Name: 91678-81-8|3,5-Dimethylpyrazin-2-amine|98%
Brand: Ambeed
SKU: A560818
Price: 20.0 USD
Availability: InStock
Rating: 91 (29 reviews)

1
[ 91678-81-8 ]
[ 60187-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride Diazotization;

Reference： [1]Sharp; Spring [Journal of the Chemical Society, 1951, p. 932]

2
[ 412341-23-2 ]
[ 91678-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium dithionite

Reference： [1]Sharp; Spring [Journal of the Chemical Society, 1951, p. 932]

Yield	Reaction Conditions	Operation in experiment
	3-Chlor-2,6-dimethylpyrazin, 28percentaq.NH3 (30h 200grad, Autoklav);
	(yield)17percent;
	3-Iod-2,6-dimethylpyrazin, 28percentaq.NH3 (15h 200grad, Autoklav);

(yield)23percent;

4
[ 91678-81-8 ]
[ 183610-69-7 ]
3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-6,8-dimethyl-imidazo[1,2-<i>a</i>]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 60℃;

Reference： [1]Almansa; De Arriba; Cavalcanti; Gómez; Miralles; Merlos; García-Rafanell; Forn [Journal of Medicinal Chemistry, 2001, vol. 44, # 3, p. 350 - 361]

5
[ 91678-81-8 ]
[ 302964-07-4 ]
N-(2-chloro-6-methylphenyl)-2-[(3,5-dimethyl-2-pyrazinyl)amino]-5-thiazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran Heating;

Reference： [1]Das, Jagabandhu; Chen, Ping; Norris, Derek; Padmanabha, Ramesh; Lin, James; Moquin, Robert V.; Shen, Zhongqi; Cook, Lynda S.; Doweyko, Arthur M.; Pitt, Sidney; Pang, Suhong; Shen, Ding Ren; Fang, Qiong; De Fex, Henry F.; McIntyre, Kim W.; Shuster, David J.; Gillooly, Kathleen M.; Behnia, Kamelia; Schieven, Gary L.; Wityak, John; Barrish, Joel C. [Journal of Medicinal Chemistry, 2006, vol. 49, # 23, p. 6819 - 6832]

6
[ 91678-81-8 ]
[ 85-44-9 ]
3,5-dimethyl-2-phthalimidopyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; chlorobenzene	1.a (a) (a) Preparation of 3,5-dimethyl-2-phthalimidopyrazine 481 g of phthalic anhydride were added to a solution of 307 g of 2-amino-3,5-dimethylpyrazine and 1100 g of chlorobenzene at 25° C., and the mixture was heated at the boil for 6 hours, the water of reaction being removed continuously. When the reaction was complete, 1 l of water was added to the resulting brown solution, after which the chlorobenzene was distilled off together with water, while keeping the volume of water constant. A further 0.5 l of water was then added to the remaining aqueous solution, and the mixture was heated to the boil and then cooled to 25°-30° C., the product being precipitated. The mixture obtained was stirred for a further 2 hours at this temperature, after which the product was isolated and taken up in 1.5 l of boiling methanol, the solution was cooled to 0° C. and the product was then filtered off. The yield was virtually quantitative, and the melting point was 142°-143° C.

Reference： [1]Current Patent Assignee: BASF SE - US4692527, 1987, A

7
[ 91678-81-8 ]
[ 1097180-24-9 ]
[ 1227852-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 150℃; for 0.5h;	1 Example 1 6,8-dimethyl-2-({(2S)-1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2-piperidinyl}methyl)imidazo[1,2-a]pyrazine (HCl salt) (E1) To a solution of 1,1-dimethylethyl(2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.140 g, 0.44 mmol) in DMF (2 ml) was added 3,5-dimethyl-2-pyrazinamine (0.054 g, 0.44 mmol) and the mixture was stirred at 150° C. for 30 min. The reaction mixture was charged into a SCX column and was eluted with methanol and ammonia 2 M in methanol. Collected fractions gave 0.115 g of a crude containing the desired 6,8-dimethyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrazine. UPLC: rt=0.34, peak observed: 245 (M+1). C14H20N4 requires 244. Into a 7 ml screw capped vial 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (0.114 g, 0.52 mmol) was dissolved in DCM (1 ml), Oxalyl chloride (0.100 ml, 1.14 mmol) then DMF (0.036 ml, 0.47 mmol) were added and the resulting mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the resulting yellow solid dissolved in DCM (1 ml) and added dropwise to the solution containing the crude (0.115 g) 6,8-dimethyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrazine and TEA (0.197 ml, 0.47 mmol) in DCM (1 ml) cooled at 0° C. The ice-bath was removed and the reaction mixture left under stirring at rt for 1 h. DCM was added and the mixture washed with a saturated NaHCO3 aqueous solution, the organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (Biotage 25 M, DCM/MeOH, 90/01) and by fraction lynx (basic method). The free base of the title compound was obtained (0.039 g, 0.079 mmol, 20% yield from D2, three steps) as a yellow solid. UPLC: rt=0.58, peak observed: 446 (M+1). C25H27N5OS requires 445. 1H NMR [the product is present as a mixture of conformers (ratio c.ca 60/40)] (500 MHz, DMSO-d6). The free base (0.037 g, 0.08 mmol) was transferred into a 7 ml screw capped vial with anhydrous DCM (1 ml) and the solution cooled to 0° C. HCl (0.125 ml of a 1 M solution in Et2O, 0.13 mmol) was added dropwise and the mixture stirred for 15 min. The solvent was removed under reduced pressure and the resulting solid triturated with anhydrous Et2O. The title compound was obtained (0.041 g, 0.08 mmol, 98% yield) as a white solid. UPLC: rt=0.58, peak observed: 446 (M+1-HCl). C25H28ClN5OS requires 482.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2010/160345, 2010, A1 Location in patent: Page/Page column 7-8

