-2-diethylamino-cyclohexyl ester) [ No CAS ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1952,vol. 72,p. 921,923
Chem.Abstr.,1953,p. 6359

4
[ 14377-68-5 ]
[ 37828-19-6 ]

Yield	Reaction Conditions	Operation in experiment
79.2%	With potassium hydroxide; In ethylene glycol; at 185 - 190℃; for 6h;	Part A. 1-Phenyl-l-cyclobutylcarbonitrile(5. 0 g, 31.83 mmol) and KOH (85%, 6.29 g, 95.49 mmol, 3 eq) were heated in ethylene glycol (10 mL) at185-190 C for 6h underN2. LC-MS showed completion of the reaction.H20 was added to the cooled mixture. It was extracted with Et2O (3x). The aqueous layer was acidified with conc. HC1, and then extracted with CHC13 (2x). The chloroform layer was washed withH20, brine, dried overMgSO4, filtered, and concentrated to dryness to give 1-phenyl-l-cyclobutyl carboxylic acid (4.43 g, yield: 79.2%). LC/MS(ESI+) 177.4 (M+H) +, tR = 2.56 min(10-90%CH3CN/H2O in a 6-min run).
55%	With potassium hydroxide; In diethylene glycol; at 190℃; for 16h;	To a stirred solution of 1-phenylcyclobutanecarbonitrile (1.6 g, 10.19 mmol) in diethylene glycol (10 mL) was added KOH (5.7 g, 101.9 mmol). The reaction was heated to reflux (190 C.) for 16 h, then cooled to 0 C. and poured onto crushed ice (50 g). The aqueous layer was washed with Et2O (2*50 mL) and acidified slowly with 6N HCl maintaining the temperature below 25 C. The solid was filtered and washed with water (50 mL) and dried under vacuum to yield the title compound (1.0 g, 55%) as an off white solid.
		To a round bottom flask containing phenyl cyclobutanecarbonitrile (1 eq ) in ethyleneglycol (4 ml) was added KOH (6 eq) at rt. Then the mixture was heated to 160 0C for 2 hrs and cooled to rt. Toluene and water were added and separated the layers. The water layer was acidified to pH ~4, the water layer extracted with ethyl acetate twice, the organic layers combined, dried with MgSO4, filtered and concentrated to give the desired crude product which is used directly in the next step.

	With hydrogenchloride; water; at 100℃; for 3h;	REFERENCE EXAMPLE 26; 1 -Phenylc yclobutanecarboxylic Acid; A mixture of l-phenylcyclobutanecarbonitrile (5.0 g, 32 mmol) in water (50 mL) and concentrated hydrochloric acid (50 mL) was heated at 1000C for 3 h. After cooling to room temperature, the product was extracted with ethyl acetate (2x50 mL), and the ethyl acetate solution was back extracted with 2 M aqueous sodium hydroxide (2x50 mL). The aqueous extracts were neutralized with concentrated hydrochloric acid (pH = 2), and the product was extracted with ethyl acetate (2 x 50 mL). The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound as a white solid (0.66 g). 1H NMR (500 MHz, CD3OD): delta 7.40-7.18 (m, 5H),2.86-2.75 (m, 2H), 2.54-2.43 (m, 2H), 2.08-1.98 (m, IH), 1.90-1.80 (m, IH).
		[237] Intermediate 61: 1-phenylcyclobutanecarboxylic acid: Intermediate 60 (2.6 g, 16.54 mmol) was dissolved in ethyleneglycol and added potassium hydroxide (5.6 g,99.2 mmol). This mixture was heated to 160 C for 2h. After two hours reaction mixture was cooled to rt and toluene and water were added. Aqueous layer separated and acidified with HC1 and pH adjusted to 4. Aqueous layer extracted with ethyl acetate and ethyl acetate layer was dried on anhydrous sodium sulphate. Ethyl acetate removed on rotavapour to obtain the title compound (930 mg) as a white solid.

