* 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.
Reference：
[1] Patent: WO2014/128588, 2014, A1,
[2] Patent: WO2016/30439, 2016, A1,
[3] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1191 - 1202
[4] Patent: CN104447739, 2016, B,
2
[ 36082-50-5 ]
[ 1003-03-8 ]
[ 733039-20-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 20℃; for 6 h;
To a solution of 5-bromo-2,4- dichloropyrimidine (45.6 g, 200 mmol) in dioxane (400 mL) was added N-cyclopentylamine (20.4 g, 240 mmol) at room temperature. The mixture thus obtained was stirred at room temperature for 6 h. The reaction mixture was then diluted with ethyl acetate and washed with brine and dried over MgSO4. The solvent was evaporated to give the title compound as a light yellow solid (56 g, 100percent) which was used in next step without further purification. 1H νMR (500 MHz, DMSO-d6) δ 8.23 (IH, s), 7.37 (IH, <n="37"/>d, J=7.3 Hz), 4.31 (IH, m), 1.92 (2H, m), 1.71 (2H, m), 1.53-1.59 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+l: Found 276.0, Calculated 275.9.
90%
With N-ethyl-N,N-diisopropylamine In ethanol at 10 - 40℃; for 5 h; Inert atmosphere
A solution of 5-bromo-2,4-dichloropyrimidine(1) (5 g, 22 mmol) and N,N-diisopropylethylamine (5.7g, 44 mmol) in ethanol (30 mL) was cooled to 10°C under nitrogenatmosphere. Charged cyclopentylamine (2.1g, 24.1 mmol)and stirred for 5 hours at 40°C. Progress of the reaction wasmonitored by TLC and solvent was evaporated undervacuum. Resulting residue was stirred with hexane (20 mL)for 2 hours at 0°C. Precipitate was filtered and washed withhexane to obtain compound (2). Off-white crystalline solid,Yield: 90percent, mp. 95-97 °C. 1H NMR (400 MHz, DMSO-d6):1.57-1.62 (m, 4H, -CH2-CH2-), 1.64-1.69 (m, 2H, CH2),1.87-1.93 (m, 2H, CH2), 4.27-4.33 (m, 1H, -NH-CH-), 7.35(d, 1H, J=7.44 Hz, -NH), 8.20 (s, 1H, Ar-H). 13C NMR(75.46 MHz, DMSO-d6): 159.4, 158.6, 157.1, 102.9, 53.0,31.8, 24.0. ESI-HRMS (m/z): Calcd. for C9H11BrClN3:276.5614. Found: m/z 277.2618 [M+H]+.
89%
With N-ethyl-N,N-diisopropylamine In ethanol at 20℃;
In a large sealed tube is added 5-bromo-2,4-dichloropyrimidine (3g, 13.2 mmol) in 100 mL of EtOH. Then cyclopentyl amine (1.95 mL, 19.75 mmol) andN,N'-diisopropylethylamine (3.36 mL, 19.8 mmol) are added to the solution at rt. The solution is then stirred rt overnight. Solvent is evaporated and the crude is purified using silica gel chromatography (15percent ethyl acetate/85percenthexane) to give (5- bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine as a white solid (3.25g, 89percent). MS(ESI) m/z 278.4 (M+H)+
88%
With N-ethyl-N,N-diisopropylamine In ethyl acetate at 18 - 40℃; for 7 h; Inert atmosphere
A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 250 g (1.097 mol, 140.4 mL, 1.0 eq.) of 5-bromo-2,4-dichloropyrimidine (A1h) and 1127 g, (1250 mL) of ethyl acetate. The content is stirred at 20° C. and 283.5 g (2.194 mol, 382.0 mL, 2.0 eq.) of N,N-diisopropylethylamine is added. A solution of 102.8 g (1.207 mol, 119 mL, 1.1 eq.) of cyclopentylamine (A1g) dissolved in 1127 g, (1250 mL) of ethyl acetate is added over 60 min. An 18° C. to 36° C. exotherm is observed. The solution is warmed to 40° C. This temperature is maintained for at least 6 h or until all the starting material A1h, is consumed as determined by HPLC analysis. The resulting slurry is cooled to 25° C. and 500 g (500 mL) of water is added. The content is stirred for 15 min and the phases are allowed to separate. The bottom (aqueous) layer is removed and the organic layer is washed once more with 500 g (500 mL) of water. The sample is stirred for 15 min, and the phases are allowed to separate. The bottom (aqueous) layer is removed. The organic phase is concentrated (atmospheric pressure) to a volume of 1500 mL (batch temp=82° C.). 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=85° C.). Again, 684 g (1 L) of heptane is added and the concentration is resumed to a volume of 1500 mL (batch temp=96° C.). The sample is cooled to 50° C. and seeded. The cooling is continued to 4° C. and the temperature is maintained at 4° C. for 1 h. The solids are filtered and the filter cake is washed once with 137 g (200 mL) of cold (4° C.) heptane. The solids are dried at 50° C. for 16 h, to afford 259.0 g (88.0percent, corrected) of Compound A1f as a white, crystalline solid, mp=95-96° C.