8
[ 91678-81-8 ]
[ 1097180-24-9 ]
[ 13743-09-4 ]
[ 1227852-62-1 ]

Yield	Reaction Conditions	Operation in experiment
20%		Example 1: 6,8-dimethyl-2-({(2S)-l-[(2-methyl-5-phenyl-l,3-thiazol-4-yl)carbonyl]-2- piperidinyl}methyl)imidazo[l,2-alpha]pyrazine (HCl salt) (El):To a solution of 1,1-dimethylethyl (25)-2-(3-bromo-2-oxopropyl)-l-piperidinecarboxylate D2 (0.140 g, 0.44 mmol) in DMF (2 ml) was added 3,5-dimethyl-2-pyrazinamine (0.054 g, 0.44 mmol) and the mixture was stirred at 150 0C for 30 min. The reaction mixture was charged into a SCX column and was eluted with methanol and ammonia 2 M in methanol. Collected fractions gave 0.115 g of a crude containing the desired 6,8-dimethyl-2-[(25)-2- piperidinylmethyl]imidazo[l,2-alpha]pyrazine. UPLC: rt = 0.34, peak observed: 245 (M+l). C14H2ON4 requires 244. Into a 7 ml screw capped vial 2-methyl-5-phenyl-l,3-thiazole-4- carboxylic acid (0.114 g, 0.52 mmol) was dissolved in DCM (1 ml), Oxalyl chloride (0.100 ml, 1.14 mmol) then DMF (0.036 ml, 0.47 mmol) were added and the resulting mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the resulting yellow solid dissolved in DCM (1 ml) and added dropwise to the solution containing the crude (0.115 g) 6,8-dimethyl-2-[(25)-2-piperidinylmethyl]imidazo[l,2-alpha]pyrazine and TEA (0.197 ml, 0.47 mmol) in DCM (1 ml) cooled at 0 0C. The ice-bath was removed and the reaction mixture left under stirring at rt for 1 h. DCM was added and the mixture washed with a saturated NaHCO3 aqueous solution, the organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (Biotage 25 M, DCM/MeOH, 90/01) and by fraction lynx (basic method). The free base of the title compound was obtained (0.039 g, 0.079 mmol, 20% yield from D2, three steps) as a yellow solid. UPLC: rt = 0.58, peak observed: 446 (M+l). C25H27N5OS requires 445. 1H NMR [the product is present as a mixture of conformers (ratio c.ca 60/40)] (500 MHz, DMSO-d6). The free base (0.037 g, 0.08 mmol) was transferred into a 7 ml screw capped vial with anhydrous DCM (1 ml) and the solution cooled to 0 0C. HCl (0.125 ml of a 1 M solution in Et2O, 0.13 mmol) was added dropwise and the mixture stirred for 15 min. The solvent was removed under reduced pressure and the resulting solid triturated with anhydrous Et2O. The title compound was obtained (0.041 g, 0.08 mmol, 98% yield) as a white solid. UPLC: rt = 0.58, peak observed: 446 (M+1-HC1). C25H28ClN5OS requires 482.

Reference： [1]Patent: WO2010/60470,2010,A1 .Location in patent: Page/Page column 17

9
[ 91678-81-8 ]
[ 1355999-71-1 ]
[ 1447364-31-9 ]

Yield	Reaction Conditions	Operation in experiment
249 mg	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 130℃; for 3h; Molecular sieve; Reflux; Microwave irradiation;	Int-2 Intermediate Example lnt-2: ferf-Butyl {1-[4-(6,8-dimethyl-3-phenylimidazo[1,2-a]pyrazin-2-yl)phenyl]- c clobutyl}carbamate Intermediate Example lnt-2: ferf-Butyl {1-[4-(6,8-dimethyl-3-phenylimidazo[1,2-a]pyrazin-2-yl)phenyl]- c clobutyl}carbamate To a mixture of crude fert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)- carbamate [lnt-1-A] (770 mg, 1.61 mmol, 1.0 eq), 3,5-dimethylpyrazin-2-amine (CAS-Nr. 91678-81-8, 218 mg, 1.77 mmol, 1.1 eq) and diisopropylethylamine (0.28 mL, 1.61 mmol, 1.0 eq) in 10 mL isopropanol was added 3A molsieves. The reaction mixture was heated to reflux temperature for 2h. No conversion was observed under these conditions (UPLC-MS). Therefore, the reaction mixture was heated to 130 for 1 h under microwave conditions ( single mode microwave oven). The reaction mixture was filtered to remove the molsieve and the filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera, 25 g Snap cartridge, DCM -> DCM/ethanol 95/5) to deliver 249 mg (31%) of the title compound. UPLC-MS (Method 1): RT = 1.40 min; m/z = 469 (M+H) +.

