Name: 1153949-15-5|tert-Butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate|98%
Brand: Ambeed
SKU: A702542
Rating: 95 (25 reviews)

1
[ 3934-20-1 ]
[ 1153949-15-5 ]
[ 1153949-18-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium phosphate In 1,4-dioxane; water at 100℃;	17.3 A mixture of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)azetidine-l-carboxylate (2.6 g, 6.7 mmol), tetrakis(triphenylphosphine)palladium (0.5 g, 0.4 mmol), and potassium phosphate (4.3 g, 20 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was heated at 100 0C overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO/t, and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to give the desired product. (2.10 g, 83%).LCMS (M+H) 375.0.
81.2%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 80℃; for 1h; Inert atmosphere;	6.2 Step 2: Compound 6e(tert-butyl 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate) preparation To compound 6d (2.13g, 5.486mmol), compound 6c (1.31g, 8.777mmol), sodium carbonate (1.16g, 10.972mmol) and 1,1'-bisdiphenylphosphine ferrocene dichloride palladium (401mg , 0.549mmol) was added to dioxane (120ml) and water (20ml), replaced with nitrogen several times, then heated to 80°C and stirred for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=0%-42%) to obtain the target compound (compound 6e, 1.67 g, yield 81.2%) as a pale yellow solid

Reference： [1]Current Patent Assignee: INCYTE CORP - WO2009/64835, 2009, A1 Location in patent: Page/Page column 44-45
[2]Current Patent Assignee: JIAXING TEKELUO BIOTECHNOLOGY; TECHNODERMA MEDICINES - CN112159394, 2021, A Location in patent: Paragraph 0120-0121; 0124-0125

2
[ 269410-08-4 ]
[ 1153949-11-1 ]
[ 1153949-15-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃;	Step 1: tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl]azetidine-l-carboxylateA mixture of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (2.0 g, 10. mmol), tert-butyl 3-(cyanomethylene)azetidine-l-carboxylate (2.0 g, 10.mmol) (Example 2, Step 2) and l,8-diazabicyclo[5.4.0]undec-7-ene (1 mL, 7 mmol) in acetonitrile (3 mL) was stirred at 50 C overnight. After cooling the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0 - 50%) to afford the desired product (quantitative). LCMS (M+Na)+: m/z = 411.2; (M-C4H9)+: m/z = 333.1.
90.5%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In isopropyl alcohol;Reflux; Inert atmosphere;	tert-Butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3) [0139] To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IPA, 200 mL), 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and <strong>[1153949-11-1]tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate</strong> (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution and the mixture was maintained at reflux for an additional 2-3 hours. After the reaction was complete as monitored by HPLC, n-heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the n-heptane addition. Once n-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with n-heptane (200 mL), and dried under vacuum at 50 C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: 1H NMR (400 MHz, DMSO-d6) delta 8.31 (s, 1H), 7.74 (s, 1H), 4.45-4.23 (m, 2H), 4.23-4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) delta 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 58.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; C19H29BN4O4 (MW 388.27), LCMS (EI) m/e 389 (M++H).
90.5%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In isopropyl alcohol;Reflux;	tert-Butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3) To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IPA, 200 mL), 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and <strong>[1153949-11-1]tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate</strong> (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution is and the mixture was maintained at reflux for an additional 2-3 hours. After the reaction was complete as monitored by HPLC, n-heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the n-heptane addition. Once n-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with n-heptane (200 mL), and dried under vacuum at 50 C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: 1H NMR (400 MHz, DMSO-d6) delta 8.31 (s, 1H), 7.74 (s, 1H), 4.45-4.23 (m, 2H), 4.23-4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) delta 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 58.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; C19H29BN4O4(MW 388.27), LCMS (EI) m/e 389 (M++H).

