Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 22536-61-4 | MDL No. : | MFCD09260903 |
Formula : | C5H5ClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | APRMCBSTMFKLEI-UHFFFAOYSA-N |
M.W : | 128.56 | Pubchem ID : | 581719 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 32.01 |
TPSA : | 25.78 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.0 cm/s |
Log Po/w (iLOGP) : | 1.72 |
Log Po/w (XLOGP3) : | 1.53 |
Log Po/w (WLOGP) : | 1.44 |
Log Po/w (MLOGP) : | 0.54 |
Log Po/w (SILICOS-IT) : | 2.04 |
Consensus Log Po/w : | 1.45 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.16 |
Solubility : | 0.898 mg/ml ; 0.00698 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.68 |
Solubility : | 2.68 mg/ml ; 0.0209 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.62 |
Solubility : | 0.311 mg/ml ; 0.00242 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.36 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With ammonia In ethanol; water at 200℃; for 4 h; Sealed tube | Step 1 : To a solution of compound 184 (10.0 g, 77.79 mmol) in IMS (100 ml.) was added aqueous ammonia (35percent, 100 ml). The reaction mixture was transferred to a sealed bomb and heated at 200 °C for 4 h. The reaction mixture was allowed to cool to room temperature and was concentrated to remove most of the solvent and water (25 ml.) added. The solid obtained was filtered and dried under vacuum to give the desired compound 185 as off-white solid (7.85 g, 92percent yield).1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 2H), 6.30 (s, 2H), 2.03 (s, 3H). LCMS m/z 1 10 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With zinc In water for 3 h; Reflux | Step 1 : A suspension of compound 242 (50.0 g, 307 mmol) and freshly activated (acid washed) Zn (59.8 g, 920 mmol) in water (500 mL) was heated at reflux for 3 hours. TLC showed consumption of SM. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and rinsed with CH2CI2 (500 mL). The phases of the filtrate were separated and the organic phase was washed with brine (300 mL), dried over MgS04, filtered and concentrated under vacuum carefully to give compound 243 as a beige powder (30.6 g, 78percent yield, 95percent purity by 1 H NMR).1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 0.9 Hz, 2H), 2.27 (t, J = 0.8 Hz, 3H). |
77% | With ammonium hydroxide; zinc In water; benzene for 18 h; Reflux | Step 1. Preparation of 2-chloro-5-methylpyrimidine To a stirred solution of 2,4-dichloro-5-methylpyrimidine (4.00 g, 24.5 mmol) in a mixture of benzene (16.0 mL) and H2O (40.0 mL) was added zinc powder (4.81 g, 73.6 mmol) and ammonia water (8.80 mL, 24.5 mmol) at room temperature. After heating at reflux for 18 hours, the reaction mixture was cooled and filtered through a pad of Celite and the reaction mixture was extracted with Et2O, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hexanes:EtOAc=1:1) to give the desired product (2.44 g, 77percent) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 2.33 (3H, s), 8.47 (2H, s). |
75% | Reflux | A mixture of 2,4-dichloro-5-methylpyrimidine (50 g, 0.31 mol), water (500 mL) and zinc dust (50 g, 0.94 mol) was heated at reflux overnight. The reaction mixture was filtered and the filtrate was extracted with dichloromethane (3*500 mL). The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from petroleum ether to afford compound C60 as a white solid. Yield: 27.9 g, 0.22 mol, 75percent. LCMS m/z 129.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.25 (s, 3H), 8.40 (5, 2H). |
69% | Stage #1: With acetic acid; zinc In tetrahydrofuran for 3.66667 h; Stage #2: With sodium hydroxide; water In dichloromethane; ethyl acetate |
EXAMPLE 84[4-(6-Bromobenzo[b]thiophen-2-yl)-5-methylpyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride(A). Preparation of 2-chloro-5-methylpyrimidine; Into a 3-necked, 500 mL round bottomed flask is added 2,4-dichloro-5-methylpyrimidine (25.0 g, 153 mmol), THF (125 mL) and zinc powder (30.1 g, 460 mmol). The mixture is heated to reflux and acetic acid (HOAc) (9.21 g, 153 mmol) in THF (20 mL) is dropwise added over 1 hour. After 1.5 hours at reflux, additional HOAc (3.93 g, 65.5 mmol) in THF (12.5 mL) is added over 10 minutes, and the mixture is refluxed for an additional 1 hour. The mixture is filtered over celite, rinsed with THF (150 mL) and the organic layers are concentrated under reduced pressure. The crude mixture is partitioned in EtOAc/dichloromethane/1 N NaOH and filtered. The organic layer is concentrated under reduced pressure to yield a peach colored solid. The crude material is subjected to chromatography on silica (in hexane) to provide the title compound as a white solid (13.5 g, 69percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.8 g | at 90℃; | A solution of Example 52B (8.8g, 79.9mmol) in phosphorus oxychloride (50mL) was stirred overnight at 90°C.The reaction solution was poured into ice water, and sodium bicarbonate solution was added, the aqueous layer wasextracted with dichloromethane. The organic layer was concentrated to give the title compound (2.8g). 1H NMR (400MHz, DMSO-d6) ppm 2.27 (s, 3 H) 8.64 (s, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
350 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine In N,N-dimethyl-formamide at 120℃; for 16 h; | To a solution of 2-chloro-5-methyl-pyrimidine (500.00 mg, 3.89 mmol, 1.00 eq) in MeOH (10.00 mL) and DMF (2.00mL) was added triethylamine (1.18 g, 11.67 mmol, 1.62 mL, 3.00 eq) and Pd(dppf)C12 (426.87 mg, 583.39 umol, 0.15 eq) under CO. The suspension was degassed and purged with CO several times. The mixture was stirred under CO (3 Mpa) at 120°C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The crude residue was purified by column chromatography (Petroleum ether : Ethyl acetate=20: l to 0: 1) to afford methyl 5-methylpyrimidine-2-carboxylate (350.00 mg). LCMS (M+H+) m/z: 153. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 6 h; Reflux | Synthesis Example 25 N-[1-((2-chloropyrimidin-5-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound 243) 2-chloro-5-methylpyrimidine (1.04 g, 8.13 mmol) was dissolved in 30 mL of carbon tetrachloride, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, and the mixture was refluxed under heating for 6 hours. Following reaction completion, the reaction mixture was returned to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate=3:1), affording 641 mg of 5-bromomethyl-2-chloropyridine (yield, 38percent). 1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 8.66 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With ammonia; In ethanol; water; at 200℃; for 4h;Sealed tube; | Step 1 : To a solution of compound 184 (10.0 g, 77.79 mmol) in IMS (100 ml.) was added aqueous ammonia (35%, 100 ml). The reaction mixture was transferred to a sealed bomb and heated at 200 C for 4 h. The reaction mixture was allowed to cool to room temperature and was concentrated to remove most of the solvent and water (25 ml.) added. The solid obtained was filtered and dried under vacuum to give the desired compound 185 as off-white solid (7.85 g, 92% yield).1H NMR (400 MHz, DMSO-d6) delta 8.06 (s, 2H), 6.30 (s, 2H), 2.03 (s, 3H). LCMS m/z 1 10 [M+H]+. |