Reference： [1]Current Patent Assignee: BAYER AG - WO2013/104610, 2013, A1 Location in patent: Page/Page column 50-51

10
[ 91678-81-8 ]
[ 638-07-3 ]
[ 1446334-80-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	In ethanol at 100℃; for 16.5h; Inert atmosphere; High pressure;
5 g	In ethanol at 100℃; for 16h;	5.2 Part 2: Preparation of ethyl 2-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)acetate A 75 mL pressure vessel was charged with ethyl 4-chloro-3-oxo-butyrate (4 g, 24.4 mmol), 3,5-dimethylpyrazin-2-amine (3 g, 24.4 mmol) and 200 proof ethanol (24 mL). After stirring at 100 °C in an oil bath for 16 hours, the reaction mixture was concentrated, diluted with dichloromethane and a saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with a gradient mixture of dichloromethane and methanol yielded ethyl 2-(6,8- dimethylimidazo[l,2-a]pyrazin-2-yl)acetate as a light brown solid (5 g). MS m/z 234 [M+H]+.

Reference： [1]Ratni, Hasane; Karp, Gary M.; Weetall, Marla; Naryshkin, Nikolai A.; Paushkin, Sergey V.; Chen, Karen S.; McCarthy, Kathleen D.; Qi, Hongyan; Turpoff, Anthony; Woll, Matthew G.; Zhang, Xiaoyan; Zhang, Nanjing; Yang, Tianle; Dakka, Amal; Vazirani, Priya; Zhao, Xin; Pinard, Emmanuel; Green, Luke; David-Pierson, Pascale; Tuerck, Dietrich; Poirier, Agnes; Muster, Wolfgang; Kirchner, Stephan; Mueller, Lutz; Gerlach, Irene; Metzger, Friedrich [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6086 - 6100]
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2013/130689, 2013, A1 Location in patent: Paragraph 00936; 00937

11
[ 91678-81-8 ]
[ 1453265-77-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ethanol / 16 h / 100 °C 2: piperidine; acetic acid / ethanol / 2 h / 150 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/130689, 2013, A1

12
[ 91678-81-8 ]
[ 1453265-07-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethanol / 16 h / 100 °C 2: piperidine; acetic acid / ethanol / 2 h / 150 °C / Microwave irradiation 3: hydrogenchloride / dichloromethane; 1,4-dioxane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/130689, 2013, A1

13
[ 91678-81-8 ]
[ 1448704-72-0 ]
3-(6,8-dimethylimidazo [1,2-a]pyrazin-2-yl)-7-fluoro-1H-isochromen-1-one hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	In acetonitrile at 100℃; Sealed tube;	6.D Preparation of Cpd 65 Step D: The bromoketone intermediate obtained in Step C (1.43 g, 5.0 mmol) was mixed with 3,5-dimethylpyrazin-2-amine (0.67 g, 5.5 mmol) and acetonitrile (10.0 mL) in a sealed tube. The mixture was stirred at 100 °C overnight and cooled to room temperature. Ethyl acetate (20 mL) was added and the precipitate was collected, washed with ethyl acetate and then dried, providing 3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-fluoro-lH-isochromen-l-one hydrobromide (1.81 g, 93%). MS m/z 310.3 [M+H]+.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1 Location in patent: Paragraph 00632

14
[ 91678-81-8 ]
[ 1448704-72-0 ]
[ 1448703-61-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetonitrile / 100 °C / Sealed tube 2: 1-methyl-pyrrolidin-2-one / 24 h / 180 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1

15
[ 91678-81-8 ]
[ 1448703-92-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: acetonitrile / 100 °C / Sealed tube 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tri tert-butylphosphoniumtetrafluoroborate; potassium fluoride / tetrahydrofuran / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C 4: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1

16
[ 91678-81-8 ]
BrH*C₂₇H₂₈N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetonitrile / 100 °C / Sealed tube 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tri tert-butylphosphoniumtetrafluoroborate; potassium fluoride / tetrahydrofuran / 60 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1

17
[ 91678-81-8 ]
[ 1448703-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: acetonitrile / 100 °C / Sealed tube 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tri tert-butylphosphoniumtetrafluoroborate; potassium fluoride / tetrahydrofuran / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1