Reference： [1]Chemische Berichte,1984,vol. 117,p. 3303 - 3319
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 7341 - 7348
[3]Patent: WO2003/99276,2003,A1 .Location in patent: Page 316-317
[4]Journal of Organometallic Chemistry,1993,vol. 448,p. 9 - 14
[5]Pharmaceutical Chemistry Journal,1980,vol. 14,p. 114 - 118
Khimiko-Farmatsevticheskii Zhurnal,1980,vol. 14,p. 40 - 45
[6]Patent: US2015/57443,2015,A1 .Location in patent: Paragraph 0247; 0249
[7]Journal of Organic Chemistry,1978,vol. 43,p. 700 - 710
[8]Chemische Berichte,1973,vol. 106,p. 2890 - 2903
[9]Patent: WO2008/70707,2008,A1 .Location in patent: Page/Page column 52
[10]Patent: WO2006/41797,2006,A2 .Location in patent: Page/Page column 49
[11]Patent: WO2011/42797,2011,A1 .Location in patent: Page/Page column 71

5
[ 37828-19-6 ]
[ 4620-67-1 ]

Reference： [1]Canadian Journal of Chemistry,1965,vol. 43,p. 3119 - 3128
[2]Chemische Berichte,1973,vol. 106,p. 2890 - 2903
[3]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318
[4]Journal of the American Chemical Society,2014,vol. 136,p. 898 - 901

6
[ 67-56-1 ]
[ 37828-19-6 ]
[ 7306-20-9 ]
[ 1007-70-1 ]

Reference： [1]Chemische Berichte,1984,vol. 117,p. 3303 - 3319

7
[ 79-37-8 ]
[ 37828-19-6 ]
[ 4620-67-1 ]

Reference： [1]Journal of Organometallic Chemistry,1989,vol. 376,p. 103 - 114

8
[ 37828-19-6 ]
[ 917-54-4 ]
[ 3972-67-6 ]

Reference： [1]Chemische Berichte,1981,vol. 114,p. 3831 - 3854

9
[ 37828-19-6 ]
[ 7306-20-9 ]
[ 1007-70-1 ]

Reference： [1]Chemische Berichte,1984,vol. 117,p. 3303 - 3319

10
[ 37828-19-6 ]
[ 70775-57-4 ]

Yield	Reaction Conditions	Operation in experiment
2.09 g	With lithium aluminium tetrahydride; In tetrahydrofuran; for 1.75h;Heating;	Example 1.15: 2',3',4',4a',5',6'-hexahydro-l'H-spiro[cyclobutane-l,7'-naphtho[l,8- cd]azepine] (Compound 131) Step A: Preparation of (l-phenylcyclobutyl)methanol To a stirred solution of <strong>[37828-19-6]1-phenylcyclobutanecarboxylic acid</strong> (2.51 g, 14.24 mmol) in 50 mL THF at 60C (oil bath), 2 M lithium aluminum hydride in THF (20 mL, 40.00 mmol) was added slowly by an additional funnel (over ca. 45 min). After stirring for at 60C for 1 h, the mixture was cooled in an ice/water-bath and quenched by the drop wise addition of 1 M NaOH. Solids were filtered, washed with additional THF, and filtrate was partly concentrated. The residue was extracted with brine and CH2CI2. Combined organic phases were dried over MgS04, filtered, and concentrated to give (1- phenylcyclobutyl)methanol (2.09 g, 90) as a white solid. NMR (400 MHz, CDC13) delta 1.19 (t, J = 6.6 Hz, 1H), 1.85-1.93 (m, 1H), 2.05-2.14 (m, 1H), 2.21-2.27 (m, 2H), 2.31-2.38 (m, 2H), 3.75 (d, /= 6.6 Hz, 2H), 7.14-7.16 (m, 2H), 7.19-7.23 (m, 1H), 7.31-7.36 (m, 2H).