With ammonium hydroxide; at 85℃; for 18h;Sealed tube; | A mixture of 2-chloro-5-methylpyrimidine (1 g, 7.78 mmol) and ammonium hydroxide (18.26 mL, 469 mmol) was heated at 85 C in a sealed tube for 18 h. The mixture was cooled to rt and and then ice/water bath, and filtered. The white filter cake was washed with hexanes and suction dried.LCMS (method C ) tR,0.33 min., MH+ = 110.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | A flask was charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (5.0 g, 38.9 mmol, Indofine Inc.), Pd(PPh3)4 (4.49 g, 3.89 mmol, Strem Chemicals Inc.) and purged with nitrogen. Degassed 1,4- dioxane (90 mL) was added followed by tributyl(1-ethoxyvinyl)stannane (19.71 mL, 58.3 mmol). The reaction was heated to 100 C for 16 h. The reaction mixture was concentrated and directly purified by chromatography through a Redi-Sep pre-packed gold silica gel column, eluting with a gradient of 0% to 40% EtOAc in hexanes to provide the title compound (Example 62.1, 3.3 g, 52%). LCMS-ESI (pos.) m/z: 165.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; for 8h;Reflux; | Preparation example 1: Preparation of 5-(bromomethyl)-2-chloropyrimidine <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12.86 g, 0.1 mol) was dissolved in carbon tetrachloride (300 mL), and N-bromobutanimide (25.72 g, 0.14 mol) and benzoyl peroxide (1.29 g, 5 mmol) were added under stirring. The resultant mixture was heated to reflux by oil bath, and was cooled to room temperature after reacting for 8 h. The mixture was filtrated under suction. The filtrate was concentrated and then subjected to silica gel column chromatography (petroleum ether: acetic ether=1:1) to get the title compound (8.7 g, yield: 42%). |
38% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux; | 1.04 g (8.13 mmol) of <strong>[22536-61-4]2-chloro-5-methyl pyrimidine</strong> was dissolved in 30 ml of carbon tetrachloride, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 3:1) to obtain 641 mg (yield 38%) of 5-bromomethyl-2-chloropyridine. [0277] 1H-NMR (CDCl3, delta, ppm): 4.42(2H, s), 8.66(2H, s) |
38% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux; | 1.04 g (8.13 mmol) of <strong>[22536-61-4]2-chloro-5-methyl pyrimidine</strong> was dissolved in 30 ml of carbon tetrachloride, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 3:1) to obtain 641 mg (yield 38%) of 5-bromomethyl-2-chloropyridine. |
38% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux; | In 30 ml of carbon tetrachloride, 1.04 g (8.13 mmol) of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> was dissolved. To this solution, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, followed by heating under reflux for 6 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1). Thus, 641 mg of 5-bromomethyl-2-chloropyrimidine was obtained (Percentage Yield: 38%). 1H-NMR (CDCl3, delta, ppm): 4.42 (2H, s), 8.66 (2H, s) |
35% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 6h; | To a solution of6l (1.5 g, 11.7 mrnoi) and NBS (2.3g, 12.8 rnrnoi)in carbontetrachloride (3OmL) is added BPO (28 rng, 0.12 mmoi) After stirring at 80 O( for 6 hours,the mixture is concentrated and purified by silica gel column chromatography (EA:PE =1:10) to give Bi as a colorless oil (850 rng, 35% yield). (MS: [M+Hi 208.9) |
35.9% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux; | <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (200mg, 1.556 mmol) was dissolved in carbon tetrachloride (5 mL), NBS (332 mg, 1.867 mmol) and benzoyl peroxide (18.84 mg, 0.078 mmol) were added , and the resulting mixture was heated and refluxed for overnight. The reaction solution was returned to RT, concentrated under reduced pressure and purified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate 202a, 116 mg, 0.559 mmol, 35.9 % yield) as a white solid. LC-MS (Method A5): 1.62 min, [M + H]+= 206.9 and 208.9; lH NMR (500 MHz, CDC13) delta 8.69 (s, 2H), 4.44 (s, 2H). |
34% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 95℃; for 18h; | Example 8 3-Methoxymethyl- 1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinoiin-6-yimethyl)-amide Route A 5-Bromomethyl-2-chloro-pyridine 2-Chloro-5-methylpyrimidine (3.0 g, 23.3 mmol) was dissolved in 1,2-dichloroethane (120 mL). To this solution was added N-bromosuccinimide (4.98 g, 28.0 mmol) and azobisisobutyronitrile (1.15 g, 7.00 mmol). The reaction was stirred at 95 C. After 18 hrs at 95 C the reaction mixture was diluted with CHCl3 (150 mL), this solution was washed with sat. NaHCO3 (1x50 mL), water (1x50 mL), brine (1x50 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 15% EtOAc, 85% Pet. Ether, fractions combined and evaporated in vacuo to give a yeliow oil identified as 5-bromomethyl-2-chloro-pyridine (1.64 g, 34%). MH+ = 207.8 |
31% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 75℃; for 6h; | To a solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (5.00 g, 38.90 rnmol) in CCb. (100 mL) was added NBS (10.38 g, 58.30 mmol) and AIBN (0.13 g, 0.78 mmol). The resulting mixturewas heated at 75 C for 6 h. The reaction was cooled to ambient temperature, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Redisep-24 g, 0-20% EtOAc/n-hexane) to obtain Intermediate 98A (2.50 g, 31.00 %) as a colorless liquid. 1H N14R (400 MHz, CDCI3) ppm 4.42 (s, 2 H), 8.67 (s, 2 H). LCMS: The compound did not ionize well. |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; ethyl acetate; | Example 178 5-Bromomethyl-2-chloro-pyrimidine A solution of <strong>[22536-61-4]2-chloro-5-methyl-pyrimidine</strong> (1 g, 7.81 mmol) in carbon tetrachloride (50 mL) was treated with NBS (2 g, excess) and benzoyl peroxide (100 mg) and refluxed for 8 hours. The reaction was filtered, the solvents removed and the product purified on silica (eluding at 15% EtOAc:hexanes). The product was contaminated with 30% starting material and used as such. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 8h;Heating / reflux; | 0.40 g of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> was dissolved in 15 ml of carbontetrachloride and then added with 0.83 g of N-bromosuccinimide and 0.05 g of azobisisobutyronitrile, followed by heating under reflux for 8 hours. The reaction mixture was cooled down to room temperature and then filtrated, followed by the filtrate being concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.27 g of 5-bromomethyl-2-chloropyrimidine represented by above formula.1H-NMR (CDCl3, TMS) , delta (ppm) : 4.43 (2H, s), 8.67 (2H, s) | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 90℃; | Step 1: A mixture of compound 12-1 (1.18 g, 9.18 mmol), NBS (1.96 g, 11.0 mmol) and benzoyl peroxide (0.11 g, 0.46 mmol) in CC14 (30 mL) was stirred overnight at 90C. After concentration, the resulting mixture was purified by column chromatography, eluting with PE/EA = 10/1 to give target compound 12-2 as yellow oil. *H NMR (300 MHz, CDC13) delta 8.65 (s, 2H), 4.41 (s, 2H). LC-MS: m/z = 206.9 [M+H]+. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 16h;Inert atmosphere; | [000121] To a stirring solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> 80 (5 g, 38.89 mmol) in CC (250 mL) under inert atmosphere were added N-bromosuccinimide (6.92 g, 38.89 mmol) and benzoyl peroxide (706 mg, 2.91 mmol) at RT; heated to 85 C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel flash column chromatography using 7% EtOAc/ hexanes to afford crude compound 81 (5 g, mixture of SM and product in the ratio of ~1: 1) as pale yellow solid. TLC: 20% EtOAc/ hexanes (R/. 0.5); LC-MS: 55.30%; 208.8 (M++l); (column; Ascentis Express C18, (50 chi 3.0 mm, 2.7 muiotaeta); RT 1.79 min. 0.025% Aq. TFA + 5% ACN: ACN + 5% 0.025% Aq. TFA, 1.2 mL/min); | |
40 mg | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 12h; | NBS (0.28g, 1.56mmol) and AIBN (0.05g, 0.31mmol) were added to a solution of Example 52C (0.2g, 1.56mmol)in carbon tetrachloride (10mL) and the mixture was stirred at 80C for 12 hours. Water was added and the aqueouslayer was extracted with dichloromethane. The organic layer was purified by preparative TLC (ethyl acetate) to give thetitle compound (40mg), LCMS (ESI) m/z: 206 [M+1]+. |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 76℃; for 18h; | To a solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (92 g, 715.62 mmol, 1.0 equiv) in CCl4 (1000 mL) was added NBS (178.31 g, 1.00 mol, 1.4 equiv) and benzoyl peroxide (3.47 g, 14.31 mmol, 0.02 equiv). The mixture was stirred at 76 C for 18 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The reaction mixture was filtered and the solid cake was washed with DCM (150 mL). The resulting solution was concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (1/0 to 0/1 petroleum ether/EtOAc) to give the product (70.8 g, 47.7% crude yield) as a yellow oil, which was used directly for the next step. LCMS (ESI) m/z: [M + H] calcd for C5H4BrClN2: 206.93; found 206.9. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 78℃; for 18h; | To a solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (92 g, 715.62 mmol, 1.0 equiv) in CCl4 (1000 mL) was added NBS (178.31 g, 1.00 mol, 1.4 equiv) and benzoyl peroxide (3.47 g, 14.31 mmol, 0.02 equiv). The mixture was stirred at 76 C for 18 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The reaction mixture was filtered and the solid cake was washed with DCM (150 mL). The resulting solution was concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (1/0 to 0/1 petroleum ether/EtOAc) to give the product (70.8 g, 47.7% crude yield) as yellow oil, which was used directly for the next step. LCMS (ESI) m/z: [M + H] calcd for C5H4BrClN2: 206.93; found 206.9. | |
76 mg | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chlorobenzene; for 16h;Reflux; | Step 1: Preparation of 5-(bromomethyl)-2-chloropyrimidine A solution of 200 mg (1.56 mmol) of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong>, 277 mg (1.56 mmol) of N-bromosuccinimide and 26 mg (0.16 mmol) of 2,2'-azobis(2-methylpropionitrile) in 17.6 ml of chlorobenzene was heated under reflux for 16 h. The reaction solution was then washed with an aqueous Na2SO3 solution and with saturated aqueous NaHCO3 solution, dried with sodium sulfate and filtered and the solvent was removed under reduced pressure. The residue was separated chromatographically by MPLC on silica gel (gradient: cyclohexane/ethyl acetate). This gave 76 mg of 5-(bromomethyl)-2-chloropyrimidine. 1H-NMR (400.0 MHz, d6-DMSO): delta=8.9119 (1.1); 8.8913 (15.0); 8.8619 (0.7); 8.8222 (1.3); 8.6390 (1.4); 5.5539 (0.5); 5.3766 (0.9); 4.8528 (2.2); 4.7481 (16.0); 4.7234 (1.3); 3.3281 (67.0); 2.6718 (0.4); 2.5248 (0.8); 2.5114 (23.6); 2.5071 (48.7); 2.5027 (64.9); 2.4983 (46.7); 2.4941 (22.6); 2.3295 (0.4); 2.2725 (2.8); 2.2461 (0.6); 1.4376 (0.4); -0.0002 (0.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With zinc; In water; for 3h;Reflux; | Step 1 : A suspension of compound 242 (50.0 g, 307 mmol) and freshly activated (acid washed) Zn (59.8 g, 920 mmol) in water (500 mL) was heated at reflux for 3 hours. TLC showed consumption of SM. The reaction mixture was cooled to room temperature, filtered through a pad of celite, and rinsed with CH2CI2 (500 mL). The phases of the filtrate were separated and the organic phase was washed with brine (300 mL), dried over MgS04, filtered and concentrated under vacuum carefully to give compound 243 as a beige powder (30.6 g, 78% yield, 95% purity by 1 H NMR).1 H NMR (400 MHz, DMSO-d6) delta 8.63 (d, J = 0.9 Hz, 2H), 2.27 (t, J = 0.8 Hz, 3H). |
77% | With ammonium hydroxide; zinc; In water; benzene; for 18h;Reflux; | Step 1. Preparation of 2-chloro-5-methylpyrimidine To a stirred solution of 2,4-dichloro-5-methylpyrimidine (4.00 g, 24.5 mmol) in a mixture of benzene (16.0 mL) and H2O (40.0 mL) was added zinc powder (4.81 g, 73.6 mmol) and ammonia water (8.80 mL, 24.5 mmol) at room temperature. After heating at reflux for 18 hours, the reaction mixture was cooled and filtered through a pad of Celite and the reaction mixture was extracted with Et2O, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hexanes:EtOAc=1:1) to give the desired product (2.44 g, 77%) as a yellow oil. 1H-NMR (400 MHz, CDCl3) delta 2.33 (3H, s), 8.47 (2H, s). |
75% | With water; zinc;Reflux; | A mixture of 2,4-dichloro-5-methylpyrimidine (50 g, 0.31 mol), water (500 mL) and zinc dust (50 g, 0.94 mol) was heated at reflux overnight. The reaction mixture was filtered and the filtrate was extracted with dichloromethane (3*500 mL). The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from petroleum ether to afford compound C60 as a white solid. Yield: 27.9 g, 0.22 mol, 75%. LCMS m/z 129.3 (M+1). 1H NMR (400 MHz, CDCl3) delta 2.25 (s, 3H), 8.40 (5, 2H). |