87.2%
at 10 - 20℃; for 3 h;
Step i): synthesis of (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine (formula 13)Step i: A 4 L 3-necked RBF, equipped with a 500 ml addition funnel, was charged with 250.0 g of 5-Bromo-2,4-dichloro-pyrimidine (1 .097 mol, 1 .00 eq.) and 880 ml absolute EtOH. The mixture was cooled to 10°C with an ice-bath A solution of 250 ml cyclopentylamine (130 mmol, 1 .18 eq.) in 250 ml absolute EtOH was added dropwise over 60 min while maintaining the temperature between 10-15°C After stirring for 1 h, the mixture was allowed to warm up to RT and further stirred for 1 h. The reaction was quenched with 1 .1 L water then seeding material was added. After stirring at RT for 2 h, the precipitated solid was collected by filtration, washed with 1 L water/EtOH (8/2) acetonitrile and left in air at RT to give crude wet (5-Bromo-2-chloro-pyrimidin-4-yl)- cyclopentyl-amine as white solid.HPLC (Method 1 ): 9.67 min (89.3percent) (254 nm).Crude product was suspended in 1 .5 L hexane and heated to reflux for 45 min. Resulting slurry was allowed to cool down slowly to RT with stirring. After 3 h, stirring was stopped and the mixture left at RT. Solid was collected by filtration, washed with hexane (350 ml), dried in air for 10 min then at 50^/35 mbar for 2 h to give 264.51 g of purified (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine (87.2percent yield) as white solid.HPLC (Method 1 ): 10.02 min (99.7percent) (254 nm).
85%
at 25℃; for 2 h;
EXAMPLE 3: Preparation of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one; Example 3A: Preparation of S-bromo^-chloro^-cyclopentyl-aminopyrimidineTo -1 -g (0.004 mol) of 5-bromo-2,4-dichloropyrimidine in ethanol was added 1.5 kg (0.018 mol) cyclopentylamine under nitrogen. The mixture was stirred at 25°C for 2hrs. Water was added to precipitate the product, and the solid was recrystallized using hexane 4:1 to give a white crystalline product (3A).
84%
With triethylamine In ethanol at 25℃; for 4 h;
To a vessel was added absolute ethanol (3000 mL, 3.0 vol) followed by 5-bromo-2,4- dichloropyrimidine (mw 227.87; 1000 g, 1.0 equiv.). Triethylamine (612 mL, 1.0 equiv.) was added, and then cyclopentylamine (mw 85.15; 520 mL, 1.2 equiv.) was added slowly over 2 hours to control the mild exotherm. After completion of cyclopentylamine addition, the reaction was seeded with 5-bromo-2-chloro-6-cyclopentylamino-pyrimidine (5 g, 0.5 wtpercent) to induce crystallization, if needed. The reaction was stirred at 25°C for 2 hours.Water (2500 mL, 2.5 vol) was added to the vessel at 20-25 °C at a rate of 30 mL/min. The mixture was cooled to 8-12°C at 2°C/min. The slurry was kept at 8-12°C for 1 hour and then filtered onto a 2 Whatman™ paper filter. The cake was rinsed with n-heptane (2000 mL). The cake was reslurried with n-heptane on the filter drier (2000 mL). The material was dried overnight in the vacuum oven at 50-55°C to give 5-bromo-2-chloro-6-cyclopentylamino- pyrimidine (1020 g; 84percent) as a white solid.