Reference： [1]Journal of Organometallic Chemistry,1993,vol. 448,p. 9 - 14
[2]Journal of the Chemical Society C: Organic,1966,p. 655 - 660
[3]Patent: WO2017/23679,2017,A1 .Location in patent: Page/Page column 139
[4]Organic Letters,2017,vol. 19,p. 2626 - 2629

11
[ 37828-19-6 ]
[ 79-03-8 ]
C₁₄H₁₆O₃ [ No CAS ]

Reference： [1]Pharmaceutical Chemistry Journal,1980,vol. 14,p. 114 - 118
Khimiko-Farmatsevticheskii Zhurnal,1980,vol. 14,p. 40 - 45

12
[ 1469-83-6 ]
[ 37828-19-6 ]

Reference： [1]Journal of the Chemical Society C: Organic,1966,p. 655 - 660

13
[ 37828-19-6 ]
[ 202737-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; potassium nitrate; In acetic acid; at 0 - 20℃; for 0.333333h;	A mixture of <strong>[37828-19-6]1-phenylcyclobutanecarboxylic acid</strong> (10) and acetic acid (20 ml) and H2SO4 (20 ml) and KNO3 (1.1 eq) was stirred at 0 C. for 20 min. The mixture was warmed to RT and stirred overnight. The mixture was poured on ice and stirred until all ice melted. The precipitate was filtered and used for next step without further purification. The above product (5 g) was dissolved into THF and stirred at 0 C., NaBH4 (3 eq) was added slowly to the reaction followed by slowly addition of BF3.Et2O (3 eq). The reaction was stirred at RT overnight and quenched with 1 N NaOH slowly until bubble ceased. The solution was extracted with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give [(4-nitrophenyl)cyclobutyl]methane-1-ol as an oil.

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 3814 - 3820
[2]Patent: US2004/259916,2004,A1 .Location in patent: Page 15
[3]Patent: WO2003/99276,2003,A1 .Location in patent: Page 236-237

15
[ 627-31-6 ]
disodium-compound of phenylacetonitrile [ No CAS ]
[ 37828-19-6 ]

Reference： [1]Journal of the American Chemical Society,1933,vol. 55,p. 2927,2930

16
[ 109-64-8 ]
disodium-compound of phenylacetonitrile [ No CAS ]
[ 37828-19-6 ]

Reference： [1]Journal of the American Chemical Society,1934,vol. 56,p. 715

17
[ 37828-19-6 ]
[ 455311-42-9 ]
(+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-1-phenyl-1-cyclobutanecarboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 5597 - 5609

18
[ 37828-19-6 ]
[ 149050-19-1 ]

Reference： [1]Journal of Organometallic Chemistry,1993,vol. 448,p. 9 - 14

19
[ 37828-19-6 ]
[ 149050-24-8 ]

Reference： [1]Journal of Organometallic Chemistry,1993,vol. 448,p. 9 - 14

20
[ 140-29-4 ]
phenylcyanopyruvic acid ethyl ester-phenylhydrazone of mp: 107-108 degree [ No CAS ]
[ 37828-19-6 ]

Reference： [1]Journal of Organometallic Chemistry,1993,vol. 448,p. 9 - 14

21
[ 37828-19-6 ]
[ 61492-32-8 ]

Reference： [1]Pharmaceutical Chemistry Journal,1980,vol. 14,p. 114 - 118
Khimiko-Farmatsevticheskii Zhurnal,1980,vol. 14,p. 40 - 45

22
[ 140-29-4 ]
disulfur dichloride [ No CAS ]
[ 37828-19-6 ]

Reference： [1]Pharmaceutical Chemistry Journal,1980,vol. 14,p. 114 - 118
Khimiko-Farmatsevticheskii Zhurnal,1980,vol. 14,p. 40 - 45

23
[ 37828-19-6 ]
[ 80606-90-2 ]

Reference： [1]Chemische Berichte,1981,vol. 114,p. 3831 - 3854

24
[ 37828-19-6 ]
[ 80606-00-4 ]

Reference： [1]Chemische Berichte,1981,vol. 114,p. 3831 - 3854

25
[ 140-29-4 ]
n-butyl halide [ No CAS ]
[ 37828-19-6 ]

Reference： [1]Journal of Organic Chemistry,1978,vol. 43,p. 700 - 710
[2]Chemische Berichte,1973,vol. 106,p. 2890 - 2903

26
[ 37828-19-6 ]
[ 68580-50-7 ]

Reference： [1]Chemische Berichte,1973,vol. 106,p. 2890 - 2903

27
[ 37828-19-6 ]
[ 17380-77-7 ]

Reference： [1]Chemische Berichte,1973,vol. 106,p. 2890 - 2903

28
[ 37828-19-6 ]
1,1'-Diphenylazocyclobutan [ No CAS ]

