[ CAS No. 360773-84-8 ] {[proInfo.proName]}

Name: 360773-84-8|tert-Butyl (1-(4-bromophenyl)cyclopropyl)carbamate|97%
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SKU: A200217
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Quality Control of [ 360773-84-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 360773-84-8 ]

CAS No. :	360773-84-8	MDL No. :	MFCD16660261
Formula :	C₁₄H₁₈BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZJEMFURAGDYBTG-UHFFFAOYSA-N
M.W :	312.20	Pubchem ID :	53216208
Synonyms :

Calculated chemistry of [ 360773-84-8 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.5
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	75.04
TPSA :	38.33 Å²

Pharmacokinetics

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

Lipophilicity

Log Po/w (iLOGP) :	3.18
Log Po/w (XLOGP3) :	3.46
Log Po/w (WLOGP) :	3.79
Log Po/w (MLOGP) :	3.18
Log Po/w (SILICOS-IT) :	3.4
Consensus Log Po/w :	3.4

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.87
Solubility :	0.0419 mg/ml ; 0.000134 mol/l
Class :	Soluble
Log S (Ali) :	-3.95
Solubility :	0.0353 mg/ml ; 0.000113 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.0
Solubility :	0.00311 mg/ml ; 0.00000995 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.05

Safety of [ 360773-84-8 ]

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

Application In Synthesis of [ 360773-84-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 360773-84-8 ]
Downstream synthetic route of [ 360773-84-8 ]

[ 360773-84-8 ] Synthesis Path-Upstream 1~6

1
[ 360773-84-8 ]
[ 345965-54-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride In methanol; water at 20℃; for 24 h;	General procedure: Compound 3a (1.42g, 4.73mmol) in a 3.0N HCl solution in MeOH (10mL) was stirred at rt for 24h. The solvent was removed under reduced pressure. The resulting residue was then suspended in DCM and basified by a 2.0N solution of NaOH (20mL). The organic phases were then separated and combined and dried by anhydrous magnesium sulfate. The solvent was then removed and the residue was purified by column chromatography with pre-packed silica gel disposable column to afford the title compound 1a (1.12g, 99percent) as a brown foam.

Reference： [1] Tetrahedron, 2016, vol. 72, # 16, p. 1941 - 1953
[2] Patent: US6359135, 2002, B1, . Location in patent: Page column 114
[3] Patent: US6369225, 2002, B1, . Location in patent: Page column 42, 112-113
[4] Patent: US6252090, 2001, B1,
[5] Patent: US6313107, 2001, B1,

2
[ 24424-99-5 ]
[ 345965-54-0 ]
[ 360773-84-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium carbonate In tetrahydrofuran; water at 20℃;	tert-Butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate In a 100-mL round bottom flask, 1-(4-bromophenyl)cyclopropan-1-amine (1 g, 4.48 mmol, 1.00 equiv) and di-tert-butyl dicarbonate (3.1 g, 13.49 mmol, 3.01 equiv) were mixed in tetrahydrofuran (20 mL), to which was added a solution of sodium bicarbonate (5 g, 59.5 mmol, 13.29 equiv) in water (10 mL) at room temperature. The resulting solution was stirred overnight at room temperature. After the reaction was done, the reaction mixture was extracted with ethyl acetate (3*10 mL) and the organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (10percent to 50percent gradient) to afford tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (1.47 g, 99percent) as light yellow solid. MS: m/z=255.7 [M+H-56]⁺.
92%	With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 18 h;	Step 1: Preparation of tert-butyl[1-(4-bromophenyl)cyclopropyl]carbamate To a solution of 1-(4-bromophenyl)cyclopropanamine (1 g) in THF (30 mL) and saturated sodium bicarbonate solution (30 mL) was added a solution of di-tert-butyl dicarbonate (3.1 g) in THF (30 mL) at 0° C. dropwise. After being stirred at room temperature for 18 h, the reaction mixture was extracted with diisopropyl ether. The organic layer was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-20percent ethyl acetate in hexanes) gave the product (1.4 g, 92percent). ¹HNMR (CDCl₃) 400 MHz δ: 7.40 (d, J=8.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 5.23 (br s, 1H), 1.48-1.15 (m, 13H).