69% | EXAMPLE 84[4-(6-Bromobenzo[b]thiophen-2-yl)-5-methylpyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride(A). Preparation of 2-chloro-5-methylpyrimidine; Into a 3-necked, 500 mL round bottomed flask is added 2,4-dichloro-5-methylpyrimidine (25.0 g, 153 mmol), THF (125 mL) and zinc powder (30.1 g, 460 mmol). The mixture is heated to reflux and acetic acid (HOAc) (9.21 g, 153 mmol) in THF (20 mL) is dropwise added over 1 hour. After 1.5 hours at reflux, additional HOAc (3.93 g, 65.5 mmol) in THF (12.5 mL) is added over 10 minutes, and the mixture is refluxed for an additional 1 hour. The mixture is filtered over celite, rinsed with THF (150 mL) and the organic layers are concentrated under reduced pressure. The crude mixture is partitioned in EtOAc/dichloromethane/1 N NaOH and filtered. The organic layer is concentrated under reduced pressure to yield a peach colored solid. The crude material is subjected to chromatography on silica (in hexane) to provide the title compound as a white solid (13.5 g, 69% yield). | |
With ammonia; water; zinc; In benzene;Heating / reflux; | General procedure 18.5 (2-chloro-5-methylpyrimidine); 2,4,Dichloro-5-methylpyrimidine (3 g, 18.4 mmol) was refluxed with Zn powder (3.61 g, 55.2 mmol) in a mixture of 28% ammonia (6.6 mL), benzene (12 mL) and water (30 ml) overnight. The reaction was cooled and filtered. The filtrate was extracted with ether, washed with brine, dried over sodium sulfate and concentrated to give the crude 2-chloro-5-methylpyrimidine. | |
With ammonia; zinc; In water; benzene;Heating / reflux; | A solution of concentrated NH4OH (4.4 mL) in water (20 mL) was added to a suspension of compound XIII-A-59 (2 g) and Zn (2.4 g) in benzene (8 mL). The mixture was heated to reflux overnight. After cooling to room temperature, the solution was filtered and extracted twice with ether. The combined ether solution was dried and concentrated to give 1.0 g of crude product that was more than 90% pure thus used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In hexane; N,N-dimethyl-formamide; | Step 2 Benzyl 4-[(5-methylpyrimidin-2-yl)amino]methyl}piperidine-1-carboxylate A stirred mixture of <strong>[157023-34-2]benzyl 4-(aminomethyl)piperidine-1-carboxylate</strong> (EXAMPLE 13, STEP 1)(20.0 g, 0.081 mol), 2-chloro-5-methylpyrimidine (10.4 g, 0.081 mol) and cesium carbonate (52.5 g, 0.161 mol) in DMF (200 mL) was heated at 150 C. for 6 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (700 mL), washed with aqueous saturated NaHCO3 (200 mL), water (5*200 mL), and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel 60 (1 kg), eluding with 50-100% ethyl acetate in hexane to give the title compound. M.S. (M+1): 341. 1H NMR (400 MHz, CDCl3): delta8.11 (s, 2 H, Pyr), 7.35 (m, 5 H, Ar), 5.12 (s, 2 H, ArCH2), 5.00 (s, 1 H, NH), 4.20 (brs, 2 H, NCH2), 3.31 (t, J=6.3 Hz,2 H, NHCH2), 2.77 (brs, 2 H, NCH2), 2.12 (s, 3 H, CH3), 1.78 (m, 1 H, CH), 1.77 (m, 2 H, CHCH2CH2), 1.20 (m, 2 H, CHCH2CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | (B). Preparation of 4-(6-bromobenzo[b]thiophen-2-yl)-2-chloro-5-methylpyrimidine; A solution of <strong>[17347-32-9]6-bromobenzo[b]thiophene</strong> (5.00 g, 23.5 mmol) in THF (50 mL) is cooled to -70 C. Lithium diisopropylamide (12.9 mL of a 2 M solution in heptane/THF/ethylbenzene, 25.8 mmol) is added dropwise over 5 minutes. After stirring for 40 minutes at -75 C., the mixture is removed from the cold bath and allowed to warm to 0 C. over 15 minutes and then recooled to -35 C. 2-Chloro-5-methylpyrimidine (3.02 g, 23.5 mmol) is added to the mixture as a solid in one portion and the resultant mixture is allowed to stir for 30 minutes at -35 C. Acetic acid (1.55 g, 25.8 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.60 g, 24.7 mmol) are added in one portion to the mixture before it is allowed to stir at room temperature for 16 hours. Then the mixture is concentrated under reduced pressure, suspended in warm dichloromethane, eluted through a pad of silica in dichloromethane (1 L) and concentrated under reduced pressure. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 50-100%. The resulting material is sonicated in ether (100 mL) and filtered to provide the title compound as an orange solid (3.08 g, 39% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Hydroiodic acid (13 mL), cooled to 0 C., was added to C60 (2.0 g, 15.6 mmol) and the reaction mixture was stirred at 0 C. for 1 h. The mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and treated with sodium thiosulfate. The aqueous layer was extracted with EtOAc, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) to afford C61 as a white powder. Yield: 1.54 g, 6.99 mmol, 45%. 1H NMR (400 MHz, CDCl3) delta 2.24 (s, 3H), 8.29 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; water; toluene; for 8h;Inert atmosphere; Reflux; | (1) 2-(4-tert-Butylphenyl)-5-methylpyrimidine 2-Chloro-5-methylpyrimidine (1.9 g, 15 mmol) was dissolved in a mixture of toluene (30 mL), ethanol (15 mL) and water (15 mL), and (4-tert-butylphenyl)boronic acid (2.9 g, 17 mmol), sodium carbonate (4.8 g, 45 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride-dichloromethane adduct (1.2 g, 1.5 mmol) were added at room temperature under a nitrogen atmosphere, followed by heating to reflux for 8 hours. The reaction solution was cooled to room temperature, and the insoluble materials were filtered off. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (Moritex Corporation, elution solvent:hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.70 (hexane/ethyl acetate=3/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (2.5 g, 11 mmol) as a white solid (yield 73%). 1H-NMR (500 MHz, CDCl3) delta: 8.62 (2H, s), 8.32 (2H, d, J=8 Hz), 7.50 (2H, d, J=8 Hz), 2.34 (3H, s), 1.37 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water;Inert atmosphere; Reflux; | To a 100 mL round-bottomed flask was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-1-one (SM-1a, 1.50 g, 5.81 mmol), <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (747 mg, 5.81 mmol), sodium carbonate (2.47 g, 23.3 mmol), 27 mL of dioxane, and 3 mL of water. The mixture was degassed with nitrogen for 15 minutes. Palladium tetrakis(triphenylphosphine) (356 mg, 0.31 mmol) was added and the mixture was degassed with nitrogen for an additional 15 minutes. The reaction was heated at reflux overnight. The reaction was cooled to room temperature and was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The final product was purified by silica chromatography on a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) eluting with 20-35% ethyl acetate in heptanes to provide a white solid (SM-1d, 1.12 g, 86%). MS (ES+) 225.2 (M+H+). 