[ CAS No. 151157-49-2 ] {[proInfo.proName]}

Name: 151157-49-2|1-(4-Bromophenyl)cyclobutanecarboxylic acid|95%
Brand: Ambeed
SKU: A442309
Price: 10.0 USD
Availability: InStock
Rating: 99 (26 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 151157-49-2

Structure of 151157-49-2 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 151157-49-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 151157-49-2 ]

SDS Specification

Alternatived Products of [ 151157-49-2 ]

Product Details of [ 151157-49-2 ]

CAS No. :	151157-49-2	MDL No. :	MFCD08443165
Formula :	C₁₁H₁₁BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CZCIJQWZBHQMNS-UHFFFAOYSA-N
M.W :	255.11	Pubchem ID :	16769919
Synonyms :

Calculated chemistry of [ 151157-49-2 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
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 :	57.88
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	2.96
Log Po/w (WLOGP) :	2.96
Log Po/w (MLOGP) :	2.87
Log Po/w (SILICOS-IT) :	3.15
Consensus Log Po/w :	2.82

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.47
Solubility :	0.0861 mg/ml ; 0.000338 mol/l
Class :	Soluble
Log S (Ali) :	-3.41
Solubility :	0.1 mg/ml ; 0.000393 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.73
Solubility :	0.0481 mg/ml ; 0.000188 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.64

Safety of [ 151157-49-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 151157-49-2 ]

* 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 [ 151157-49-2 ]

[ 151157-49-2 ] Synthesis Path-Downstream 1~50

1
[ 151157-49-2 ]
[ 847730-39-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(4-bromophenyl)cyclobutane-1-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene for 2h; Heating / reflux; Stage #2: With hydrogenchloride In water; toluene for 3h; Heating / reflux;	129.1 EXAMPLE 129 4-R L 5-CHLORO-2-(3-FLUOROPHENOXY) PYRIDIN-3- YLICARBONYLIAMINO) CYCLOBUTYLIBENZOIC ACID STEP 1. N-[1-(4-Bromophenyl)cyclobutyl]-5-chloro-2-(3- fluorophenoxy) nicotinamide; A mixture of 1- (4-BROMOPHENYL) cyclobutanecarboxylic acid (200 mg, 0.78 mmol), diphenylphosphoryl azide (202 UL, 0.94 mmol), and triethylamine (131 µL, 0.94 mmol) in toluene (3 mL) was heated under reflux with stirring for 2 h. To the reaction mixture was added concentrated hydrochloric acid (1 mL). The resulting mixture was heated under reflux with stirring for 3 h. Then an ammonium hydroxide solution (5 ML) was added to the reaction mixture and the whole was extracted with ethyl acetate (15 INL X 3). The combined organic phase was washed with brine (30 mL) and concentrated to give [1- (4-BROMOPHENYL) cyclopropyl] amine as black oil. The crude amine was reacted with 5-chloro-2- (3-fluorophenoxy) nicotinic acid (step 1 of Example 128) according to the procedure described in step 3 of Example 1 to give the title compound : H-NMR (CDCI3) 6 8.47 (1H, d, J = 2.4 Hz), 8.24 (1H, br. s), 8.14 (1H, d, J = 2.4 Hz), 7.51-6. 92 (8H, m), 2.74-1. 43 (6H, M) ; MS (ESI) m/z 475 (M + H) +, 473 (M-H)-.

Reference： [1]Current Patent Assignee: RAQUALIA PHARMA INC. - WO2005/21508, 2005, A1 Location in patent: Page/Page column 168

2
[ 16532-79-9 ]
[ 109-64-8 ]
[ 151157-49-2 ]

Yield	Reaction Conditions	Operation in experiment
		10 1-(4-Bromophenyl)cyclobutanecarboxylic Acid 1-(4-Bromophenyl)cyclobutanecarboxylic Acid The title compound was prepared in an analogous manner to that in Example 9 from 4-bromophenylacetonitrile and 1,3-dibromopropane. The yield was 6 g (46%); 1 H NMR (CDCl3) δ 1.79-1.94 (m, 1H), 2.00-2.17 (m, 1H), 2.42-2.53 (m, 2H), 2.78-2.88 (m, 2H), 7.17 (d, 2H), 7.45 (d, 2H).