80%
With triethylamine In dichloromethane at 0 - 45℃; for 6 h;
Add 5-bromo-2,4-dichloropyrimidine (IV-1) (11.4 g, 50 mmol) to the reaction flask.Triethylamine (2.24 g, 20 mmol) and methylene chloride (150 mL) were stirred and cooled to 0-5 °C.Cyclopentylamine (V) (4.257 g, 50 mmol) was slowly added dropwise. After the addition was complete, the reaction was heated to 45° C. for 6 hours.TLC detection reaction is complete. At the end of the reaction, 150 mL of quenched water was added.The organic phase is washed twice with saturated saline solution.The aqueous phase is extracted twice with ethyl acetate,Combine the organic phase,Drying with anhydrous sodium sulfate,Distillation under reduced pressure to recover the solventThe resulting concentrate was purified by column chromatography using a mixture of petroleum ether and ethyl acetate to give 2-chloro-4-cyclopentylamino-5-bromopyrimidine (VI-1) (11.0 g).Yield 80percent; Purity 99.8percent
80%
With triethylamine In dichloromethane at 0 - 45℃; for 6 h;
To the reaction flask was added 5-bromo-2,4-dichloropyrimidine (I) (11.4 g, 50 mmol), triethylamine (2.24 g, 20 mmol)Dichloromethane (150 mL) was added and the mixture was stirred and cooled to 0-5°C. Cyclopentylamine (II) (4.257 g, 50 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 45° C. for 6 hours. TLC reaction was completed. . At the end of the reaction, 150 mL of water was quenched, the organic phase was washed twice with saturated brine, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting concentrate was used with petroleum ether and The compound 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) was isolated by column chromatography of ethyl acetate mixed solvent to give 11.0 g; the yield was 80percent; the purity was 99.8percent (HPLC area normalization method).
74%
With triethylamine In tetrahydrofuran at 0 - 20℃;
5-BROMO-2, 4-dichloro-pyrimidine (18.21 g, 79.9 mmol) was dissolved in THE and place in a 0°C ice bath. Triethylamine (23.77 g, 235 mmol) was added. Reaction became light yellow. Following this, cyclopentyl amine (3.67 g, 78.31 mmol) was added. The ice bath was removed and the reaction was stirred overnight. Reaction was filtered and concentrated. Purified on silica gel using 20: 1 Hexane/EtOAc to afford 16.09 g (74percent) of (5-BROMO-2-CHLORO-PYRIMIDIN-4- yl) -cyclopentyl-amine.
8 g
With triethylamine In ethanol for 2 h;
7gcyclopentaneamine (Compound 5b) was dissolved in 100ml of absolute ethanol.16ml of Et3N was added. Under stirring conditions, 9g2,4-dichloro-5-bromopyrimidine (Compound 5a) was added portionwise to thesystem. The reaction was continued after addition for 2h. After completion ofthe reaction, the system was filtered, and the filtrate was concentrated. Waterwas added to precipitate a white solid, to which was added a small amount ofpetroleum ether. After stirred for 10 minutes, the system was filtered to give8g white solid as Compound 14.
Reference：
[1] Patent: WO2009/85185, 2009, A1, . Location in patent: Page/Page column 35
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 8, p. 3430 - 3449
[3] Combinatorial Chemistry and High Throughput Screening, 2017, vol. 20, # 8, p. 703 - 712
[4] Patent: WO2010/20675, 2010, A1, . Location in patent: Page/Page column 89
[5] Patent: US2012/115878, 2012, A1, . Location in patent: Page/Page column 5-6
[6] Patent: WO2016/30439, 2016, A1, . Location in patent: Page/Page column 30; 31
[7] Patent: WO2008/32157, 2008, A2, . Location in patent: Page/Page column 26
[8] Patent: WO2014/128588, 2014, A1, . Location in patent: Page/Page column 34
[9] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1191 - 1202
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 12, p. 4033 - 4037
[11] Patent: CN107759596, 2018, A, . Location in patent: Paragraph 0054; 0055
[12] Patent: CN107936029, 2018, A, . Location in patent: Paragraph 0047; 0050-0052; 0065; 0082
[13] Patent: WO2004/65378, 2004, A1, . Location in patent: Page 55
[14] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 174 - 184
[15] Patent: CN104447739, 2016, B, . Location in patent: Paragraph 0141; 0143; 0144
3
[ 733039-20-8 ]
[ 107-93-7 ]
[ 1013916-37-4 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With palladium diacetate; triethylamine In 1-methyl-pyrrolidin-2-one at 65℃; Inert atmosphere Stage #2: With acetic anhydride In 1-methyl-pyrrolidin-2-one at 65℃; Inert atmosphere
To a vessel was added 5-bromo-2-chloro-6-cyclopentylamino-pyridimidine (10.0 g, 1.0 equiv.) along with N-methylpyrrolidone (NMP) (50 mL, 5.0 vol.) at ambient temperature. To the reaction mixture was added crotonic acid (4.7 g, 1.5 equiv.) and triethylamine (20.2 mL, 4.0 equiv.). The vessel was degassed and purged three times with nitrogen. To the degassed reaction mixture was added Pd(OAc)2(0.25 g, 0.03 equiv.). The vessel was degassed and purged three times with nitrogen using the same method as step 3. The mixture was heated to 65°C and allowed to stir until starting material was consumed (at least 6 hours).Acetic anhydride (6.8 mL, 2.0 equiv) was added to the reaction mixture. The reaction was allowed to react at 65 °C until starting material was consumed (usually 1-2 hours). The reaction mixture was cooled to 20°C and H20 (100 mL, 10 vol) was added to dissolve triethylamine-HBr salts and precipitate out 2-chloro-8-cyclopentyl-5-methyl-8/-/- pyrido[2,3-c]pyrimidin-7-one. The material was granulated at 20 °C for 1 hour. The solids were filtered and washed with H20 (20 mL, 2.0 vol), and a 4: 1 mixture of isopropanol/H20 (50 mL, 5.0 vol). The crude product was dried under vacuum at 55-70°C to give 2-chloro-8-cyclopentyl-5- methyl-8/-/-pyrido[2,3-c]pyrimidin-7-one, (7.8 g; 81 percent) as a tan to gray solid.