1H NMR (CDCl3) delta 2.38 (s, 3H), 2.74-2.78 (m, 2H), 3.23 (t, 2H), 7.85 (d, 1H), 8.44 (d, 1H), 8.53 (s, 1H), 8.68 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 5h; | 4-Hydroxy-piperidine (2.0 g, 19.8 mmol), <strong>[22536-61-4]2-chloro-5-methyl-pyrimidine</strong> (2.8 g, 19.38 mmol) and triethylamine (5.5 mL, 39.5 mmol) were dissolved in dimethylformamide (100 mL). The temperature was elevated to 100 C and the mixture was stirred for 5 hours. The temperature was changed to room temperature, and water and ethyl acetate were added thereto. The mixture was extracted with ethyl acetate (100 mL) three times, concentrated by distilling under reduced pressure, and separated by column chromatography using 3:1 mixture solution of ethyl acetate and hexane to obtain 1-(5-methyl-pyrimidin-2-yl)-piperidin-4-ol (2.5 g, 65% yield). 1-(5-Methyl-pyrimidin-2-yl)-piperidin-4-ol (2.5 g, 12.9 mmol) was then reacted according to the method of Preparation Example 4 to obtain the title compound (2.2 g, 82% yield).[341] NMR: 1H-NMR(CDCl3) 8.15(2H, s), 5.33(2H, s), 4.32~4.22(2H, m), 3.83~3.74(1H, m), 3.37~3.27(2H, m), 2.11(3H, s), 2.03~1.94(2H, m), 1.62~1.50(2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 18h;Inert atmosphere; | General procedure: To an oven-dried round-bottom flask containing tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (1.0 mmol) was added bis(pinacolato)diboron (1.1 mmol), potassium acetate (4.0 mmol) and 10 mL of anhydrous 1,4-dioxane. The resulting mixture was purged with N2 for three times. Pd(dppf)Cl2 (0.05 mmol) was added, the reaction mixture was purged with N2 again three times and heated under N2 at 110 C for 46 h. The course of the reaction was followed by TLC (5% MeOH in CH2Cl2) and LCMS. The reaction mixture was cooled to room temperature, and the aryl halide 5 (1.1 mmol)], Pd(dppf)Cl2 (0.05 mmol) and 3.5 mL of 2M aqueous solution of potassium carbonate (de-oxygenated by bubbling through N2 for 15 minutes before addition) were added. The reaction mixture was purged with N2 three times and then heated under N2 for 618 h at 110 C. The course of the reaction was followed by LCMS. The reaction mixture was cooled to room temperature, and the solvent removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and 1N NaOH solution (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude product as a dark brown oil. The crude product was purified by silica gel chromatography, eluting with 010% MeOH in CH2Cl2 to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux; | Synthesis Example 25 N-[1-((2-chloropyrimidin-5-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound 243) 2-chloro-5-methylpyrimidine (1.04 g, 8.13 mmol) was dissolved in 30 mL of carbon tetrachloride, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, and the mixture was refluxed under heating for 6 hours. Following reaction completion, the reaction mixture was returned to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/ethyl acetate=3:1), affording 641 mg of 5-bromomethyl-2-chloropyridine (yield, 38%). 1H-NMR (CDCl3, delta, ppm): 4.42 (2H, s), 8.66 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In N,N-dimethyl-formamide; at 120℃; under 22502.3 Torr; | To a solution of 2-chloro-5-methyl-pyrimidine (10.0 g, 77.8 mmol, 1 equiv) in MeOH (200 mL) and DMF (40 mL) were added triethylamine (23.6 g, 233.4 mmol, 32.4 mL, 3 equiv) and Pd(dppf)Cl2 (8.5 g, 11.7 mmol, 0.15 equiv). The suspension was degassed and purged with CO several times. The mixture was stirred under CO (3 Mpa) at l20C for 72 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (eluted with PE/EtOAc = 20/1 ~ 10/1) to afford the title compound methyl 5-methylpyrimidine-2-carboxylate as a light yellow solid (6.7 g, 57% yield). To a solution of 2-chloro-5-methyl-pyrimidine (10.0 g, 77.8 mmol, 1 equiv) in MeOH (200 mL) and DMF (40 mL) were added triethylamine (23.6 g, 233.4 mmol, 32.4 mL, 3 equiv) and Pd(dppf)Cl2 (8.5 g, 11.7 mmol, 0.15 equiv). The suspension was degassed and purged with CO several times. The mixture was stirred under CO (3 Mpa) at l20C for 72 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (eluted with PE/EtOAc = 20/1 ~ 10/1) to afford the title compound methyl 5-methylpyrimidine-2-carboxylate as a light yellow solid (6.7 g, 57% yield). |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In acetonitrile; at 20 - 100℃;Inert atmosphere; | [0613] Synthesis of methyl 5-methylpyrimidine-2-carboxylate: Me [0614] To a stirred solution of 2-chloro-5-methylpyrimidine (200 mg, 1.55 mmol) in MeOH: CH3CN (4: 1, 10 mL) under argon atmosphere were added Pd(dppf)Cl2 (227 mg, 0.31 mmol) and triethyl amine (0.45 mL, 3.11 mmol) at RT; heated to 100 C and stirred for 16 h in steel bomb under CO pressure. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 60% EtOAc/ Hexanes to afford 5-methylpyrimidine-2-carboxylate (146 mg, 62%) as brick red solid. [0615] 1H-NMR (CDCls, 400 MHz): delta 8.74 (s, 2H), 4.08 (s, 3H), 2.42 (s, 3H); LC-MS: 81.73%; 153 (M++l); (column: X Bridge C-18, 50 3.0 mm, 3.5 mupiiota); RT 2.10 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: 70% EtOAc/ Hexanes (R 0.2) | |
350 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In N,N-dimethyl-formamide; at 120℃; under 22502.3 Torr; for 16h; | To a solution of 2-chloro-5-methyl-pyrimidine (500.00 mg, 3.89 mmol, 1.00 eq) in MeOH (10.00 mL) and DMF (2.00mL) was added triethylamine (1.18 g, 11.67 mmol, 1.62 mL, 3.00 eq) and Pd(dppf)C12 (426.87 mg, 583.39 umol, 0.15 eq) under CO. The suspension was degassed and purged with CO several times. The mixture was stirred under CO (3 Mpa) at 120C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The crude residue was purified by column chromatography (Petroleum ether : Ethyl acetate=20: l to 0: 1) to afford methyl 5-methylpyrimidine-2-carboxylate (350.00 mg). LCMS (M+H+) m/z: 153. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 1.5h;Microwave irradiation; | A solution of the compound (556 mg, 1.0 mmol) obtained in Example 16-5), <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (193 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130C for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate = 0:100 to 20:80, gradient) to obtain the title compound (298 mg, 57%) as a brown oily substance. 