Reference： [1] Patent: US2016/96834, 2016, A1, . Location in patent: Paragraph 0390
[2] Patent: US2012/108574, 2012, A1, . Location in patent: Page/Page column 113
[3] Patent: WO2016/57762, 2016, A1, . Location in patent: Page/Page column 30
[4] Patent: WO2016/102672, 2016, A2, . Location in patent: Page/Page column 115

3
[ 345965-52-8 ]
[ 75-65-0 ]
[ 360773-84-8 ]

Yield	Reaction Conditions	Operation in experiment
23 g	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine In toluene for 5 h; Molecular sieve; Reflux	To the solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (40 g, 165 mmol, available from Amatek Chemical AC-0350) in toluene (800 ml), in the presence of activated molecular sieves (15g), N,N-diisopropylethylamine (27.5 g, 497 mmol), Diphenylphosphoryl azide (54.7 g, 215 mmol) and tert-Butanol (380 ml) were added. The resulting mixture was refluxed 5 hours. The mixture was cooled to room temperature and the solvents evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 5percent citric acid (200 ml), aqueous NaHCO₃(200 ml) and brine (200 ml). Collected organics after drying over Na₂SO₄and solvent evaporation afforded a crude residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 4:1. Collected fractions after solvent evaporation afforded the title compound (D4) (23.0 g) as a solid.
1.3 g	at 20℃; Molecular sieve; Reflux	General procedure: A solution of 2a (2.26g, 9.42mmol) in MeOH (19mL) was added a 6.0N solution of sodium hydroxide (9.42mL, 56.5mmol). The reaction mixture was refluxed overnight and was added a 4.0M HCl solution in dioxane (15.0mL, 60mmol) at rt. The solvent was removed under reduced pressure. A solution of the residue in anhydrous t-BuOH (0.20L) with flame dried 4 molecular sieve powder (1.0g) was added diphenyl phosphorazidate (2.45mL, 11.3mmol) and triethylamine (2.64mL, 18.8mmol). The reaction mixture was stirred at rt for 1.0h and then heated under reflux overnight. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with pre-packed silica gel disposable column to afford the title compound 3a (1.42g, 51percent) and 4a (0.63g, 30percent).

Reference： [1] Patent: US6359135, 2002, B1, . Location in patent: Page column 113-114
[2] Patent: US6369225, 2002, B1, . Location in patent: Page column 42, 112
[3] Patent: US2008/81802, 2008, A1, . Location in patent: Page/Page column 8
[4] Patent: WO2012/76063, 2012, A1, . Location in patent: Page/Page column 36-37
[5] Patent: US2013/261100, 2013, A1, . Location in patent: Paragraph 0264-0265
[6] Tetrahedron, 2016, vol. 72, # 16, p. 1941 - 1953

4
[ 345965-52-8 ]
[ 24424-99-5 ]
[ 360773-84-8 ]

Reference： [1] Patent: WO2005/63239, 2005, A1, . Location in patent: Page/Page column 129

5
[ 133017-10-4 ]
[ 360773-84-8 ]

Reference： [1] Tetrahedron, 2016, vol. 72, # 16, p. 1941 - 1953

6
[ 360773-84-8 ]
[ 1014645-87-4 ]

Reference： [1] Patent: WO2012/76063, 2012, A1,

[ 360773-84-8 ] Synthesis Path-Downstream 1~56

1
[ 360773-84-8 ]
[ 952289-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 20℃;	47 mL hydrochloric acid (4 M in dioxane) is added to a solution of H-2b (19.5 g, 37.4 mmol) in 50 mL dioxane and stirred overnight at RT. The precipitate formed is filtered off, the filtrate is evaporated down to about half and filtered again. The filter cakes are combined and dried. Yield: 10.1 g (w=0.90)

Reference： [1]Patent: US2008/81802,2008,A1 .Location in patent: Page/Page column 9; 10