68%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 70℃; for 16 h; Stage #2: With acetic anhydride In tetrahydrofuran for 1.5 h;
Example 3: Preparation of 2-Chloro-8-Cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one 41.5 g (0.15 mol) of δ-bromo^-chlorcMl-cyclopentylaminopyrimidine 3a and 32.3g (0.375 mol) of crotonic acid were mixed in 100L of THF and 105ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred, evacuated and refilled with nitrogen three times, after which 860mg (0.0022 mol) palladium dichloride dibenzonitrile complex and 685mg(0.0022mol) tri-ortho-tolylphosphine were added and the resulting slurry degassed an additional three times. The mixture was then heated and stirred at 700C for 16hrs, after which 35 ml acetic anhydride was added and the mixture stirred for an additional 1.5hrs. The mixture was cooled and diluted with 100ml MTBE and then extracted with 1NHCI, then aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated in vacuo, and recrystallized from IPA to yield 31.2 g {68percent) of crude product {3).
With triethylamine; palladium dichloride In 1-methyl-pyrrolidin-2-one at 20 - 75℃; for 6 h; Inert atmosphere
Compound 2 (10.0 g, 36.2 mmol, 1.0 eq) was added at room temperature.N-methylpyrrolidone (NMP, 50 mL),Crotonic acid (4.7 g, 54.6 mmol, 1.5 eq) and triethylamine (14.7 g, 144.9 mol, 4.0 eq).The container is passed through three times of nitrogen,PdCl 2 (0.195 g, 1.10 mmol, 0.03 eq) was added to the exhausted reaction mixture.Three more nitrogen passes.After the raw materials are stirred and dissolved at room temperature,Rapidly warm up to 75 ° C,The stirring reaction was closed for 6 h,Sampling (diluted with ethyl acetate),TLC detection (DCM: MeOH = 12:1),The starting compound 1 is completely reacted,Add acetic anhydride to react 0.5h sampling point plate,The intermediate reaction is complete,The reaction mixture will be brought to 20 ° C,Add triethylamine hydrobromide solution (100 mL),Stir for 1h,Filtering,Water washing,Get a gray solid. Add ethyl acetate to dissolve,Add anhydrous magnesium sulfate to dry the mixture,Insoluble matter (salt and insoluble catalyst) is filtered out,Wash with ethyl acetate.Concentrate the filtrate to a low volume,Add n-hexane,Beating at 65 ° C for 30 min,Cool to 20 ° C and stir for 1 h.Filtering the solid,Vacuum drying,Obtained a brownish yellow solid,That is, Compound 1 (9.04 g, yield 94.8percent, purity 99.1percent).