18
[ 91678-81-8 ]
[ 1448704-80-0 ]
[ 1448704-81-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	In acetonitrile at 100℃; Sealed tube;	12.2.D Part 2, Step D: The intermediate obtained in Part 2, Step C (4.84 g, 14.0 mmol) was mixed with 3,5-dimethylpyrazin-2-amine (1.81 g, 14.7 mmol), obtained in Part 1, and acetonitrile (30 mL) in a sealed tube. The mixture was stirred at 100 °C overnight and cooled to room temperature. Ethyl acetate (60 mL) was added and the precipitate was collected, then washed with ethyl acetate and dried, providing 3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7- bromo-lH-isochromen-l-one hydrobromide (5.04 g, 80%). MS m/z 370.2, 372.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50-8.54 (1H, m), 8.34 (1H, s), 8.21 (1H, d, J=1.89 Hz), 8.02 (1H, dd, J=8.35, 2.05 Hz), 7.80 (1H, d, J=8.51 Hz), 7.51-7.57 (1H, m), 2.79 (3H, s), 2.41 (3H, d, J=0.95 Hz).

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1 Location in patent: Paragraph 00665

19
[ 108-50-9 ]
[ 91678-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sulfuryl dichloride / N,N-dimethyl-formamide / 2.5 h / 60 °C / Cooling with ice 2: copper(II) oxide; ammonium hydroxide / 72 h / 150 °C / Sealed tube

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2013/112788, 2013, A1

20
[ 38557-72-1 ]
[ 91678-81-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With ammonium hydroxide; copper(II) oxide; at 150℃; for 72.0h;Sealed tube;	Part 1, Step B: A mixture of <strong>[38557-72-1]2-chloro-3,5-dimethylpyrazine</strong> (28.5 g, 0.2 mol), prepared above, CuO (0.8 g, 0.01 mol) and concentrated aqueous NH3 (28-30 %, 150 mL) was stirred in a sealed pressure vessel at 150 C for 3 days. After cooling, the mixture was concentrated to dryness and the residue was treated with ethyl acetate (500 mL), then stirred for 15 minutes and filtered. The precipitate was washed with additional ethyl acetate (about 1.5 L) until the starting material was no longer detected in the filtrate. The filtrates were combined and concentrated. The residue was chromatographed on a silica gel column (MeOH/CH2Cl2, 0-10%) to furnish a yellow/brownish solid (20.7 g, 84%). 1H NMR (500 MHz, CHLOROFORM-^) delta ppm 7.68 (1H, s), 2.46 (3H, s), 2.42 (3H, d, J=0.63 Hz).

Reference： [1]Patent: WO2013/112788,2013,A1 .Location in patent: Paragraph 00661

21
[ 91678-81-8 ]
[ 70-23-5 ]
ethyl 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylate hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.3%	In 1,2-dimethoxyethane at 0 - 20℃; for 2h;	B.1.a.1 a) step1 : Ethyl 6,8-dimethylimidazo[l,2-a]pyrazine-2-carboxylate hydrobromide a) step1 : Ethyl 6,8-dimethylimidazo[l,2-a]pyrazine-2-carboxylate hydrobromide To a solution of 3,5-dimethylpyrazin-2-amine (200 mg, 1.62 mmol) in DME (6.00 ml) was added ethyl3-bromo-2-oxopropanoate (380 mg, 245 f..Ll, 1.95 mmol) at 0°C. The mixture wasstirred for 2 hours at room temperature. The suspension was filtered and washed withdimethoxyethane. The filtrate was taken in ethanol ( 4 ml) and refluxed for 1.5 hours. Thereaction mixture was cooled to room temperature, filtered and washed with ethanol to provide 323 mg (66.3 %) of the title compound as a light yellow solid. MS (m/e): 220.1 (M+H+)

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; PTC THERAPEUTICS INC - WO2014/209841, 2014, A2 Location in patent: Page/Page column 40

22
[ 91678-81-8 ]
7-bromo-3-(2-bromoacetyl)-2H-chromen-2-one [ No CAS ]
7-bromo-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In acetonitrile at 90℃; for 4h;
88%	In acetonitrile at 90℃; for 4h;	48.A Step A: A mixture of 7-bromo-3-(2-bromoacetyl)-2H-chromen-2-one (2.0 g, 5.78 mmol, prepared in Example 37, Step B), 2-amino-3,5-dimethylpyrazine (825 mg, 6.71 mmol) and CH3CN (22 mL) was heated at 90° C. for 4 h. The addition of an aqueous saturated NaHCO3 solution to the mixture resulted in the formation of a precipitate. The precipitate was collected by vacuum filtration and triturated with 1:1 hexane/acetone, yielding 7-bromo-3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2H-chromen-2-one (1.9 g, 88%) as an orange solid. 1H NMR (500 MHz, DMSO-d6): δ 8.81 (1H, s), 8.61 (1H, s), 8.31 (1H, s), 7.93 (1H, d, J=8 Hz), 7.76 (1H, d, J=1.5 Hz), 7.58 (1H, dd, J=8 Hz, 1.5 Hz), 2.76 (3H, s), 2.37 (3H, s).