Reference： [1]Current Patent Assignee: PFIZER INC - US6124354, 2000, A

3
1-(4-bromophenyl)cyclobutane-1-carboxylic acid [ No CAS ]
[ 24424-99-5 ]
[ 1032350-06-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium azide; tetrabutylammomium bromide; zinc trifluoromethanesulfonate; In tetrahydrofuran; for 14.0h;Reflux;	Di-tert-butyl dicarbonate (12.0 g), sodium azide (11.3 g), tetrabutylammonium bromide (2.41 g), and zinc trifluoromethanesulfonate (181 mg) were sequentially added to a THF (150 mL) solution of the product (12.7 g) of Reference Example 56(2), and the mixture was heated under reflux for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (14.7 g, yield: 91%) as a colorless solid. 1H-NMR (CDCl3) delta: 7.45 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 5.08 (1H, br s), 2.56-2.43 (4H, m), 2.16-2.04 (1H, m), 1.91-1.79 (1H, m), 1.37 (9H, s) ESI-MS m/z 326, 328 (MH+)
91%	With sodium azide; tetrabutylammomium bromide; zinc trifluoromethanesulfonate; In tetrahydrofuran; for 14.0h;Reflux;	Reference Example 56(3) tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate Di-tert-butoxy dicarbonate (12.0 g), sodium azide (11.3 g), tetrabutylammonium bromide (2.41 g), and zinc ditriflate (181 mg) were sequentially added to a THF (150 mL) solution of the product (12.7 g) of Reference Example 56(2), and the mixture was heated under reflux for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate) to give the desired product (14.7 g, yield: 91%) as a colorless solid. 1H-NMR (CDCl3) delta: 7.45 (2 H, d, J = 8.5 Hz), 7.30 (2 H, d, J = 8.5 Hz), 5.08 (1 H, br s), 2.56 - 2.43 (4 H, m), 2.16 - 2.04 (1 H, m), 1.91 - 1.79 (1 H, m), 1.37 (9 H, s) ESI-MS m/z326, 327 (MH+)
	With sodium azide; tetrabutylammomium bromide; zinc trifluoromethanesulfonate; In tetrahydrofuran; at 60℃; for 4.0h;Product distribution / selectivity;	tert-butyl[1-(4-bromophenyl)cyclobutyl]carbamate (7-2) 1-(4-bromophenyl)cyclobutanecarboxylic acid (7-1, 10.89 g, 42.7 mmol), Boc anhydride (10.90 mL, 47.0 mmol), sodium azide (9.71 g, 149 mmol), tetrabutylammonium bromide (2.048 mL, 6.40 mmol) and zinc trifluoromethansulfonate (0.155 g, 0.427 mmol) were stirred in THF (100 ml) at 600 for 4 h. The reaction mixture was cooled to room temperature and EtOAc and saturated aqueous sodium bicarbonate were added to the mixture. The suspension was filtered through a glass frit and the filtrate was extracted with EtOAc, washing with water and brine. The organic layer was dried over Na2SO4, filtered and reduced in vacuo to a tan oil. The crude product was purified by normal phase flash chromatography eluding with 5-15% EtOAc/Hex to give 7-2 as a white solid.