2
[ 345965-52-8 ]
[ 75-65-0 ]
[ 360773-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; In toluene; for 5h;Heating / reflux; Molecular sieve;	Under an argon atmosphere a suspension of H-2a (5.7 g, 24 mmol), N-ethyldiisopropylamine (5.3 mL, 31 mmol), tert-butanol (55 mL, 0.59 mol), diphenylphosphorylazide (6.1 mL, 28 mmol) and activated molecular sieve (4 ) in 120 mL toluene is refluxed for 5 h. The reaction mixture is evaporated down and the residue is combined with 100 mL ethyl acetate and extracted with 50 mL of 5% citric acid solution, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase is dried on magnesium sulphate and evaporated down. Yield 7.7 g.
	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; In toluene; for 5h;Molecular sieve; Reflux;	Description 4: tert-butyl (1-(4-bromophenyl)cyclopropyl)carbamate (D4) To the solution of 1 -(4-bromophenyl)cyclopropanecarboxylic acid (40 g, 165 mmol, available from Amatek Chemical No.AC-0350) in toluene (800ml), in the presence of activated molecular sieves (15 g), N,N-diisopropylethylamine (27.5 g, 497 mmol), Diphenylphosphoryl azide (54.7 g, 215 mmol) and tert-Butanol (380ml) were added. The resulting mixture was refluxed 5 hours. The mixture was cooled to room temperature and the solvents evaporated in vacuo. The residue was dissolved in ethyl acetate (200ml) and washed with 5% citric acid (200ml), aqueous NaHC03 (200ml) and brine (200ml). Collected organics after drying over Na2S04 and solvent evaporation afforded a crude residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 4:1 . Collected fractions after solvent evaporation afforded the title compound (D4) (23.0 g) as a solid.1 H NMR (400MHz ,CHLOROFORM-d) delta (ppm): 7.39 (2H, d, J= 8.0 Hz), 7.09 (2H, d, J= 8.0 Hz), 5.27 (1 H, s), 1 .43 - 1 .37 (9H, s), 1 .19-1 .28 (4H, m).
23 g	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; In toluene; for 5h;Molecular sieve; Reflux;	To the solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (40 g, 165 mmol, available from Amatek Chemical AC-0350) in toluene (800 ml), in the presence of activated molecular sieves (15g), N,N-diisopropylethylamine (27.5 g, 497 mmol), Diphenylphosphoryl azide (54.7 g, 215 mmol) and tert-Butanol (380 ml) were added. The resulting mixture was refluxed 5 hours. The mixture was cooled to room temperature and the solvents evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and washed with 5% citric acid (200 ml), aqueous NaHCO3 (200 ml) and brine (200 ml). Collected organics after drying over Na2SO4 and solvent evaporation afforded a crude residue which was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 4:1. Collected fractions after solvent evaporation afforded the title compound (D4) (23.0 g) as a solid.

1.3 g

With diphenyl phosphoryl azide; triethylamine; at 20℃;Molecular sieve; Reflux;

General procedure: A solution of 2a (2.26g, 9.42mmol) in MeOH (19mL) was added a 6.0N solution of sodium hydroxide (9.42mL, 56.5mmol). The reaction mixture was refluxed overnight and was added a 4.0M HCl solution in dioxane (15.0mL, 60mmol) at rt. The solvent was removed under reduced pressure. A solution of the residue in anhydrous t-BuOH (0.20L) with flame dried 4 molecular sieve powder (1.0g) was added diphenyl phosphorazidate (2.45mL, 11.3mmol) and triethylamine (2.64mL, 18.8mmol). The reaction mixture was stirred at rt for 1.0h and then heated under reflux overnight. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography with pre-packed silica gel disposable column to afford the title compound 3a (1.42g, 51%) and 4a (0.63g, 30%).