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]
[2]Current Patent Assignee: PTC THERAPEUTICS INC; ROCHE HOLDING AG - US9617268, 2017, B2 Location in patent: Page/Page column 381

23
[ 91678-81-8 ]
C₁₄H₁₃BrO₄ [ No CAS ]
C₂₀H₁₉N₃O₃*BrH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
320 mg	In acetonitrile at 120℃; for 0.333333h; Sealed tube;

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]

24
[ 91678-81-8 ]
[ 1446333-79-4 ]
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-2H-chromen-2-one hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In acetonitrile at 120℃; for 0.333333h; Sealed tube;
90%	In acetonitrile at 120℃; for 0.333333h; Sealed tube;	43.A Step A: A mixture of 3-(2-bromoacetyl)-7-fluoro-2H-chromen-2-one (0.684 g, 2.4 mmol, prepared in Example 36, Part 2) and 3,5-dimethylpyrazin-2-amine (0.246 g, 2.0 mmol) in CH3CN (10 mL) was stirred at 120° C. in a sealed tube for 20 min. The mixture was cooled to room temperature and diluted with Et2O to produce a precipitate. The solid was collected by vacuum filtration, washed with Et2O and dried to give 3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-2H-chromen-2-one hydrobromide (0.7 g, 90%) as a tan solid. MS m/z 310.1 [M+H]+.

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]
[2]Current Patent Assignee: PTC THERAPEUTICS INC; ROCHE HOLDING AG - US9617268, 2017, B2 Location in patent: Page/Page column 375; 376

25
[ 91678-81-8 ]
tert-butyl 3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-3-oxopropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 1,2-dimethoxyethane / 0.75 h / 20 °C 1.2: 3 h / 90 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 1.5 h / -50 °C / Inert atmosphere

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]

26
[ 91678-81-8 ]
2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 1,2-dimethoxyethane / 0.75 h / 20 °C 1.2: 3 h / 90 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 1.5 h / -50 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid; trimethyl orthoformate / methanol / 1 h / 65 °C 3.2: 1 h / 150 °C

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]

27
[ 91678-81-8 ]
2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(piperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: 1,2-dimethoxyethane / 0.75 h / 20 °C 1.2: 3 h / 90 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 1.5 h / -50 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid; trimethyl orthoformate / methanol / 1 h / 65 °C 3.2: 1 h / 150 °C 4.1: dimethyl sulfoxide / 1.5 h / 120 °C

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]

28
[ 91678-81-8 ]
[ 70-23-5 ]
ethyl 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 2-amino-3,5-dimethyl pyrazine; ethyl Bromopyruvate In 1,2-dimethoxyethane at 20℃; for 0.75h; Stage #2: In ethanol at 90℃; for 3h;

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]

29
[ 91678-81-8 ]
[ 1448704-72-0 ]
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-1H-iso-chromen-1-one hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	In acetonitrile at 100℃; for 16h; Sealed tube;

Reference： [1]Woll, Matthew G.; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G.; Naryshkin, Nikolai A.; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M. [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6070 - 6085]

30
[ 91678-81-8 ]
[ 1453265-64-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethanol / 16.5 h / 100 °C / Inert atmosphere; High pressure 2: acetic acid; piperidine / ethanol / 4 h / Heating; Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Inert atmosphere

Reference： [1]Ratni, Hasane; Karp, Gary M.; Weetall, Marla; Naryshkin, Nikolai A.; Paushkin, Sergey V.; Chen, Karen S.; McCarthy, Kathleen D.; Qi, Hongyan; Turpoff, Anthony; Woll, Matthew G.; Zhang, Xiaoyan; Zhang, Nanjing; Yang, Tianle; Dakka, Amal; Vazirani, Priya; Zhao, Xin; Pinard, Emmanuel; Green, Luke; David-Pierson, Pascale; Tuerck, Dietrich; Poirier, Agnes; Muster, Wolfgang; Kirchner, Stephan; Mueller, Lutz; Gerlach, Irene; Metzger, Friedrich [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6086 - 6100]

31
[ 91678-81-8 ]
C₂₆H₃₀N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ethanol / 16.5 h / 100 °C / Inert atmosphere; High pressure 2: acetic acid; piperidine / ethanol / 4 h / Heating; Inert atmosphere

Reference： [1]Ratni, Hasane; Karp, Gary M.; Weetall, Marla; Naryshkin, Nikolai A.; Paushkin, Sergey V.; Chen, Karen S.; McCarthy, Kathleen D.; Qi, Hongyan; Turpoff, Anthony; Woll, Matthew G.; Zhang, Xiaoyan; Zhang, Nanjing; Yang, Tianle; Dakka, Amal; Vazirani, Priya; Zhao, Xin; Pinard, Emmanuel; Green, Luke; David-Pierson, Pascale; Tuerck, Dietrich; Poirier, Agnes; Muster, Wolfgang; Kirchner, Stephan; Mueller, Lutz; Gerlach, Irene; Metzger, Friedrich [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6086 - 6100]

32
[ 91678-81-8 ]
[ 1448704-71-9 ]
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-fluoro-1H-iso-chromen-1-one hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 3-acetyl-7-fluoro-1H-isochromen-1-one With bromine In chloroform at 20℃; for 1h; Inert atmosphere; Stage #2: 2-amino-3,5-dimethyl pyrazine In acetonitrile at 90℃; for 24h; Inert atmosphere;