1H-NMR (400 MHz, CDCl3) delta: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.49-1.52 (2H, m), 1.58-1.67 (2H, m), 2.34 (3H, s), 2.50 (1H, ddd, J = 15.6, 8.0, 2.2 Hz), 2.63 (1H, ddd, J = 15.6, 7.7, 2.2 Hz), 3.40 (2H, s), 3.50 (1H, d, J = 10.2 Hz), 3.54 (1H, d, J = 10.2 Hz), 4.06 (1H, ddd, J = 14.6, 8.0, 2.2 Hz), 4.31 (1H, ddd, J = 14.6, 7.7, 2.2 Hz), 7.17 (2H, dt, J = 8.7, 2.0 Hz), 8.32 (2H, dt, J = 8.7, 2.0 Hz), 8.62 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 140℃; for 2h;Microwave irradiation; | The compound (600 mg, 1.08 mmol) obtained in Example 52-2), <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (155 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.05 mmol), tricyclohexylphosphine (36 mg, 0.13 mmol), and tripotassium phosphate (400 mg, 1.84 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), and the mixture was stirred at 140C for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, then diluted with methylene chloride (100 mL), and separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (30 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate = 0% to 20%) to obtain the title compound (348 mg, 62%) in a light yellow solid form. 1H-NMR (400 MHz, CDCl3) delta: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.46-1.53 (2H, m), 1.61-1.68 (2H, m), 2.34 (3H, s), 2.50 (1H, ddd, J = 15.6, 7.8, 2.3 Hz), 2.63 (1H, ddd, J = 15.7, 7.7, 2.2 Hz), 3.40 (2H, s), 3.52 (2H, dd, J = 15.8, 10.0 Hz), 4.06 (1H, ddd, J = 14.5, 7.8, 2.3 Hz), 4.31 (1H, ddd, J = 14.5, 7.8, 2.3 Hz), 7.17 (2H, d, J = 8.6 Hz), 8.32 (2H, d, J = 8.6 Hz), 8.62 (2H, d, J = 0.8 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 110℃;Inert atmosphere; | General procedure: To 1,4-dioxane (15 mL) were added chloro-substituted N-heterocycles(10.0 mmol), aromatic boronic acid (or pinacol ester, 12.0 mmol), Pd(dppf)Cl2 (0.73 g, 1.0mmol) and aqueous Cs2CO3 (2 N, 10 mL, 20.0 mmol) under N2 atmosphere. The content washeated and kept at 110 C overnight. The reaction mixture was cooled to room temperature after the completion of the reaction. Dioxane was removed under reduced pressure. The resultant aqueous solution was extracted with EtOAc. The combined organic phase was washed with water and saturated brine for three times, and dried over Na2SO4. After the removal of the solvent under reduced pressure, the residue was charged to flash chromatography, which gave the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 110℃;Inert atmosphere; | General procedure: To 1,4-dioxane (15 mL) were added chloro-substituted N-heterocycles(10.0 mmol), aromatic boronic acid (or pinacol ester, 12.0 mmol), Pd(dppf)Cl2 (0.73 g, 1.0mmol) and aqueous Cs2CO3 (2 N, 10 mL, 20.0 mmol) under N2 atmosphere. The content washeated and kept at 110 C overnight. The reaction mixture was cooled to room temperature after the completion of the reaction. Dioxane was removed under reduced pressure. The resultant aqueous solution was extracted with EtOAc. The combined organic phase was washed with water and saturated brine for three times, and dried over Na2SO4. After the removal of the solvent under reduced pressure, the residue was charged to flash chromatography, which gave the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In acetonitrile; at 120℃; for 2.5h;Sealed tube; Microwave irradiation; | In a sealed glass tube a suspension of l-cyclopropyl-6-(lH-imidazol-5-yl)-3,3-dimethylindolin- 2-one (example 71a, 70 mg), <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (37.0 mg) and cesium carbonate (158 mg) in acetonitrile (1.05 ml) was heated to 120 C for 30 minutes under microwave irradiation. Then again 18 mg <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> and 89 mg cesium carbonate were added and the reaction mixture heated to 120C under conventional heating for 2 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, gradient, 0% to 100% EtOAc in n-heptane). The title compound was obtained as off white solid (75 mg, 80%). MS (ESI, m/z): 360.2 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.7% | With sodium hydroxide; In N,N-dimethyl-formamide; at 0 - 20℃; for 4.16667h;Inert atmosphere; | 4-(4-pyridyl)-1-butanol hydrochloride (50mg, 0.27mmol) was dissolved in 3 ml of DMF, cooled to 0 deg. C ice bath, followed by the addition of sodium hydroxide (20mg, 0.83mmol), nitrogen blanket for 10 minutes after addition of <strong>[22536-61-4]2,4-dichloro-5-methylpyrimidine</strong> (56mg, 0.34mmol). The reaction was stirred at room temperature for 4 hours until the end of the reaction. Quenched with water, dilute hydrochloric PH4-5, extracted with ethyl acetate, washed with water, sodium bicarbonate and the aqueous phase was adjusted PH8-10, extracted with ethyl acetate, washed with water, the organic phase was dried and concentrated to give 2-chloro-5-methyl-4-(4-(pyridin-4-yl)butyloxy)pyrimidine (34mg, 56.7% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium sulfide; In toluene; at 40℃; for 12h; | The <strong>[22536-61-4]2-chloro-5-methyl pyrimidine</strong> (128 mg, 1mmol), three ethylene diamine (224 mg, 2mmol), sodium sulfide (39 mg, 0 . 5mmol), potassium phosphate (217 mg, 1mmol), toluene (2 ml) is added to the dry reaction tubes, at 40 C reaction in oil bath 12h. After cooling the reaction system, by adding 15 ml of water, the aqueous phase with ethyl acetate 30 ml extraction 3 time, combined with the phase, solvent evaporation to dryness under reduced pressure, column chromatography to obtain 130 mg of colorless solid 2 - ((2 - (4 - (2-pyrimidinyl) - 1-piperazinyl) ethyl) sulfur) pyrimidine, yield is 79%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0) at 100℃; for 16h; Inert atmosphere; | 738.0 [01458j 5-methylpyrimidine-2-carbonitrile, Example 738.1. A solution of 2-chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv) in DMF (5000 mL) was degassed with N2 for 20 mm and then dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was added, and the reaction mixture was heated at 100 °C for 16 h. The reaction was quenched with water (5000 mL) and stirred for 10 mm. The reaction mixture was filtered through a pad of Celite brand filter agent. The filtrate was diluted with water (4000 mL) and extracted with EtOAc (2 x 4000 mL). The combined organic layer was washed with brine (4000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexane to obtain Example 738.1 (330 g, 71%) as off white solid. ‘HNMR(400 MI-Tz, DMSO-d6) 8.89 (s, 2H), 2.39 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | (E)-2-(but-2-en-2-yl)-5-methylpyrimidine, Example 10.01. 2- Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask, which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel, then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 10.01 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | (E)-2-(But-2-en-2-yl)-5-methylpyrimidine, Example 1.01 2-Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2-yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask, which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 C. for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 1.01 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h; | 2- Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3(13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction mixture was heated at 100 C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and was then loaded onto silica gel and purified (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 464.01 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | 2-Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexyiphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1 ,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 27.1 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | 2- Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 102.01 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask, which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel, and was then loaded onto silica gel and purified (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 81.1 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | 2-Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (Sigma Aldrich, 31 g, 191 mmol), tricyclohexyiphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1 ,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine, Example 371.01 (19 g, 125 mmol), in 83% yield. |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; | 2-Chloro-5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2- yltrifluoroborate (commercially available from Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol) and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask, which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel (0-20% EtOAc in heptanes) to afford (E)-2-(but-2-en-2-yl)-5-methylpyrimidine 27.01 (19 g, 125 mmol, 83% yield). |
83% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | 2-Chloro- (0580) 5-methyl-pyrimidine (18 mL, 151 mmol), potassium (Z)-but-2-en-2-yltrifluoroborate (commercially available from Sigma Aldrich, 31 g, 191 mmol), tricyclohexylphosphine (8.5 g, 30.2 mmol), and Pd2(dba)3 (13.82 g, 15.09 mmol) were added to a flask which was then degassed and backfilled with nitrogen. To the flask was added 1,4-dioxane (252 mL) and aqueous potassium phosphate tribasic (37.5 mL, 453 mmol). The resulting reaction was heated at 100 C for 16 h. The reaction was then cooled to RT. The residue was filtered through a plug of silica gel and then loaded onto silica gel and purified eluting with 0-20% EtOAc in heptanes to afford Example 27.1 (19 g, 125 mmol, 83% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate; triphenylphosphine; palladium dichloride; In tetrahydrofuran; water; at 62℃;Inert atmosphere; | [0397j 5-methyl-2-vinylpyrimidine, Example 11.01. A 3 L 3-necked round bottomed flask was fitted with a reflux condenser, a temperature controller and a septum and was charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (81 mL, 778 mmol), potassium vinyltrifluoroborate (156 g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar. Water (1565 mL) was added and the mixture was stirred for several minutes and then THF (244 mL) was added. Argon was bubbled through the mixture for 5 mm and then added palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 mins. The temperature was raised to 62 C and stirring continued to completion. The reaction was then cooled to RT and filtered through two Whatman GF/F filter cups, rinsing with ether. The mixture was transferred to a separatory funnel, and the the layers were separated. The aqueous layer was further extracted with diethyl ether (4 x 200 mL). The organic layers were combined and dried over anydrous MgSO4 and then filtered. The mixture was partially concentrated on the roto evaporator at 20 C and 115 torr for an extended period of time to give an orange liquid. The material was further purified by Kugelrohr distillation to isolate the title compound (65.4 g, 70%) as a light yellow oil. ?HNMR(400MHz, CDC13)E2.31 (s, 3H), 5.68 (d,J10.56Hz, 1H), 6.55 (d,J17.22Hz, 1H), 6.86 (dd, J=17.41, 10.56 Hz, 1H), 8.54 (s, 2H). LCMS-ESI (pos.) mlz: 121.1 (M+H). |
70% | With caesium carbonate; triphenylphosphine; palladium dichloride; In tetrahydrofuran; water; at 62℃;Inert atmosphere; | 5-Methyl-2-vinylpyrimidine, Example 28.1 A 3 L 3-necked round bottomed flask was fitted with a reflux condenser, a temperature controller and a septum and was charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (81 mL, 778 mmol), potassium vinyltrifluoroborate (156 g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar. Water (1565 mL) was added, and the mixture was stirred for several min and then THF (244 mL) was added. Argon was bubbled through the mixture for 5 min and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 mins. The temperature was raised to 62 C. and stirring continued to completion. The reaction was then cooled to RT and filtered through two Whatman GF/F filter cups, rinsing with ether. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was further extracted with diethyl ether (4*200 mL). The organic layers were combined and dried over anhydrous MgSO4 and then filtered. The mixture was partially concentrated on a rotary evaporator at 20 C. and 115 torr for an extended period of time to give an orange liquid. The material was further purified by Kugel Rohr distillation to isolate the title compound (65.4 g, 70%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) delta 2.31 (s, 3H), 5.68 (d, J=10.56 Hz, 1H), 6.55 (d, J=17.22 Hz, 1H), 6.86 (dd, J=17.41, 10.56 Hz, 1H), 8.54 (s, 2H). LCMS-ESI (pos) m/z:121.1 (M+H)+. |
70% | A 3-necked 3 L RBF was fitted with a reflux condenser, a temperature controller and a septum and was charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (81 mL, 778 mmol), potassium vinyltrifluoroborate (156 g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), and cesium carbonate (156 mL, 1945 mmol). Water (1565 mL) was added, and the mixture was stirred for 2 min and then THF (244 mL) was added. Argon was sparged through the mixture for 5 min and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 min. The temperature was raised to 62 C and stirring was continued until completion. The reaction was cooled to RTand filtered through two Whatman GF/F filter cups, rinsing with diethyl ether. The mixture was transfered to a separatory funnel and the layers were separated. The aqueous layer was further extracted with diethyl ether (4X). The combined organic layers were dried over anhydrous magnesium sulfate and partially concentrated in vacuo at 20 C and 115 torr for an extended period of time to give an orange liquid. The initial product was purified by Kugelrohr distillation to provide 405.01 (65.4 g, 70% yield) as a light yellow oil. LCMS- ESI (pos.) m/z: 121.1 (M+H)+. |