Reference： [1]Patent: US2014/5185,2014,A1 .Location in patent: Paragraph 0253-0255
[2]Patent: EP2868660,2015,A1 .Location in patent: Paragraph 0171
[3]Patent: US2008/161317,2008,A1 .Location in patent: Page/Page column 69

4
[ 485828-58-8 ]
1-(4-bromophenyl)cyclobutane-1-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With water; potassium hydroxide In ethanol for 16h; Reflux;	72.1 1-(4-bromophenyl)cyclobutanecarboxylic acid To a solution of 1-(4-bromophenyl)cyclobutanecarbonitrile (1.0 g, 4.2 mmol) in EtOH (28 mL) and water (2 mL) was added KOH (2.1 g, 42 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction was then quenched with 1M hydrochloric acid in order to adjust pH to 7. The organic solvents were removed in vacuo to give a residue, which was dissolved in ethyl acetate (40 mL), then washed with brine (3*10 mL). The organic phase was concentrated in vacuo, and the resulting oil was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=8:1) to give 1-(4-bromophenyl)cyclobutanecarboxylic acid (0.8 g, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, 2H), 7.19 (d, 2H), 2.70-2.63 (m, 2H), 2.33-2.26 (m, 2H), 1.89-1.87 (m, 1H), 1.75-1.71 (m, 1H).
79%	With water; sodium hydroxide In butan-1-ol at 120℃; for 14h;	56.56.2 Reference Example 56(2) 1-(4-bromophenyl)cyclobutanecarboxylic acid A 50% aqueous sodium hydroxide solution (35 mL) was added to a butanol (100 mL) solution of the product (24.0 g) of Reference Example 56(1), and the mixture was stirred at 120° C. for 14 hours. After cooling to room temperature, water (100 mL) was added to the reaction mixture, followed by washing with ether. The ether layer was further extracted twice with 1 M aqueous sodium hydroxide solution (50 mL). 5 M hydrochloric acid was added to the combined aqueous layer, and the pH was adjusted to 2, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By adding hexane to the obtained residue and conducting filtration, the desired product (20.4 g, yield: 79%) was obtained as a colorless solid. 1H-NMR (CDCl3) δ: 7.45 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.5 Hz), 2.88-2.79 (2H, m), 2.53-2.43 (2H, m), 2.15-2.02 (1H, m), 1.93-1.81 (1H, m) ESI-MS m/z 255, 257 (MH+)
79%	With water; sodium hydroxide In butan-1-ol at 120℃; for 4h;	56.2 Reference Example 56(2) 1-(4-bromophenyl)cyclobutanecarboxylic acid Reference Example 56(2) 1-(4-bromophenyl)cyclobutanecarboxylic acid A 50% aqueous sodium hydroxide solution (35 mL) was added to a butanol (100 mL) solution of the product (24.0 g) of Reference Example 56(1), and the mixture was stirred at 120°C for 14 hours. After cooling to room temperature, water (100 mL) was added to the reaction mixture, followed by washing with ether. The ether layer was further extracted twice with 1N aqueous sodium hydroxide solution (50 mL). 5 M hydrochloric acid was added to the combined aqueous layer, and the pH was adjusted to 2, followed by extraction with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By adding hexane to the obtained residue and conducting filtration, the desired product (20.4 g, yield: 79%) was obtained as a colorless solid. 1H-NMR (CDCl3) δ: 7.45 (2 H, d, J = 8.5 Hz), 7.17 (2 H, d, J = 8.5 Hz), 2.88 - 2.79 (2 H, m), 2.53 - 2.43 (2 H, m), 2.15 - 2.02 (1 H, m), 1.93-1.81 (1 H, m) ESI-MS m/z255, 257 (MH+)