Reference： [1]Chemische Berichte,1973,vol. 106,p. 2890 - 2903

29
[ 37828-19-6 ]
[ 630382-89-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium iodate; sulfuric acid; iodine; In acetic acid; at 20 - 70℃; for 48h;	Part B. The product from part A (4.43 g, 25.2 mmol) was stirred inHOAc (20 mL) at RT underN2. I2 (6.40 g, 25.2 mmol) was added, followed by the addition of NaIO3 (1.25 g, 6.3 mmol) and conc.H2SO4 (0.5 mL). The resulting mixture was stirred at70 C for 2 days. LC-MS showed completion of the reaction. The cooled mixture was poured into H2O, and extracted with EtOAc. The organic layer was washed with sodium thiosulfate, brine, dried overMgSO4, filtered, and concentrated to dryness to give 4-iodophenylcylcobutyl carboxylic acid (6.49 g,85%). LC/MS (ESI+) 303.2 (M+H) +,tR = 2.55 min(10-90%CH3CN/H2O in a 4-min run).

Reference： [1]Patent: WO2003/99276,2003,A1 .Location in patent: Page 317

30
[ 50921-39-6 ]
[ 37828-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium formate;5%-palladium/activated carbon; In water; isopropyl alcohol; at 65℃; for 5h;	[0406] A stirred suspension of palladium on carbon (3.6 g, 5%) in isopropanol (200 mL) was treated in one portion with a solution of ammonium formate (9 g) in water (12.5 mL) followed by a solution of 1-(4-chloro-phenyl)-cyclobutanecarboxylic acid (15 g) in isopropanol (150 mL) also in one portion. The resultant suspension was stirred at 65 C. for 30 minutes and then treated with a further aliquot of a solution of ammonium formate (9 g) in water (12.5 mL). After stirring at 65 C. for a further 4.5 hours the reaction mixture was filtered through Hyflo and the filter pad was washed three times with isopropanol (75 mL). The combined filtrate and washings were evaporated. The solid obtained after standing at room temperature for 3 days was treated with ethyl acetate (350 mL) and water (150 mL) and the organic phase was separated, then dried over magnesium sulfate and then evaporated to give the title compound (9.25 g) as a white solid. LC-MS: RT=3.08 minutes, MS(ES+): very weak 177(M+H)+.

Reference： [1]Patent: US2004/6056,2004,A1 .Location in patent: Page 39

31
N,N-diisopropylaminoethanol [ No CAS ]
toluene-Et₃ N [ No CAS ]
[ 37828-19-6 ]
[ 7008-48-2 ]

Yield	Reaction Conditions	Operation in experiment
1.3 g (73%)	With thionyl chloride; In toluene;	EXAMPLE 36 2-(Diethylamino)ethyl 1-phenylcyclobutanecarboxylate Hydrochloride 1-Phenylcyclobutanecarboxylic acid (1.9 mmol) was refluxed with SOCl2 (5 mL). After 0.5 h, the reaction mixture was evaporated and the residue dissolved in toluene. Diisopropylaminoethanol (3.8 mmol) was added and the mixture was heated at 80 C. for 1.5 h. The reaction mixture was filtered and chromatographed on silica gel using toluene-Et3 N 95:5 as eluent. The yield was 1.3 g (73%); mp 137-139 C.; 1 H NMR (D2 O) delta 1.25 (t, 6H), 1.92-2.01 (m, 1H), 2.07-2.16 (m, 1H), 2.64 (m, 2H), 2.89 (m, 2H), 3.11 (q, 4H), 3.50 (t, 2H), 4.48 (t, 2H), 7.44 (m, 1H), 7.48 (m, 2H), 7.53 (m, 2H). Anal. (C17 H25 NO2.HCl) C, H, N.