88%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20 - 30℃;	To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3.06 g, 0.0158 mol) in acetonitrile (50 mL) was added tert-butyl 3-(cyanomethylene)azetidine-l-carboxylate (3.06 g, 0.0158 mol), followed by l,8-diazabicyclo[5.4.0]undec-7-ene (2.36 mL, 0.0158 mol). The resulting mixture was stirred at room temperature overnight. After evaporating to dryness, the residue was purified on silica gel, eluting with 0-100% EtOAc in hexanes, to give the desired product (5.40 g, 88%). LCMS (M+H) 389.1.
85%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	Step B: Preparation of tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)azetidine-l-carboxylate: In a 5L flask, tert-butyl 3- (cyanomethylene)azetidine-l-carboxylate (Preparation F, Step A; 94.2 g, 485 mmol) and 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (85.6 g, 441 mmol) were dissolved in acetonitnle (882 mL). To this was then added DBU (33.0 mL, 220 mmol). The resulting clear orange brown mixture was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated down to remove solvents and afforded a dark reddish- orange oil. Solid crystals formed within a few hours at ambient temperature. This was isolated by washing with cold Et20 and cold EtOAc (carefully to prevent dissolution) to afford 110 g (64% yield) of the title compound. The recrystallization was repeated to give another 13.7 g (8% yield). Additional compound was isolated by purification of the filtrate from the above recrystallization. This was purified by silica chromatography eluting with a 20-50% EtOAc/Hexanes gradient to afford an additional 22.7 g (13%) of the title compound. MS (apci) m/z = 289.2 (M+H-Boc).
84.8%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60℃; for 2h;	A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.990 g, 5.10 mmol), <strong>[1153949-11-1]tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate</strong> (1.00 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60 C. for 2 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product (1.68 g, 84.8%). LCMS cacld. for C15H22BN4O4 (M-55)+: m/z=333.2. Found: 333.1.
78%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 18h;Inert atmosphere;	To a solution of <strong>[1153949-11-1]tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate</strong> (CAS 1153949-11-1, 7.00 g, 36.1 mmol) in MeCN (100 mL) was added 4-pyrazoleboronic acid pinacol ester (7.71 g, 39.7 mmol) and DBU (2.75 g, 18.0 mmol) at about 25 C. After about 18 hrs, the mixture was concentrated and the residue was purified column chromatography to afford the title compound as a white solid (11 g, 78%).1H NMR (400 MHz, CDCl3) delta: 7.92 (s, 1H), 7.86 (s, 1H), 4.40 (m, 2H), 4.21 (m, 2H), 3.52 (s, 2H), 1.44 (s, 9H), 1.32 (s, 12H).LC-MS m/z=333.0 [MH-C4H8]+
59.2%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60℃; for 18h;	To a solution of compound 5-c (6.0 g, 30.93 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.2 g, 47.42 mmol) in acetonitril (60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (10.0 g, 65.79 mmol). The mixture was stirred at 60 C. for 18 hours. The mixture was concentrated in vacuum. To the residue was added 1 N aqueous hydrogen chloride solution (100 mL), then the mixture was extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (60 mL×3) and saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate. The resultant mixture was filtrated, the filtrate was concentrated in vacuum, and the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=3:1) to give a white solid 5-b (7.1 g, yield: 59.2%). LC-MS (ESI): m/z=389 [M+H]+.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 70℃;	To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.0 mmol, Aldrich, Cat. 525057) and <strong>[1153949-11-1]tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate</strong> (0.40 g, 2.0 mmol) in acetonitrile (7 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL, 2.5 mmol). The mixture was stirred at 70 C. overnight. The mixture was concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-90%) to afford the desired product. LCMS (M+Na)+: m/z=411.2.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 15h;	In a 5L flask, tert-butyl 3- (cyanomethylene)azetidine-l-carboxylate (Preparation F, Step A; 94.2 g, 485 mmol) and 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (85.6 g, 441 mmol) were dissolved in acetonitrile (882 mL). To this was then added DBU (33.0 mL, 220 mmol). The resulting clear orange brown mixture was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated down to remove solvents and afforded a dark reddish- orange oil. Solid crystals formed within a few hours at ambient temperature. This was isolated by washing with cold Et20 and cold EtOAc (carefully to prevent dissolution) to afford 110 g (64% yield) of the title compound. The recrystallization was repeated to give another 13.7 g (8% yield). Additional compound was isolated by purification of the filtrate from the above recrystallization. This was purified by silica chromatography eluting with a 20-50% EtOAc/Hexanes gradient to afford an additional 22.7 g (13%) of the title compound. MS (apci) m/z = 289.2 (M+H-Boc).
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 12h;	A mixture of 4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole (19.4 mg, 0.10 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 13 mL, 0.209 mmol), and tert-butyl 3- (cyanomethylene)azetidine-1-carboxylate (19.4 mg, 0.10 mmol) in acetonitrile (0.5 mL) was stirred at room temperature for 12 hours. The resulting mixture was quenched with saturatedaqueous NH4C1, and extracted with DCM (3x2 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was used directly in the next step without further purification.

Reference： [1]Patent: WO2012/177606,2012,A1 .Location in patent: Page/Page column 108
[2]Patent: US2014/256941,2014,A1 .Location in patent: Paragraph 0139
[3]Patent: US2019/233392,2019,A1 .Location in patent: Paragraph 0096-0097
[4]Patent: WO2009/64835,2009,A1 .Location in patent: Page/Page column 44
[5]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 85
[6]Patent: US2014/343030,2014,A1 .Location in patent: Paragraph 0420; 0423; 0424
[7]Patent: US2017/240552,2017,A1 .Location in patent: Paragraph 0264; 0265; 0266; 0267
[8]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0134; 0136
[9]Patent: US2012/165305,2012,A1 .Location in patent: Page/Page column 49
[10]Patent: WO2013/55645,2013,A1 .Location in patent: Paragraph 00369
[11]Patent: WO2016/134320,2016,A1 .Location in patent: Page/Page column 117; 118

3
[ 398489-26-4 ]
[ 1153949-15-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0 - 20 °C 1.2: 0 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 15 h / 20 °C
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 - 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 50 °C
	Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 2 h / 20 °C / Cooling with ice 1.2: 16 h / 0 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 15 h / 20 °C

	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 - 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 2 h / 60 °C
	Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran; hexane / 1 h / 0 - 20 °C / Inert atmosphere 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 18 h / 60 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/130146, 2011, A1
[2]Current Patent Assignee: INCYTE CORP - WO2012/177606, 2012, A1
[3]Current Patent Assignee: PFIZER INC - WO2013/55645, 2013, A1
[4]Current Patent Assignee: INCYTE CORP - US2014/343030, 2014, A1
[5]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2015/336982, 2015, A1

4
[ 1153949-15-5 ]
[ 1339888-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium phosphate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane; water / 6 h / 70 °C 2: hydrogenchloride / 1,4-dioxane / Inert atmosphere; Cooling with water