Reference： [1]Patent: US6359135,2002,B1 .Location in patent: Page column 113-114
[2]Patent: US6369225,2002,B1 .Location in patent: Page column 42, 112
[3]Patent: US2008/81802,2008,A1 .Location in patent: Page/Page column 8
[4]Patent: WO2012/76063,2012,A1 .Location in patent: Page/Page column 36-37
[5]Patent: US2013/261100,2013,A1 .Location in patent: Paragraph 0264-0265
[6]Tetrahedron,2016,vol. 72,p. 1941 - 1953

3
[ 360773-84-8 ]
[ 345965-54-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride; In methanol; water; at 20℃; for 24h;	General procedure: Compound 3a (1.42g, 4.73mmol) in a 3.0N HCl solution in MeOH (10mL) was stirred at rt for 24h. The solvent was removed under reduced pressure. The resulting residue was then suspended in DCM and basified by a 2.0N solution of NaOH (20mL). The organic phases were then separated and combined and dried by anhydrous magnesium sulfate. The solvent was then removed and the residue was purified by column chromatography with pre-packed silica gel disposable column to afford the title compound 1a (1.12g, 99%) as a brown foam.
	With hydrogenchloride; sodium hydroxide; In tetrahydrofuran; methanol;	1-(4-Bromophenyl)-cyclopropylamine (Intermediate 116) To a solution of tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115, 1.08 g, 3.40 mmols) in 20 mL MeOH and 20 mL THF was added 20 mL of 3M aqueous HCl. The solution was warmed to 35 C. for 3 hours and then stirred for 17 h at 25 C. The reaction was quenched by adjusting the pH of the solution to 12 with 3M aqueous NaOH. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound 613 mg (85%) was used without further purification. 1H NMR (CDCl3) delta: 7.43 (2H, d, J=8.3 Hz), 7.17 (2H, d, J=8.3 Hz), 1.89 (2H, bs), 1.07 (2H, m), 0.95 (2H, m).

Reference： [1]Tetrahedron,2016,vol. 72,p. 1941 - 1953
[2]Patent: US6359135,2002,B1 .Location in patent: Page column 114
[3]Patent: US6369225,2002,B1 .Location in patent: Page column 42, 112-113
[4]Patent: US6252090,2001,B1

4
[ 345965-52-8 ]
[ 24424-99-5 ]
[ 360773-84-8 ]

Reference： [1]Patent: WO2005/63239,2005,A1 .Location in patent: Page/Page column 129

5
[ 360773-84-8 ]
[ 630384-19-9 ]

Reference： [1]Patent: WO2005/63239,2005,A1 .Location in patent: Page/Page column 130
[2]Journal of Medicinal Chemistry,2020

Yield	Reaction Conditions	Operation in experiment
2.01 g (67%)		Tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115) A solution of 1-(4-bromophenyl)-cyclopropanecarboxylic acid (Intermediate 114, 2.32 g, 9.62 mmols), diphenylphosphoryl azide (2.65 g, 9.62 mmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL tert-BuOH (distilled from Na) was heated to reflux for 17 h. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc and washed with 5% aqueous HCl, H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried over MgSO4. Concentration of the dry solution under reduced pressure and column chromatography (5-10% EtOAc -hexanes) afforded 2.01 g (67%) of the title compound as a colorless solid. 1H NMR (CDCl3) delta: 7.39 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.3 Hz), 5.35 (1H, bs), 1.43 (9H, s), 1.26 (2H, m), 1.17 (2H, m).
2.01 g (67%)		Tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115) A solution of 1-(4-bromophenyl)-cyclopropanecarboxylic acid (Intermediate 114, 2.32 g, 9.62 mmols), diphenylphosphoryl azide (2.65 g, 9.62 mmols), triethylamine (973.0 mg, 9.62 mmols) in 40 mL tert-BuOH (distilled from Na) was heated to reflux for 17h. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc and washed with 5% aqueous HCl, H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried over MgSO4. Concentration of the dry solution under reduced pressure and column chromatography (5-10% EtOAc-hexanes) afforded 2.01 g (67%) of the title compound as a colorless solid. 1H NMR (CDCl3) delta: 7.39 (2H, d, J=8.3 Hz), 7.08 (2H, d, J=8.3 Hz), 5.35 (1H, bs), 1.43 (9H, s), 1.26 (2H, m), 1.17 (2H, m).
	In dichloromethane; at 0 - 20℃;	General procedure: To a stirring solution of (-)-l-(4-bromophenyl)ethylamine (1.00 g, 5.0 mmol) in dichloromethane (10 mL) at 0 C, add di-tert-butyldicarbonate (1.09 g, 5.0 mmol). Allow the reaction mixture to warm to room temperature, then stir for two hours. To the stirring mixture, add 1 M aqueous hydrochloric acid (25 mL), followed by Et20 (25 mL). Separate the layers, and extract the aqueous layer with Et20 (2 x 25 mL). Combine the organic layers, wash with saturated aqueous NaCl (25 mL), dry the organic layer over MgSC^, filter to remove the solids, and concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (1.50 g, 99% yield). Mass spectrum (m/z) (79Br/81Br) 244/246 (M + 2H - t-Bu)+, 322/324 (M + Na)+. NMR (400 MHz, CDC13): delta 7.46-7.43 (m, 2H), 7.19-7.15 (m, 2H), 4.81^1.65 (m, 1H), 1.48-1.36 (m, 12H).