Reference： [1]Patent: US6124354,2000,A

32
[ 37828-19-6 ]
1-(2,4-dinitrophenyl)cyclobutanecarboxylic Acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.5 g (73%)	With nitric acid;	1-(2,4-dinitrophenyl)cyclobutanecarboxylic Acid 1-Phenylcyclobutanecarboxylic acid (28.4 mmol) was added to fuming HNO3 (81 mL) kept at 0 C. and stirred for 1 h. The reaction mixture was then poured over ice and the resulting crystals were filtered off and washed with EtOH to give 5.5 g (73%) of 1-(2,4-dinitrophenyl)-cyclobutanecarboxylic acid; 1 H NMR (CDCl3) delta 1.83-1.96 (m, 1H), 2.38-2.48 (m, 3H), 2.90-3.00 (m, 2H), 7.70 (d, 1H), 8.47 (dd, 1H), 8.77 (d, 1H).

Reference： [1]Patent: US6124354,2000,A

33
[ 37828-19-6 ]
[ 79-19-6 ]
[ 1032464-42-8 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; at 20 - 100℃; for 2h;	Method A:; To a T-vial containing carboxylic acid (leq) and hydrazinecarbothioamide (1 eq) was added phosphorus oxychloride (1.2 eq) dropwise at room temperature. The mixture was heated to 100 0C, kept for 2 hrs and cooled to room temperature. Ethyl acetate and aq. saturated NaHCObeta were added, extract with ethyl acetate twice, combined the organic layers, dried with MgSO4, and concentrate to give the desired product, which is used directly in the next step.

Reference： [1]Patent: WO2008/70707,2008,A1 .Location in patent: Page/Page column 52

34
[ 37828-19-6 ]
[ 1252638-10-0 ]
[ 1268444-76-3 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318

35
[ 37828-19-6 ]
[ 1268445-18-6 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318

36
[ 140-29-4 ]
[ 37828-19-6 ]

Reference： [1]Patent: WO2011/42797,2011,A1
[2]Patent: US2015/57443,2015,A1
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 7341 - 7348

37
[ 37828-19-6 ]
[ 1240806-35-2 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 898 - 901

38
[ 37828-19-6 ]
[ 1534433-47-0 ]
2,4-bis(4-methoxyphenyl)-1-phenyl-N-(quinolin-8-yl)cyclobutanecarboxamide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 898 - 901

39
[ 37828-19-6 ]
[ 1260682-29-8 ]

Yield	Reaction Conditions	Operation in experiment
12%	With [bis(acetoxy)iodo]benzene; iodine; palladium diacetate; In N,N-dimethyl-formamide; at 60℃; for 26h;	(C) 1-(2-Iodophenyl) cyclobutanecarboxylic acid (A52)A solution of <strong>[37828-19-6]1-phenyl-1-cyclobutanecarboxylic acid</strong> (2.00 g, 11.4 mmol) in DMF (10mL) containing palladium (II) acetate (0.109 g, 0.567 mmol), iodine (2.16 g, 8.51mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) was stirred at 60 00 for 18hours in the absence of light. Additional iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) were added and stirring was continued at 60 00 for 8 hours. A final addition of iodine (2.16 g, 8.51 mmol) and (diacetoxyiodo)benzene (2.47 g, 8.51 mmol) was performed and stirring wascontinued at 60 00 for 16 hours. The reaction mixture was partitioned between EtOAc and water and the aqueous phase was extracted several times with EtOAc. The combined organic fractions were washed with 10% sodium metabisulfate (3 x 30 mL), 10% citric acid (2 x 30 mL), water, brine, and then dried (MgSO4), filtered and the solvent evaporated. The crude product was dry loaded onto silica gel and theproduct was separated using silica column chromatography (Biotage Isolera, 40 g Si02 Cartridge, 0-100% EtOAc in petroleum benzine 40-60 00) to give the title compound A52 as a cream solid (425 mg, 12%). LCMS-A: rt 5.711 mm.