Reference： [1]Ratni, Hasane; Karp, Gary M.; Weetall, Marla; Naryshkin, Nikolai A.; Paushkin, Sergey V.; Chen, Karen S.; McCarthy, Kathleen D.; Qi, Hongyan; Turpoff, Anthony; Woll, Matthew G.; Zhang, Xiaoyan; Zhang, Nanjing; Yang, Tianle; Dakka, Amal; Vazirani, Priya; Zhao, Xin; Pinard, Emmanuel; Green, Luke; David-Pierson, Pascale; Tuerck, Dietrich; Poirier, Agnes; Muster, Wolfgang; Kirchner, Stephan; Mueller, Lutz; Gerlach, Irene; Metzger, Friedrich [Journal of Medicinal Chemistry, 2016, vol. 59, # 13, p. 6086 - 6100]

33
[ 91678-81-8 ]
tert-butyl 2-(3-(2-bromoacetyl)-2-oxo-2H-chromen-7-yloxy)ethylcarbamate [ No CAS ]
tert-butyl 2-(3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7-yloxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In acetonitrile at 100℃; for 16h;	74.D Step D: Following the procedure in Example 43, Step A, tert-butyl 2-(3-(2-bromoacetyl)-2-oxo-2H-chromen-7-yloxy)ethylcarbamate (108 mg, 0.25 mmol) and 3,5-dimethylpyrazin-2-amine (32 mg, 0.25 mmol) in CH3CN (2.0 mL) provided tert-butyl 2-(3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7-yloxy)ethylcarbamate (88 mg, 80%). MS m/z 451.3 [M+H]+.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC; ROCHE HOLDING AG - US9617268, 2017, B2 Location in patent: Page/Page column 417; 418

34
[ 91678-81-8 ]
3-(2-bromoacetyl)-7-(2-hydroxyethoxy)-2H-chromen-2-one [ No CAS ]
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(2-hydroxyethoxy)-2H-chromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In acetonitrile at 100℃;	75.C Step C: Following the procedure in Example 43, Step A, 3-(2-bromoacetyl)-7-(2-hydroxyethoxy)-2H-chromen-2-one (0.26 g, 0.8 mmol) and 3,5-dimethylpyrazin-2-amine (0.10 g, 0.8 mmol) in CH3CN (2.0 mL) provided 3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(2-hydroxyethoxy)-2H-chromen-2-one (0.32 g, 88%). MS m/z 352.2 [M+H]+.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC; ROCHE HOLDING AG - US9617268, 2017, B2 Location in patent: Page/Page column 419; 420

35
[ 91678-81-8 ]
3-(2-bromoacetyl)-7-(hydroxymethyl)-2H-chromen-2-one [ No CAS ]
3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(hydroxymethyl)-2H-chromen-2-one hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	In acetonitrile at 80℃; for 16h;	77.D Step D: 3-(2-Bromoacetyl)-7-(hydroxymethyl)-2H-chromen-2-one (2.1 g, 7.0 mmol) was combined with 3,5-dimethylpyrazin-2-amine (940 mg, 7.7 mmol) in CH3CN (10 mL). The mixture was heated at 80° C. for 16 h. The mixture was cooled to room temperature and filtered. The solid material was washed with CH3CN and dried to afford 3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-7-(hydroxymethyl)-2H-chromen-2-one hydrobromide (1.0 g, 35%) as a tan powder. MS m/z 322.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 8.91 (1H, s), 8.73 (1H, s), 8.45 (1H, s), 7.96 (1H, d, J=8.1 Hz), 7.41 (1H, s), 7.37 (1H, d, J=8.1 Hz), 4.65 (2H, s), 2.83 (3H, s), 2.42 (3H, s).

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC; ROCHE HOLDING AG - US9617268, 2017, B2 Location in patent: Page/Page column 422; 423

36
[ 91678-81-8 ]
tert-butyl 4-(7-(2-bromoacetyl)-5-fluorocinnolin-3-yl)piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-(7-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-fluorocinnolin-3-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	In ethanol at 90℃; for 4h;	39.C Step C: tert -Butyl 4-(7-(2-bromoacetyl)-5-fluorocinnolin-3-yl)piperidine-l-carboxylate (477 mg, 1.06 mmol) was combined with 3, 5-dimethylpyrazin-2-amine (234 mg, 1.9 mmol) in EtOH (20 mL). The mixture was stirred at 90 °C for 4 h. Then the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 30-50% EtOAc in CH2C12 to yield tert-butyl 4-(7-(6,8-dimethylimidazo[l,2- a]pyrazin-2-yl)-5-fluorocinnolin-3-yl)piperidine-l-carboxylate (270 mg, 53%). MS m/z 477 .2 [M+H]+.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2018/226622, 2018, A1 Location in patent: Page/Page column 215