7
[ 24424-99-5 ]
[ 345965-54-0 ]
[ 360773-84-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium carbonate; In tetrahydrofuran; water; at 20℃;	tert-Butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate In a 100-mL round bottom flask, <strong>[345965-54-0]1-(4-bromophenyl)cyclopropan-1-amine</strong> (1 g, 4.48 mmol, 1.00 equiv) and di-tert-butyl dicarbonate (3.1 g, 13.49 mmol, 3.01 equiv) were mixed in tetrahydrofuran (20 mL), to which was added a solution of sodium bicarbonate (5 g, 59.5 mmol, 13.29 equiv) in water (10 mL) at room temperature. The resulting solution was stirred overnight at room temperature. After the reaction was done, the reaction mixture was extracted with ethyl acetate (3*10 mL) and the organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (10% to 50% gradient) to afford tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (1.47 g, 99%) as light yellow solid. MS: m/z=255.7 [M+H-56]+.
92%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 18h;	Step 1: Preparation of tert-butyl[1-(4-bromophenyl)cyclopropyl]carbamate To a solution of <strong>[345965-54-0]1-(4-bromophenyl)cyclopropanamine</strong> (1 g) in THF (30 mL) and saturated sodium bicarbonate solution (30 mL) was added a solution of di-tert-butyl dicarbonate (3.1 g) in THF (30 mL) at 0 C. dropwise. After being stirred at room temperature for 18 h, the reaction mixture was extracted with diisopropyl ether. The organic layer was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-20% ethyl acetate in hexanes) gave the product (1.4 g, 92%). 1HNMR (CDCl3) 400 MHz delta: 7.40 (d, J=8.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 5.23 (br s, 1H), 1.48-1.15 (m, 13H).
	In ethanol; at 20℃; for 16h;	To a solution of <strong>[345965-54-0]1-(4-bromophenyl)cyclopropanamine</strong> (2 g, 9.4 mmol) in ethanol (20 mL) was added (BOC)2O (4.4 mL, 19 mmol), then the mixture was stirred at room temperature for 16 h. When TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. The residue was triturated with petroleum ether (20 mL), and the solid was collected by suction to afford crude product tert-butyl (1-{4-bromophenyI)cydopropyl)carbamate. 1H NMR (CDCl3, 400 MHz) delta: 7.38 (d, J= 8.0 Hz, 2H), 7.08 (d, J- 8.0 Hz, 2H), 5.23 (brs, 1H), 1.42 (s, 9H), 1.26-1.17 (m, 4H).

1.43 g

In dichloromethane;

Step 1: tert-butyl (l-(4-bromophenyl)cyclopropyl)carbamate: A stirred solution of l-(4- bromophenyl)cyclopropanamine (1.00 g, 4.72 mmol) in DCM (10 ml) was treated with B0C2O (1.08 g, 4.95 mmol) and the resultant mixture stirred overnight. The solution was diluted with DCM (20 ml), was washed with brine (20 ml) and filtered through a phase separation cartridge. The filtrate was concentrated in vacuo to afford the title compound (1.43 g, 4.50 mmol, 98% purity) as a white solid. 1H NMR (400 MHz, Chloroform-d) (two rotamers in a 3: 1 ratio) delta 7.44 - 7.36 (m, 2H), 7.10 (d, / = 8.3 Hz, 2H), 5.22 (br s, 1H, major), 5.01 (br s, 1H, minor), 1.43 (br s, 9H), 1.32 - 1.11 (m, 4H).