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 158

40
[ 37828-19-6 ]
[ 1566544-19-1 ]

Reference： [1]Patent: WO2014/26243,2014,A1

41
[ 37828-19-6 ]
[ 1566544-20-4 ]

Reference： [1]Patent: WO2014/26243,2014,A1

42
[ 37828-19-6 ]
tert-butyl 4-(4-((4-(2-(1-(methoxycarbonyl)cyclobutyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2014/26243,2014,A1

43
[ 37828-19-6 ]
[ 1566544-22-6 ]

Reference： [1]Patent: WO2014/26243,2014,A1

44
[ 37828-19-6 ]
[ 1566544-23-7 ]

Reference： [1]Patent: WO2014/26243,2014,A1

45
[ 37828-19-6 ]
[ 1566543-27-8 ]

Reference： [1]Patent: WO2014/26243,2014,A1

46
[ 37828-19-6 ]
1-[(1-phenylcyclobutyl)methyl]piperidine [ No CAS ]

Reference： [1]Patent: US2015/57443,2015,A1

47
[ 37828-19-6 ]
1-[(1-phenylcyclobutyl)methyl]piperidin-1-ium chloride [ No CAS ]

Reference： [1]Patent: US2015/57443,2015,A1

48
[ 110-89-4 ]
[ 37828-19-6 ]
1-[1-(phenyl)cyclobutanecarbonyl]piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		Step 3: 1-[1-(Phenyl)cyclobutanecarbonyl]piperidine To a stirred solution of <strong>[37828-19-6]1-(phenyl)cyclobutane-1-carboxylic acid</strong> (600 mg, 3.46 mmol) and HATU (2 g, 5.19 mmol) in THF was added di-isopropylethylamine (1.3 g, 10.38 mmol). The reaction mixture was stirred at 0 C. for 1 h, then piperidine (880 mg, 10.38 mmol) added at 0 C. After stirring at room temperature for 16 h the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2*10 mL). The combined organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel column chromatography (5-10% EtOAc/hexane) to afford the title compound (600 mg, 73%) as a pale yellow viscous liquid.

Reference： [1]Patent: US2015/57443,2015,A1 .Location in patent: Paragraph 0247; 0250

49
[ 37828-19-6 ]
[ 97-50-7 ]
N-(5-chloro-2,4-dimethoxyphenyl)-1-phenylcyclobutanecarboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7341 - 7348

50
[ 37828-19-6 ]
N-(5'-chloro-2',4'-dihydroxyphenyl)-1-phenylcyclobutanecarboxyamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 7341 - 7348

51
[ 37828-19-6 ]
[ 865156-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	With Rh/Al2O3; hydrogen; In acetic acid; under 5688.78 Torr; for 72h;	<strong>[37828-19-6]1-phenylcyclobutanecarboxylic acid</strong> (800 mg, 4.5 mmol), acetic acid (10 mL) and 5% wt Rh/Al2O3 (200 mg) were added to a glass beaker and placed in the stainless steel pressure reactor under H2 atmosphere (110 psi) for 72 hours with stirring. The reaction mixture was filtered through celite and washed with EtOAc then concentrated. The residue was dissolved in ether and washed with water (50 mL×4), and brine (50 mL×2), dried over MgSO4 and concentrated to give 1-cyclohexylcyclobutanecarboxylic acid. UPLC MS (M-H)=181. 1H NMR indicated the purity was greater than 90%.

Reference： [1]Patent: US2015/376136,2015,A1 .Location in patent: Paragraph 0587

52
[ 37828-19-6 ]
1-cyclohexylcyclobutanecarbonyl chloride [ No CAS ]

Reference： [1]Patent: US2015/376136,2015,A1

53
[ 37828-19-6 ]
methyl (2R)-2-amino-2-[4-(2-methylpentyloxy)phenyl]acetate hydrochloride [ No CAS ]
C₂₆H₃₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 5h;Inert atmosphere;	General procedure: To a solution of 8a (90 mg, 0.33 mmol) in MeCN (10 mL) at room temperature under nitrogen was added TEA (0.14 mL,0.99 mmol), followed by (S)-2-phenylpropionic acid (50 mg,0.33 mmol) and HBTU (152 mg, 0.4 mmol). After stirring for 5 h, the reaction was quenched by H2O (5 mL), followed by addition of EtOAc (50 mL). The layers were separated. The organic layer was washed with saturated NaHCO3 (10 mL), brine (10 mL), dried (Na2-SO4) and concentrated under reduced pressure. Flash column chromatography of the crude product on silica gel using 0-30% EtOAc in hexanes afforded 3 (65 mg, 53%) as an off-white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 805 - 812

54
[ 37828-19-6 ]
(1-phenylcyclobutyl)methyl methanesulfonate [ No CAS ]