37
[ 91678-81-8 ]
1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 70 °C 4: trifluoroacetic acid / dichloromethane / 16 h / 0 - 20 °C 5: dichloromethane / 16 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1.1: <i>tert</i>-butyl alcohol / 19 h / 80 °C 2.1: sodium hydrogencarbonate / water / 0.55 h / 20 °C 3.1: acetic acid; bromine / 1 h / 20 °C 4.1: 2-methyltetrahydrofuran / 5 h / Inert atmosphere 4.2: 41 h / Inert atmosphere

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US2020/239481, 2020, A1

38
[ 91678-81-8 ]
3-bromo-2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C
	Multi-step reaction with 3 steps 1: <i>tert</i>-butyl alcohol / 19 h / 80 °C 2: sodium hydrogencarbonate / water / 0.55 h / 20 °C 3: acetic acid; bromine / 1 h / 20 °C
	Multi-step reaction with 2 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US2020/239481, 2020, A1
[3]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1

39
[ 91678-81-8 ]
tert-butyl N-[2-[4-(2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 70 °C
	Multi-step reaction with 3 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 70 °C

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1

40
[ 91678-81-8 ]
2-[4-(2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazin-3-yl)phenyl]ethanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 70 °C 4: trifluoroacetic acid / dichloromethane / 16 h / 0 - 20 °C
	Multi-step reaction with 4 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 70 °C 4: trifluoroacetic acid / dichloromethane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1

41
[ 91678-81-8 ]
1-[2-[4-(2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazin-3-yl)phenoxy]ethyl]-3-(p-tolylsulfonyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 80 °C

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1

42
[ 91678-81-8 ]
1-[2-[4-(2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(4-fluorophenyl)sulfonyl urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: ethanol / 16 h / 65 °C 2: acetic acid; bromine / 2 h / 20 °C 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane / 16 h / 70 °C 4: trifluoroacetic acid / dichloromethane / 16 h / 0 - 20 °C 5: dichloromethane / 16 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1

43
[ 91678-81-8 ]
[ 816-40-0 ]
2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	In ethanol at 65℃; for 16h;	1 Intermediate 1: 2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine Dissolved 3,5-dimethylpyrazin-2-amine (10.0 g, 81.7 mmol) in EtOH (500 mL). To this solution added 1-bromo-2-butanone (12.4 mL, 122 mmol). Heated to 65° C. for 16 hours. Removed the solvent in vacuo. Brought up residue in H2O (500 mL) and extracted with EtOAc (3*500 mL). Washed the combined organics with brine and dried over Na2SO4. Filtered and removed solvent. Purified using normal phase chromatography (0-10% MeOH in DCM) to yield 8.7 g (49.5 mmol, 60%) of product; 1H NMR (400 MHz, CHLOROFORM-d) δ=7.70 (s, 1H), 7.33 (s, 1H), 2.95-2.76 (m, 5H), 2.50-2.40 (m, 3H), 1.34 (t, J=7.6 Hz, 3H); LCMS (M/Z): 176.2 (M+H).
60%	In ethanol at 65℃; for 16h;	1 Intermediate 1: 2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazine Dissolved 3,5-dimethylpyrazin-2-amine (10.0 g, 81.7 mmol) in EtOH (500 mL). To this solution added 1-bromo-2-butanone (12.4 mL, 122 mmol). Heated to 65 °C for 16 hours. (0225) Removed the solvent in vacuo. Brought up residue in H2O (500 mL) and extracted with EtOAc (3 x 500 mL). Washed the combined organics with brine and dried over Na2SO4. Filtered and removed solvent. Purified using normal phase chromatography (0-10% MeOH in DCM) to yield 8.7 g (49.5 mmol, 60%) of product; 1H NMR (400 MHz, CHLOROFORM-d) d = 7.70 (s, 1H), 7.33 (s, 1H), 2.95 - 2.76 (m, 5H), 2.50 - 2.40 (m, 3H), 1.34 (t, J = 7.6 Hz, 3H); LCMS (M/Z): 176.2 (M + H).

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US10239885, 2019, B1 Location in patent: Page/Page column 18-19
[2]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1 Location in patent: Paragraph 0115-0118

44
[ 91678-81-8 ]
2-bromo-1-(5-bromothiazolo[5,4-d]thiazol-2-yl)ethanone [ No CAS ]
5-bromo-2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)thiazolo[5,4-d]thiazolehydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.5%	In acetonitrile at 90℃; for 3h;	14.3 Step 3: A mixture of 2-bromo-l-(5-bromothiazolo[5,4-d]thiazol-2-yl)ethanone (121 mg, 0.35 mmol), 3,5-dimethylpyrazin-2-amine (44 mg, 0.36 mmol) and acetonitrile (2.0 mL) was stirred at 90 °C for 3 h and diluted with EtOAc. The precipitate was collected and washed with EtOAc and dried to provide 5-bromo-2-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)thiazolo[5,4-d]thiazole hydrobromide (140 mg, 88.5%). LC-MS 366.2, 368.2 [M+H]+ , RT 1.49 min.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2020/5882, 2020, A1 Location in patent: Page/Page column 147