80%
Stage #1: With bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In tetrahydrofuran at 75℃; for 20 h; Inert atmosphere Stage #2: at 75℃; for 2 h;
Step ii): synthesis of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin- 7-one formula 15)Step ii): A 1 L 3-necked RBF was charged with 50.0 g of (5-Bromo-2-chloro-pyrimidin- 4-yl)-cyclopentyl-amine (0.181 mol, 1 .00 eq.), 39.0 g crotonic acid (0.452 mol, 2.5 eq.), 125 ml diisopropylethylamine (0.741 mol, 4.1 eq.) and 125 ml THF. The mixture was degassed by applying 3 vacuum/argon cycles then 1 .10 g of tri-o-tolyl-phosphine (3.62 mmol, 0.02 eq.) and 1 .39 g dichlorobis(benzonitrile)palladium(ll) (3.62 mmol, 0.02 eq.) were added. The mixture was degassed again by applying 3 vacuum/argon cycles then heated to 75°C and stirred under argon for 20 h. Then, 43.0 ml of acetic anhydride (0.452 mol, 2.5 eq.) were added and the mixture further stirred at 75^ for 2 h. The reaction was quenched with 250 ml water and the mixture allowed to cool down to RT. After 1 h stirring, 125 ml water was added while cooling to Ι δ'. The precipitated solid was collected by filtration, washed with water (125 ml), cold isopropanol (3 x 125 ml), dried in air for 10 min then at 50<€/25 mbar for 20 h to give 38.13 g of 2-Chloro-8- cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (formula 15) (80.0percent yield) as yellowish solid. HPLC (Method 1 ): 8.67 min (99.6percent) (254 nm).1H NMR (400 MHz, CDCI3, δ ppm): 1 .68 (br. s, 2 H), 1 .84 - 1 .98 (m, 2 H), 2.12 (br. s, 2 H), 2.22 (br. s, 2 H), 2.44 (s, 3 H), 5.84 (m, 1 H), 6.53 (br. s, 1 H), 8.74 (s, 1 H).
Reference：
[1] Patent: CN108117550, 2018, A, . Location in patent: Paragraph 0029; 0030, 0031; 0034; 0036; 0037
[2] Patent: WO2016/30439, 2016, A1, . Location in patent: Page/Page column 31; 32
To a vessel was added 5-bromo-2-chloro-6-cyclopentylamino-pyridimidine (10.0 g, 1.0 equiv.) along with N-methylpyrrolidone (NMP) (50 mL, 5.0 vol.) at ambient temperature. To the reaction mixture was added crotonic acid (4.7 g, 1.5 equiv.) and triethylamine (20.2 mL, 4.0 equiv.). The vessel was degassed and purged three times with nitrogen. To the degassed reaction mixture was added Pd(OAc)2(0.25 g, 0.03 equiv.). The vessel was degassed and purged three times with nitrogen using the same method as step 3. The mixture was heated to 65C and allowed to stir until starting material was consumed (at least 6 hours).Acetic anhydride (6.8 mL, 2.0 equiv) was added to the reaction mixture. The reaction was allowed to react at 65 C until starting material was consumed (usually 1-2 hours). The reaction mixture was cooled to 20C and H20 (100 mL, 10 vol) was added to dissolve triethylamine-HBr salts and precipitate out 2-chloro-8-cyclopentyl-5-methyl-8/-/- pyrido[2,3-c]pyrimidin-7-one. The material was granulated at 20 C for 1 hour. The solids were filtered and washed with H20 (20 mL, 2.0 vol), and a 4: 1 mixture of isopropanol/H20 (50 mL, 5.0 vol). The crude product was dried under vacuum at 55-70C to give 2-chloro-8-cyclopentyl-5- methyl-8/-/-pyrido[2,3-c]pyrimidin-7-one, (7.8 g; 81 %) as a tan to gray solid.
68%
Example 3: Preparation of 2-Chloro-8-Cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one 41.5 g (0.15 mol) of delta-bromo^-chlorcMl-cyclopentylaminopyrimidine 3a and 32.3g (0.375 mol) of crotonic acid were mixed in 100L of THF and 105ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred, evacuated and refilled with nitrogen three times, after which 860mg (0.0022 mol) palladium dichloride dibenzonitrile complex and 685mg(0.0022mol) tri-ortho-tolylphosphine were added and the resulting slurry degassed an additional three times. The mixture was then heated and stirred at 700C for 16hrs, after which 35 ml acetic anhydride was added and the mixture stirred for an additional 1.5hrs. The mixture was cooled and diluted with 100ml MTBE and then extracted with 1NHCI, then aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated in vacuo, and recrystallized from IPA to yield 31.2 g {68%) of crude product {3).