	Stage #1: 1-(4- bromophenyl)cyclobutane-1-carbonitrile With potassium hydroxide; ethylene glycol for 4h; Heating / reflux; Stage #2: With hydrogenchloride; water	7 1-(4-bromophenyl)cyclobutanecarboxylic acid (7-1) 1-(4-bromophenyl)cyclobutanecarbonitrile (1-2c, 12.04 g, 51.0 mmol), potassium hydroxide (11.44 g, 204 mmol) and ethylene glycol (50 mL, 897 mmol) were heated to reflux for 4 h. The reaction mixture was cooled to room temperature, then diluted with EtOAc and water. The aqueous layer was acidified with 1 M HCl, then was extracted into EtOAc. The organic layer was dried over Na2SO4, filtered and reduced in vacuo to give 7-1 as a tan oil.
	Stage #1: 1-(4- bromophenyl)cyclobutane-1-carbonitrile With potassium hydroxide In ethanol at 110℃; for 48h; Stage #2: With hydrogenchloride In water	S nthesis of l-(4-bromo-phenyl)-cyclobutanecarboxylic acidTo a solution of I-l (2.7 g, 11.0 mmol) in EtOH (25 mL) at room temperature is added KOH (1.9 g, 34.0 mmol). The mixture is heated at 110 °C for 48 hours, allowed to cool to room temperature, and concentrated in vacuo. The residue is slurried with 1H HC1 solution, and the resulting solid is filtered, collected, and dried to give the title intermediate 1-17 (2.74 g).
1.3 g	Stage #1: 1-(4- bromophenyl)cyclobutane-1-carbonitrile With hydrogenchloride In water; ethylene glycol Stage #2: With hydrogenchloride In water at 20℃;	Synthesis of 1-(4-bromophenyl)cyclobutanecarboxylic acid (Intermediate 51) Method 35 Synthesis of 1-(4-bromophenyl)cyclobutanecarboxylic acid (Intermediate 51) To a solution of I-50 (1.5 g, 6.25 mmol) in a mixture of ethylene glycol (7.5 mL) and water (4 mL) is added KOH (1.5 g, 26 mmol). The mixture is stirred at 120° C. for 18 h, before cooling to room temperature and pouring into 1M HCl (100 mL). The resultant precipitate is filtered and washed with water to give the title intermediate I-51 (1.3 g). The following intermediates are also prepared according to the method described in Method 35:
	With potassium hydroxide In ethylene glycol Reflux;
	With potassium hydroxide In water; ethylene glycol at 100℃; for 24h;

Reference： [1]Current Patent Assignee: PFIZER INC; KIMBERLY-CLARK CORP - US2013/267493, 2013, A1 Location in patent: Paragraph 1036; 1037
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2014/5185, 2014, A1 Location in patent: Paragraph 0250-0252
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - EP2868660, 2015, A1 Location in patent: Paragraph 0170
[4]Current Patent Assignee: MERCK & CO INC - US2008/161317, 2008, A1 Location in patent: Page/Page column 69
[5]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/82817, 2012, A1 Location in patent: Page/Page column 85
[6]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2013/196967, 2013, A1 Location in patent: Paragraph 0266; 0267
[7]He, Wu; Zhou, Bin; Liu, Weijia; Zhang, Meizi; Shen, Zhenhua; Han, Zhifu; Jiang, Qingwei; Yang, Qinghua; Song, Chuanjun; Wang, Ruiyong; Niu, Tianhui; Han, Shengna; Zhang, Lirong; Wu, Jie; Guo, Feima; Zhao, Renbin; Yu, Wenquan; Chai, Jijie; Chang, Junbiao [Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7341 - 7348]
[8]Chen, Xiang; Chen, Lili; Zhao, Hongliang; Gao, Qian; Shen, Zhenlu; Xu, Senmiao [Chinese Journal of Chemistry, 2020, vol. 38, # 12, p. 1533 - 1537]

5
[ 151157-49-2 ]
[ 1195178-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(4-bromophenyl)cyclobutane-1-carboxylic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0 - 20℃; for 4h; Stage #2: With sodium azide In tetrahydrofuran at 20℃; for 48h;	165.1 A solution of l-(4-bromophenyl)cyclobutanecarboxylic acid (4.97 g, 19.5 mmol) and triethylamine (3.0 mL, 21.5 mmol) in THF (65 mL) at 00C was added ethyl chloroformate (2.0 mL, 21.5 mmol). After addition, the mixture was stirred at room temperature for 4 h. Then, a solution of sodium azide (2.5 g, 39.0 mmol) in H2O (5 mL) was added and the mixture was stirred at room temperature for 48 h. Then, H2O (10 mL) was added and the mixture was extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give azido(l-(4-bromophenyl)cyclobutyl)methanone as a yellow solid which was used without purification.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2009/137404, 2009, A1 Location in patent: Page/Page column 72