45
[ 91678-81-8 ]
tert-butyl 4-[6-(2-bromoacetyl)-4-fluoro-1,3-benzothiazol-2-yl]piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-[6-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluoro-1,3-benzothiazol-2-yl]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 2h;	21.5 Step 5 A mixture of tert-butyl 4-[6-(2-bromoacetyl)-4-fluoro-1,3-benzothiazol-2-yl]piperidine-1- carboxylate (62 mg, 0.14 mmol, 1.0 eq.), 3,5-dimethylpyrazin-2-amine (20 mg, 0.16 mmol, 1.2 eq.) and DIPEA (18 mg, 0.024 mL, 0.14 mmol, 1.0 eq.) in acetonitrile (0.5 mL) was heated at 90 °C for 2 h. Aqueous work up followed by purification with ethyl acetate in dichloromethane (0 to 100% gradient) provided tert-butyl 4-[6-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluoro-1,3- benzothiazol-2-yl]piperidine-1-carboxylate (38 mg, 58%). MS m/z 482.3 [M+H]+.

Reference： [1]Current Patent Assignee: PTC THERAPEUTICS INC - WO2020/5877, 2020, A1 Location in patent: Page/Page column 192-193

46
[ 91678-81-8 ]
[ 463-71-8 ]
[ 1173984-08-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	With pyridine In dichloromethane at 20℃; for 1h;	2-lsothiocvanato-3,5-dimethyl-pyrazine To a solution of pyridine (0.51 ml, 6.20 mmol) and 3,5-dimethylpyrazin-2-amine [91678-81-8] (308 mg, 2.50 mmol) in DCM (4.5 ml) was added a solution of thiophosgene (0.21 ml, 2.70 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 1 h then concentrated in vacuo to give a brown gum. This was purified by flash column chromatography on silica (gradient elution with 0% to 50% EtOAc in isohexane) to afford the title compound (303 mg, 1.83 mmol, 73% Yield) as a dark red liquid.

Reference： [1]Current Patent Assignee: UCB - WO2019/243550, 2019, A1 Location in patent: Page/Page column 254

47
[ 91678-81-8 ]
(5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[3-[(3,5-dimethylpyrazin-2-yl)amino]-1,2,4-triazol-4-yl]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 20 °C / Inert atmosphere 3: mercury dichloride; triethylamine / N,N-dimethyl-formamide / 16 h / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: UCB - WO2019/243550, 2019, A1

48
[ 91678-81-8 ]
(5S)-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-5-[(3,5-dimethylpyrazin-2-yl)carbamothioylamino]-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: UCB - WO2019/243550, 2019, A1

49
[ 91678-81-8 ]
2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: <i>tert</i>-butyl alcohol / 19 h / 80 °C 2: sodium hydrogencarbonate / water / 0.55 h / 20 °C

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US2020/239481, 2020, A1

50
[ 91678-81-8 ]
[ 816-40-0 ]
(x)BrH*C₁₀H₁₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	In <i>tert</i>-butyl alcohol at 80℃; for 19h;	1 2-ethyl-6,8-dimethylimidazo[1,2-a]pyrazine HBr salt To a solution of 2-amino-3,5-dimethyl pyrazine (112 g, 0.910 mol) in t-BuOH (1.7 L, 15 vol) was added 1-bromo-2-butanone (175 mL, 80% by weight, 1.36 mol). Reaction was heated to 80° C. for 19 h before the solution was cool to 30° C. and diluted with MTBE (1.7 L). Suspension was filtered on a Buchner funnel and solids rinsed with heptane (1.2 L). Filter cake was dried in the Buchner funnel under vacuum for 2 h to give 179 g of 2-ethyl-6,8-dimethylimidazo [1,2-a]pyrazine HBr salt (77%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ=8.58 (s, 1H), 8.23 (s, 1H), 2.89 (q, J=7.6 Hz, 2H), 2.83 (s, 3H), 2.50 (s, 3H), 1.32 (t, J=7.6 Hz, 3H)

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - US2020/239481, 2020, A1 Location in patent: Paragraph 0064

51
[ 91678-81-8 ]
[ 70-11-1 ]
C₁₄H₁₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In <i>tert</i>-butyl alcohol

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1 Location in patent: Paragraph 0199-0200

52
[ 91678-81-8 ]
2-bromo-1-isoxazol-3-yl-ethanone [ No CAS ]
C₁₁H₁₀N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In <i>tert</i>-butyl alcohol

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1 Location in patent: Paragraph 0201-0202

53
[ 91678-81-8 ]
[ 1101023-98-6 ]
C₁₂H₁₅N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In <i>tert</i>-butyl alcohol

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1 Location in patent: Paragraph 0203-0204

54
[ 91678-81-8 ]
[ 301221-79-4 ]
tert-butyl 4-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In <i>tert</i>-butyl alcohol

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2020/160075, 2020, A1 Location in patent: Paragraph 0207-0208

55
[ 91678-81-8 ]
3-bromo-6,8-dimethyl-2-phenylimidazo[1,2-a]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: <i>tert</i>-butyl alcohol 2: acetic acid; bromine