Intermediate 2-chloro-4-cyclopentylamino-5-bromopyrimidine (VI-1) (4.15 g, 15 mmol) was added to the reaction flask.Potassium carbonate (1.036 g, 7.5 mmol) and dichloromethane 20 mL,The temperature was raised to 60C and the reaction was stirred for 30 minutes. To room temperature,Add tert-butyl 4-(6-aminopyridin-3-yl)-piperazine-1-carboxylate (VII) (4.4 g, 15 mmol),The temperature was again raised to 60C, and the reaction was stirred for 1 hour. TLC detected the end of the reaction. Quenching the reaction with water,The aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure.A solid precipitated and the resulting crude product was recrystallized from n-hexane and ethyl acetate (2:1, v/v).Vacuum drying gave an off-white solid 2-[4-(6-aminopyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl]-4-cyclopentylamino-5-bromopyrimidine (VIII-1) 6.59g; yield 85%;Purity 99.5%
To 2-chloro-4-cyclopentylamino-pyrimidine-5-carboxylic acid ethyl ester (-2 mmol) in butanol (1.7 mL) was added 4- (6-AMINO-PYRIDIN-3-YL)-PIPERAZINE-L- carboxylic acid tert-butyl ester (0.7g). This mixture was heated to 100 C. After 2 hrs, xylenes (2 mL) was added and the temperature was raised to 140 C. Heating was continued overnight. The mixture then was allowed to cool and diluted with ethyl acetate. The organic solution was washed twice with 1 M NAOH (aq), saturated ammonium chloride solution, then brine. After drying over magnesium sulfate, the solvents were evaporated and the residue was purified by chromatography on silica gel eluting with 35-45% ethyl acetate in hexanes to give 4- [6- (5-BROMO-4-CYCLOPENTYLAMINO-PYRIMIDIN-2-YLAMINO)-PYRIDIN-3-YL]- PIPERAZINE-1-CARBOXYLIC acid tert-butyl ester. MS (APCI) M++1 Calc'd, 519.18 ; Found, 520.0.
With sodium t-butanolate; In toluene; at 115℃; for 48h;
(5-Bromo-2-chloro-pyrimidin-4-yl) -cyclopentyl-amine (0.155 g, 0.560 mmol) and 4- (5-amino-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (0.156 g9 0.560 mmol) were dissolved in toluene and heated to 115C for 48H. The reaction was cooled and concentrated. Purification on silica gel using 4: 1 HEXANE/ETOAC PROVIDED 0. 130 g (45%) OF 4- [5- (5-BROMO-4-CYCLOPENTYLAMINO- PYRIMIDIN-2-YLAMINO)-PYNIDIN-2-YL]-PIPERAZINE-1-CARBOXYLIC acid tert-butyl ester.
With potassium carbonate; lithium chloride In N,N-dimethyl-formamide at 120℃; for 5h;
384 7-Cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester
Example 384 7-Cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester A solution of (5-Bromo-2-chloro-pyrimidin-4-yl)cyclopentylamine (8 g, 28.93 mmol), lithium chloride (1.23 g, 28.9 mmol), potassium carbonate (10 g, 72 mmol) and palladium acetate (324.68 mg, 1.45 mmol) in DMF (300 mL) is degassed and back-filled filled with nitrogen three times. Methyl-2-butynoate (8.5 mL, 87 mmol) is added and the reaction solution is heated at 120° C. for 5 h. LC-MS indicated the formation of two regioisomers and no starting material remaining. After cooling to room temperature the solution is filtered through Celite, diluted with water and extracted with ethyl acetate three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is purified using silica gel chromatography (~20% ethyl acetate/80% hexane) to give 2-chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester as a yellow solid (2.11 g, 25%).
Multi-step reaction with 3 steps
1: palladium diacetate; 1,4-diaza-bicyclo[2.2.2]octane; potassium carbonate / N,N-dimethyl-formamide / 3 h / 85 °C / Inert atmosphere
2: potassium hydroxide / N,N-dimethyl-formamide / 0.25 h / 0 °C / Inert atmosphere
3: anhydrous Sodium acetate; bromine; glacial acetic acid / 35 h / 50 °C / Inert atmosphere
Multi-step reaction with 3 steps
1.1: triethylamine / 0.5 h / Inert atmosphere
1.2: 8.5 h / 80 °C
2.1: bis(trichloromethyl) carbonate / chlorobenzene / 4 h / 45 °C / Reflux
3.1: NBS; oxalic acid / N,N-dimethyl-formamide / 4 h / 65 °C
Multi-step reaction with 2 steps
1.1: triethylamine; palladium (II) chloride / tetrahydrofuran / 5 h / 60 °C
1.2: 2 h
2.1: glacial acetic acid; potassium bromide; bromine / 1 h / 55 °C
Multi-step reaction with 2 steps
1: triethylamine; palladium (II) chloride / 1-methyl-pyrrolidin-2-one / 6 h / 75 °C / Inert atmosphere
2: NBS / N,N-dimethyl-formamide / 6.5 h / 50 °C / Inert atmosphere
Multi-step reaction with 2 steps