6
[ 41841-16-1 ]
[ 109-64-8 ]
[ 151157-49-2 ]

Yield	Reaction Conditions	Operation in experiment
21%	Stage #1: (4-bromo-phenyl)-acetic acid methyl ester With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 20℃; Stage #2: 1,3-dibromo-propane In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 5 - 20℃; for 3.66667h; Stage #3: With acetic acid In tetrahydrofuran; water; N,N-dimethyl-formamide; mineral oil	60% Sodium hydride in mineral oil (4.36 g, 109 mmol) was carefully added portion wise to a solution of the methyl 2-(4-bromophenyl)acetate (4.99 g, 21.78 mmol) in tetrahydrofuran (50 mL) and dimethylformamide (30 mL) at room temperature. Once addition was complete, reaction was stirred at room temperature for 20 minutes and then cooled to 5° C. 1,3-dibromopropane (6.160 g, 30.5 mmol) was added portion wise over 40 minutes. Once addition was complete, the reaction was stirred at room temperature for 3 hours. Acetic acid (8 mL) was slowly added to the reaction followed by water (150 mL). Solution was extracted with 1:1 ethyl acetate: heptane, dried over sodium sulfate, filtered and concentrated. Crude purified on silica gel, eluding with a gradient from 20% to 100% ethyl acetate in heptane to give 1-(4-bromophenyl)cyclobutanecarboxylic acid (1.180 g, 21%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.85-1.96 (m, 1H) 2.06-2.17 (m, 1H) 2.47-2.56 (m, 2H) 2.82-2.91 (m, 2H) 7.21 (d, 2H) 7.48 (d, 2H) 11.54 (br. s., 1H) 1-(4-Bromophenyl)cyclobutanecarboxylic acid (290 mg, 1.14 mmol) in tetrahydrofuran (6 mL) was added a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (0.231 mL, 2.27 mmol) drop wise at room temperature and stirred for 24 hours. Methanol (1 mL) was slowly added to the reaction mixture and then concentrated.

Reference： [1]Current Patent Assignee: PFIZER INC - US2010/197591, 2010, A1 Location in patent: Page/Page column 18

7
[ 151157-49-2 ]
[ 100-39-0 ]
[ 1236409-31-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 42h;	1-(4-Bromophenyl)cyclobutanecarboxylic acid (970 mg, 3.8 mmol), benzyl bromide (0.543 mL, 4.56 mmol) and cesium carbonate (1.73 g, 5.32 mmol) combined in dimethylformamide (9 mL) and stirred at room temperature for 18 hours and then heated to 60° C. for 24 hours. Reaction diluted with water and extracted with 1:1 ethyl acetate:heptane. Organic layers washed with brine, dried over magnesium sulfate, filtered and concentrated. Toluene added and concentrated to give benzyl 1-(4-bromophenyl)cyclobutanecarboxylate (1.3 g, 99%) which was used in the Buchwald reaction without further purification.1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.85-1.93 (m, 1H) 2.02-2.12 (m, 1H) 2.46-2.53 (m, 2H) 2.83-2.90 (m, 2H) 5.10 (s, 2H) 7.17-7.21 (m, 4H) 7.30-7.34 (m, 3H) 7.46 (d, 2H)

Reference： [1]Current Patent Assignee: PFIZER INC - US2010/197591, 2010, A1 Location in patent: Page/Page column 18-19

8
1-(4-bromophenyl)cyclobutane-1-carboxylic acid [ No CAS ]
[ 1227159-85-4 ]