Reference： [1]Patent: US2016/96834,2016,A1 .Location in patent: Paragraph 0390
[2]Patent: US2012/108574,2012,A1 .Location in patent: Page/Page column 113
[3]Patent: WO2016/57762,2016,A1 .Location in patent: Page/Page column 30
[4]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 115

8
[ 360773-84-8 ]
[ 73183-34-3 ]
[ 1313441-88-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 70℃; for 12h;Inert atmosphere;	A mixture of <strong>[360773-84-8]tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate</strong> (3 g, 9.61 mmol, CAS360773-84-8), Pin2B2 (4.88 g, 19.2 mmol), KOAc (2.83 g, 28.8 mmol) and cyclopentyl(diphenyl) phosphane; dichloromethane; dichloropalladium; iron (392 mg, 480 umol) in DMSO (30 mL) was degassed and then heated to 70 C. for 12 hours under N2. On completion, the mixture was quenched with water (200 mL) and filtered. The filter cake was purified by silica gel chromatography (SiO2) to give the title compound (3.0 g, 87% yield) as a white solid. LC-MS (ESI+) m/z 398.2 (M+K)+.
80%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃; for 5h;	Step 2: Preparation of tert-butyl {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbamate A suspension of tert-butyl[1(4-bromophenyl)cyclopropyl]carbamate (400 mg) and 4,4,4',4',5,5,5',51-octamethyl-2,2'-bi-1,3,2-dioxaborolane (390 mg) and potassium acetate (377 mg) and PdCl2(dppf)CH2Cl2 (31 mg) in dimethylsulfoxide (6.5 mL) was degassed for 5 min then stirred at 80 C. for 5 h. The reaction mixture was diluted with benzene and filtered. The filtrate was washed with brine (5 times). The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (0-20% ethyl acetate in hexanes) gave the product (367 mg, 80%). 1HNMR (CDCl3) 400 MHz delta: 7.73 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 5.25 (br s, 1H), 1.47-1.18 (m, 25H).
	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In N,N-dimethyl-formamide; at 100℃;	5-tert-butyl-N-(1-[4-[2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl]phenyl]cyclopropyl)-1,2,4-oxadiazole-3-carboxamide 22.6 mg (2.1% for 6 steps) was prepared from <strong>[360773-84-8]tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate</strong>, 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane, 4-chloro-3-nitropyridin-2-amine and 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate using Method 19R, 2J, 1G, 15P, 19T and 11N. HPLC: 99.9% purity. MS: m/z=483.1 [M+H]+. 1H NMR (400 MHz, CD3OD): delta 8.45-8.25 (m, 2H), 8.23-8.15 (m, 1H), 8.05-8.01 (m, 1H), 7.75 (s, 1H), 7.53-7.52 (m, 2H), 7.35-7.25 (m, 1H), 4.01 (s, 3H), 1.52 (s, 9H), 1.48 (s, 4H).

1.46 g	With potassium acetate; palladium diacetate; XPhos; In acetonitrile; at 80℃;Inert atmosphere;	Step 2: tert-butyl (l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropyl)carbamate: The product from Step 1 above (1.43 g, 4.50 mmol, 98% purity), b 5,-(pinacolato)diboron (1.39 g, 5.48 mmol), palladium(II) acetate (0.051 g, 0.229 mmol), X-Phos (0.219 g, 0.457 mmol) and potassium acetate (1.35 g, 13.7 mmol) were combined in a vessel, which was evacuated and purged with N2 three times. MeCN (25 ml) was added and the vessel was purged with N2 and then heated at 80 C overnight. The mixture was diluted with DCM (20 ml) and filtered through Celite, washing with DCM (3 x 20 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography (80 g cartridge, 0-25% EtOAc/isohexane) to afford the title compound (1.46 g, 3.91 mmol, 96% purity) as a cream powder. 1H NMR (400 MHz, DMSO- ) delta 7.74 (s, 1H), 7.62 - 7.50 (m, 2H), 7.15 - 7.10 (m, 2H), 1.41 - 1.22 (m, 21H), 1.17 - 1.10 (m, 4H).
6.5 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 2-methyltetrahydrofuran; at 80℃; for 8h;Inert atmosphere;	Compound B (2.4g, 7.7mmol) was dissolved in dry 2-methyltetrahydrofuran,Add bis(pinacolate) diboron (2.4g, 9.4mmol),Potassium acetate (1.5g, 15.4mmol),Pd(dppf)Cl2 (0.28g, 0.38mmol),After nitrogen substitution, the reaction was carried out at 80 degrees for 8 hours.The reaction solution was filtered through celite, and the filtrate was evaporated to dryness and washed with petroleum ether to obtain white solid product C (6.5g).That is (4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)phenyl)boronic acid ester.