1.1: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine / tetrahydrofuran / 16 h / 80 °C / Inert atmosphere
1.2: 24 h / 90 °C / Inert atmosphere
2.1: anhydrous Sodium acetate; glacial acetic acid; bromine / 72 h / 50 °C / Inert atmosphere
Multi-step reaction with 3 steps
1: tris-(o-tolyl)phosphine; palladium diacetate / tetrahydrofuran / 18 h / 70 °C / Sealed tube
2: triethylamine; acetic anhydride / 2 h / 70 °C
3: NBS; oxalic acid / acetonitrile / 12 h / 75 °C
With triethylamine; palladium dichloride; In 1-methyl-pyrrolidin-2-one; at 20 - 75℃; for 6h;Inert atmosphere;
Compound 2 (10.0 g, 36.2 mmol, 1.0 eq) was added at room temperature.N-methylpyrrolidone (NMP, 50 mL),Crotonic acid (4.7 g, 54.6 mmol, 1.5 eq) and triethylamine (14.7 g, 144.9 mol, 4.0 eq).The container is passed through three times of nitrogen,PdCl 2 (0.195 g, 1.10 mmol, 0.03 eq) was added to the exhausted reaction mixture.Three more nitrogen passes.After the raw materials are stirred and dissolved at room temperature,Rapidly warm up to 75 C,The stirring reaction was closed for 6 h,Sampling (diluted with ethyl acetate),TLC detection (DCM: MeOH = 12:1),The starting compound 1 is completely reacted,Add acetic anhydride to react 0.5h sampling point plate,The intermediate reaction is complete,The reaction mixture will be brought to 20 C,Add triethylamine hydrobromide solution (100 mL),Stir for 1h,Filtering,Water washing,Get a gray solid. Add ethyl acetate to dissolve,Add anhydrous magnesium sulfate to dry the mixture,Insoluble matter (salt and insoluble catalyst) is filtered out,Wash with ethyl acetate.Concentrate the filtrate to a low volume,Add n-hexane,Beating at 65 C for 30 min,Cool to 20 C and stir for 1 h.Filtering the solid,Vacuum drying,Obtained a brownish yellow solid,That is, Compound 1 (9.04 g, yield 94.8%, purity 99.1%).
80%
Step ii): synthesis of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin- 7-one formula 15)Step ii): A 1 L 3-necked RBF was charged with 50.0 g of (5-Bromo-2-chloro-pyrimidin- 4-yl)-cyclopentyl-amine (0.181 mol, 1 .00 eq.), 39.0 g crotonic acid (0.452 mol, 2.5 eq.), 125 ml diisopropylethylamine (0.741 mol, 4.1 eq.) and 125 ml THF. The mixture was degassed by applying 3 vacuum/argon cycles then 1 .10 g of tri-o-tolyl-phosphine (3.62 mmol, 0.02 eq.) and 1 .39 g dichlorobis(benzonitrile)palladium(ll) (3.62 mmol, 0.02 eq.) were added. The mixture was degassed again by applying 3 vacuum/argon cycles then heated to 75C and stirred under argon for 20 h. Then, 43.0 ml of acetic anhydride (0.452 mol, 2.5 eq.) were added and the mixture further stirred at 75^ for 2 h. The reaction was quenched with 250 ml water and the mixture allowed to cool down to RT. After 1 h stirring, 125 ml water was added while cooling to Iota delta'. The precipitated solid was collected by filtration, washed with water (125 ml), cold isopropanol (3 x 125 ml), dried in air for 10 min then at 50
With dichloro bis(acetonitrile) palladium(II); N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; In tetrahydrofuran; at 75 - 80℃;Inert atmosphere;
Step b: Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido j2,3-dj pyrimidin-7- one (Formula II)Method ATrimethylsilyl (2E)-but-2-enoate (obtained from step a) and diisopropylethylamine(52 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine(20 g, Formula III) in tetrahydrofuran (100 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Transdichlorobis(acetonitrile) palladium (II) (0.970 g) followed by the addition of tri-o30 tolylphosphine (0.770 g) was added to the reaction mixture under a nitrogen atmosphere.The reaction system was again degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75C to 80C overnight. The progress of the reaction was monitored by thin layer chromatography (TLC) (60% ethyl acetate/toluene). Trans-dichlorobis(acetonitrile)palladium (II) (0.725 g) was again added followed by the addition of tri-o-tolylphosphine (0.725 g) to the reaction mixture at 75C to 80C. The reaction mixture was heated at 75C to 80C for 4 hours. After completion of the reaction, acetic anhydride (17 mL) was added, and then the mixture was stirred at 75C to 80C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) and iN hydrochloric acid(100 mL) were added and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (40 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (2 g) was added