Yield	Reaction Conditions	Operation in experiment
96%		Bromophenyl)cyclobutanecarboxylic acid (290 mg, 1.14 mmol) in tetrahydrofuran (6 mL) was added a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (0.231 mL, 2.27 mmol) drop wise at room temperature and stirred for 24 hours. Methanol (1 mL) was slowly added to the reaction mixture and then concentrated. Water (10 mL) and 1M aqueous hydrochloric acid added and reaction extracted with a 1:1 ethyl acetate: heptane solution. Extract washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude purified on silica gel, eluting with a gradient from 20% to 80% ethyl acetate in heptane to give (1-(4-bromophenyl)cyclobutyl)methanol (265 mg, 96%).1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.81-1.92 (m, 1H) 2.01-2.11 (m, 1H) 2.16-2.31 (m, 4H) 3.71 (s, 2H) 7.00 (d, 2H) 7.43 (d, 2H)
62%	With dimethylsulfide borane complex; In 1,4-dioxane; at 0 - 20℃; for 0.166667h;	To a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (300 mg, 1.20 mmol) in 1,4-dioxane (5 mL) was added borane dimethylsulfide complex (0.24 mL, 2.4 mmol) dropwise at 0 C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with methanol (20 mL). The organic solvents were removed under reduced pressure to give a residue, which was dissolved in ethyl acetate, then washed with brine. The organic phase was concentrated to give [1-(4-bromophenyl)cyclobutyl]methanol (170 mg, 62% yield) as a yellow oil which was used directly in the next step.

Reference： [1]Patent: US2010/197591,2010,A1 .Location in patent: Page/Page column 18
[2]Patent: US2013/267493,2013,A1 .Location in patent: Paragraph 1038

9
[ 16532-79-9 ]
[ 151157-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0 °C 1.2: 0 - 20 °C 2.1: potassium hydroxide / ethanol / 48 h / 110 °C
	Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / water; toluene / 3 h / 70 - 100 °C 2: sodium hydroxide; water / butan-1-ol / 14 h / 120 °C
	Multi-step reaction with 2 steps 1: potassium hydroxide; tetrabutylammomium bromide / water; toluene / 3 h / 100 °C 2: water; sodium hydroxide / butan-1-ol / 4 h / 120 °C

	Multi-step reaction with 2 steps 1: potassium hydroxide / dimethyl sulfoxide / 0 - 20 °C 2: potassium hydroxide / ethylene glycol / Reflux
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 °C 1.2: 1 h / 0 - 20 °C 2.1: hydrogenchloride / water; ethylene glycol 2.2: 20 °C
	Multi-step reaction with 2 steps 1: potassium hydroxide / dimethyl sulfoxide / 12 h / 20 °C 2: potassium hydroxide / ethylene glycol; water / 24 h / 100 °C

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/82817, 2012, A1
[2]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - US2014/5185, 2014, A1
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - EP2868660, 2015, A1
[4]He, Wu; Zhou, Bin; Liu, Weijia; Zhang, Meizi; Shen, Zhenhua; Han, Zhifu; Jiang, Qingwei; Yang, Qinghua; Song, Chuanjun; Wang, Ruiyong; Niu, Tianhui; Han, Shengna; Zhang, Lirong; Wu, Jie; Guo, Feima; Zhao, Renbin; Yu, Wenquan; Chai, Jijie; Chang, Junbiao [Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7341 - 7348]
[5]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2013/196967, 2013, A1
[6]Chen, Xiang; Chen, Lili; Zhao, Hongliang; Gao, Qian; Shen, Zhenlu; Xu, Senmiao [Chinese Journal of Chemistry, 2020, vol. 38, # 12, p. 1533 - 1537]

10
[ 151157-49-2 ]
[ 151157-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride In dichloromethane at 50℃; for 16h;	S nthesis of l-(4-bromo-phenyl)-cyclobutanecarbonyl chloride1-17 I-72To a solution of 1-17 (400 mg, 1.57 mmol), in CH2C12 (3 mL) at room temperature is added thionyl chloride (1.7 mL, 14.3 mmol). The mixture is heated at 50 °C for 16 h, allowed to cool to room temperature, and concentrated in vacuo to give the title intermediate 1-72 (430 mg).

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/82817, 2012, A1 Location in patent: Page/Page column 99

11
[ 151157-49-2 ]
[ 1382486-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.25 h / 20 °C 2.2: 2 h / 80 °C