Reference： [1]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 3175; 3176
[2]Patent: US2012/108574,2012,A1 .Location in patent: Page/Page column 114
[3]Patent: US2016/96834,2016,A1 .Location in patent: Paragraph 0391
[4]Patent: WO2016/102672,2016,A2 .Location in patent: Page/Page column 115
[5]Patent: CN111171065,2020,A .Location in patent: Paragraph 0020; 0024-0026; 0030-0032; 0036-0037

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[ 1374261-40-1 ]

Reference： [1]Patent: US2012/108574,2012,A1

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[ 1374263-34-9 ]

Reference： [1]Patent: US2012/108574,2012,A1

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[ 67-56-1 ]
[ 360773-84-8 ]
[ 201230-82-2 ]
[ 1338243-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,3-bis-(diphenylphosphino)propane; triethylamine;palladium diacetate; In methanol; N,N-dimethyl-formamide; at 80℃; under 30003.0 Torr; for 48h;	Description 5: methyl 4-(1-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (D5)A mixture of tert-butyl (1 -(4-bromophenyl)cyclopropyl)carbamate (D4) (2.6 g, 8.33 mmol), 1 .3-bis(diphenylphosphine)-propane (680 mg, 0.83 mmol), Palladium(ll) acetate (370 mg, 0.83 mmol) and triethylamine (2.52 g, 24.9 mmol) in dimethylformamide (40ml) and methanol (60ml) was stirred at 80 C for 2 days under 4.0 Mpa CO atmosphere. The resulting mixture was cooled to room temperature and water was added. The mixture was extracted with diethylether (3x200ml) and the collected organics were washed with water (500ml) and brine (500ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silca gel eluting with a mixture petroleum ether/ethyl acetate from 40:1 to 10:1 . Collected fractions after solvent evaporation afforded the title compound (D5) (1 g).1 H NMR (400MHz ,CHLOROFORM-d) delta (ppm): 7.95 (2H, d, J= 8.8 Hz), 7.22 (2H, d, J= 8.8 Hz), 3.90 (3H, s), 5.32 (1 H, s), 1 .45 (9H, s), 1 .35 - 1 .30 (4H, m).
1 g	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 80℃; under 30003.0 Torr; for 48h;	A mixture of <strong>[360773-84-8]tert-butyl (1-(4-bromophenyl)cyclopropyl)carbamate</strong> (D4) (2.6 g, 8.33 mmol), 1,3-bis(diphenylphosphine)-propane (680 mg, 0.83 mmol), Palladium(II) acetate (370 mg, 0.83 mmol) and triethylamine (2.52 g, 24.9 mmol) in dimethylformamide (40 ml) and methanol (60 ml) was stirred at 80 C. for 2 days under 4.0 Mpa CO atmosphere. The resulting mixture was cooled to room temperature and water was added. The mixture was extracted with diethylether (3×200 ml) and the collected organics were washed with water (500 ml) and brine (500 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silca gel eluting with a mixture petroleum ether/ethyl acetate from 40:1 to 10:1. Collected fractions after solvent evaporation afforded the title compound (D5) (1g).

Reference： [1]Patent: WO2012/76063,2012,A1 .Location in patent: Page/Page column 37-38
[2]Patent: US2013/261100,2013,A1 .Location in patent: Paragraph 0267-0268

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