to the mixture. The mixture was stirred for 20 minutes at roomtemperature. The mixture was filtered through a Hyflo bed and then washed with dichloromethane (40 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (80 mL) was added to the residue and the solvent was evaporated under reduced pressure until 40 mL of isopropyl alcohol remained. Isopropyl alcohol (40 mL) was again added to the mixture, and then the solvent was evaporatedunder reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered, thenwashed with isopropyl alcohol (20 mL), and then dried under vacuum at 45C to obtain the title compound.Yield: 0.535% wlwChromatographic purity: 99.5 1%
With N,N'-Diphenyloxamid; potassium carbonate; copper(l) chloride; In dimethyl sulfoxide; at 90 - 100℃; for 12h;
The N, N-dimethylpropynamide (29.1 g, 0.3 mol) prepared in Example 4,N-cyclopentyl-5-bromo-2-chloro-4-aminopyrimidine (123.8 g, 0.45 mol),Cuprous chloride (29.7g, 0.3mol), N, N-diphenyloxalate diamide (71.4g, 0.3mol)And potassium carbonate (41.4 g, 0.3 mol) were added to a 1000 mL eggplant-shaped bottle, DMSO (300 mL) was added, and the reaction was stirred at 90-100 C for 12 hours.After the reaction was completed, 200 ml of water was added.The reaction solution was extracted with ethyl acetate (300 mL x 3). The ethyl acetate layer was washed with saturated brine (200 mL x 2). The ethyl acetate layer was evaporated under reduced pressure to obtain an oily liquid. Recrystallization from anhydrous ethanol gave a white solid 63.9 g, yield is 73%, mp: 103-105 C.
71%
With N,N,N,N,-tetramethylethylenediamine; potassium carbonate; copper(l) chloride; In dimethyl sulfoxide; at 90 - 100℃; for 12h;
The N, N-dimethylpropynamide (9.7 g, 0.1 mol) prepared in Example 3,N-cyclopentyl-5-bromo-2-chloro-4-aminopyrimidine (27.5g, 0.1mol), cuprous chloride (1.98g, 0.02mol),Tetramethylethylenediamine (2.32g, 0.02mol) and potassium carbonate (13.8g, 0.1mol) were added to a 250mL eggplant-shaped bottle.Add DMSO (150mL) and stir the reaction at 90 100 for 12h.After the reaction was completed, 200 ml of water was added. The reaction solution was extracted with ethyl acetate (150 mL × 3), and the ethyl acetate layer was washed with saturated brine (150 mL × 2).The ethyl acetate layer was evaporated under reduced pressure to obtain an oily liquid.Recrystallization from anhydrous ethanol yielded 20.7 g of a white solid with a yield of 71%,
With copper(II) trifluoroacetate; sodium hydroxide; In 1,4-dioxane; at 80℃; for 6h;
Compound II: cyclopentyl bromide: sodium hydroxide:Copper trifluoroacetate = 1: 1.5: 1.5: 0.01.(2) Compound 2 (208.4g, 1mol) was added to the 2L three-necked flask,Copper trifluoroacetate (2.8g, 0.01mol) 1,4-dioxane (833.6g),Sodium hydroxide (60g, 1.5mol), cyclopentyl bromide (223.6g, 1.5mol),Incubate at 80 for 6 hours, the reaction is over,Add saturated ammonium chloride solution (832g) and stir well, extract with ethyl acetate (300g),The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure,The obtained solid was collected in a 2L three-necked flask, and isopropyl alcohol (832g) was added,Activated carbon (10g), stirred at 60 C for 1 hour, filtered while hot,The filtrate was naturally cooled to 10 C to precipitate solids and filtered,The filter cake was vacuum dried at 40 C to obtain Compound I, a white solid 249g, and a yield of 90%.The HPLC purity was 99.5%.
With copper diacetate; sodium hydroxide; In dichloromethane; at 80℃; for 10h;
Compound II: Cyclopentyl chloride:Sodium hydroxide:Copper acetate = 1: 2.5: 2.5: 0.01.(2) Compound 2 (208.4g, 1mol) was added to the 2L three-necked flask,Copper acetate (2g, 0.01mol), dichloroethane (625g), sodium hydroxide (100g, 2.5mol), cyclopentyl chloride (261.5g, 2.5mol), incubate at 80 for 10 hours,After the reaction, add saturated ammonium chloride solution (832g) and stir well.Extracted with ethyl acetate (300g), the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure,The obtained solid was collected in a 2L three-necked flask, ethyl acetate (832g) was added,Activated carbon (10g), stirred at 60 C for 1 hour, filtered while hot,The filtrate was naturally cooled to 10 C to precipitate solids and filtered,The filter cake was vacuum dried at 40 C to obtain Compound I, white solid 213g, yield 77%,The HPLC purity was 98.5%.
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