70% | A 3 L 3-necked round bottom flask was fitted with a reflux condenser, a temperature controller and a septum and was charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (81 mL, 778 mmol), potassium vinyltrifluoroborate (156g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar. Water (1565 mL) was addedand the mixture was stirred for several mm and then THF (244 mL) was added. Argon was bubbled through the mixture for 5 mm and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 mins. The temperature was raised to 62 C and stirring was continued to completion. The reaction was then cooled to RT and filtered through two Whatman GF/F filter cups, rinsing with ether. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was further extracted with diethyl ether (4 x 200 mL). The organic layers were combined and dried over anhydrous MgSO4 and then filtered. The mixture was partially concentrated on the rotory evaporator at 20 C and 115 torr for an extended period of time to give an orange liquid. The material was further purified by Kugelrohr distillation to isolate the title compound (65.4g, 70%) as a light yellow oil. 1H NMR (400 MHz, CDC13) oe 2.31 (s, 3H), 5.68 (d,J10.56 Hz, 1H), 6.55 (d,J17.22 Hz, 1H), 6.86 (dd,J17.41, 10.56 Hz, 1H), 8.54 (s, 2H). LCMS-ESI (pos.)m/z:121.1 (M+H)t | |
70% | With caesium carbonate; triphenylphosphine; palladium dichloride; In tetrahydrofuran; water; at 62℃;Inert atmosphere; | A 3 L 3 -neck round bottomed flask was fitted with a reflux condenser, a temperature controller and a septum and charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (81 mL, 778 mmol), potassium vinyltrifluoroborate (156 g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar. Water (1565 mL) was added, and the mixture was stirred for several min before THF (244 mL) was added. Argon was bubbled through the mixture for 5 min and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 mins. The temperature was raised to 62 C and stirring was continued to completion. The reaction was then cooled to RT and filtered through two Whatman GF/F filter cups, rinsing with ether. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was further extracted with diethyl ether (4 x 200 mL). The organic layers were combined and dried over anhydrous MgS04 and then filtered. The mixture was partially concentrated on the rotary evaporator at 20 C and 115 torr for an extended period of time to give an orange liquid. The material was further purified by Kugelrohr distillation to isolate the title compound (65.4g, 70%) as a light yellow oil. NMR (400 MHz, CDC13) delta 2.31 (s, 3H), 5.68 (d, J=10.56 Hz, 1H), 6.55 (d, J=17.22 Hz, 1H), 6.86 (dd, J=17.41, 10.56 Hz, 1H), 8.54 (s, 2H). LCMS-ESI (pos.) m/z: 121.1 (M+H)+. |
70% | A 3-necked 3 L RBF was fitted with a reflux condenser, a temperature controller and a septum and was charged with <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (100 g, 778 mmol), potassium vinyltrifluoroborate (156 g, 1167 mmol), triphenyiphosphine (20.5 g, 78 mmol), cesium carbonate (633.7 g, 1945 mmol), and a large stir bar. Water (1565 mL) was added, and the mixture was stirred for several mm and then THF (244 mL) was added. Argon was bubbled through the mixture for 5 mm and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was then further sparged with argon for 5 mm. The temperature was raised to 62 C, and the mixture was stirred until completion. The reaction was ten cooled to RT and filtered through two Whatman GF/F filter cups rinsing with ether. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with Et20 (4X). The combined organic layers were dried over anhydrous MgSO4 and partially concentrated in vacuo at 20 C and 115 ton for an extended period of time to give an orange liquid. The initial product was purified by Kugelrohr distillation to provide Example 356.01 (65.4 g, 70% yield) as a light yellow oil. LCMS-ESI (pos.) m/z: 121.1 (M+H)t | |
70% | With caesium carbonate; triphenylphosphine; palladium dichloride; In tetrahydrofuran; at 62℃;Inert atmosphere; | A 3 L 3-necked round bottom flask was fitted with a reflux condenser, a temperature controller and a septum and then charged with 2-chloro-5-methylpyrimidme (81 mL, 778 mmol), potassium vinyltrifluoroborate (156 g, 1167 mmol), triphenylphosphine (18.02 mL, 78 mmol), cesium carbonate (156 mL, 1945 mmol) and a large stir bar. Water (1.6 L) was added and the mixture was stirred for several mm and then THF (244 mL) was added. Argon was bubbled through the mixture for 5 mm and then palladium (II) chloride (1.72 g, 38.9 mmol) was added. The reaction was further sparged with argon for 5 mm. The temperature was raised to 62 C and stirring was continued to completion. The reaction was then cooled to RT and filtered through two Whatman GF/F filter cups, rinsing with ether. The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with diethyl ether (4 x 200 mL). The organic layers were combined and dried over anhydrous MgSO4 and then filtered. The mixture was partially concentrated on the rotory evaporator at 20 C and 115 torr for an extended period of time to give an orange liquid. The material was further purified by Kugelrohr distillation to provide the title compound (65.4 g, 70%) as a light yellow oil. 1H NMR (400 MHz, CDC13) oe 2.31 (s, 3H), 5.68 (d,J10.56 Hz, 1H), 6.55 (d,J17.22 Hz, 1H), 6.86 (dd,J=17.41, 10.56 Hz, 1H), 8.54 (s, 2H). LCMS-ESI (pos.)m/z:121.1 (M+H)t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium phosphate; In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | [0409j (E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine, Example 14.01. To a 500 mL round bottomed flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop-1-en-1-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 mm and then 1,1 -bis [(di-t-butyl-p-methylaminophenyljpalladium(II) chloride (Amphos, commercially avaliable from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached and the reaction warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl- 2-(prop-1-en-1-yl)pyrimidine 14.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. ?H NMR (300 MHz, CDC13) = 8.49 (s, 2H), 7.0 1-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). MS (ESI pos. ion) m/z:(M--H). |
100% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | (E)-5-Methyl-2-(prop-1-en-1-yl)pyrimidine, Example 11.01 To a 500 mL round bottomed flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop-1-en-1-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5*) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium (II) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached, and the reaction was warmed to 90 C. in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2*250 mL). The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl-2-(prop-1-en-1-yl)pyrimidine 11.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. 1H NMR (300 MHz, CDCl3) delta=8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J=15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J=6.8, 1.6 Hz, 3H). LCMS (ESI pos ion) m/z: 135.2 (M+H)+. |
100% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium acetate; In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | To a 500 mL RBF was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)- trifluoro(prop-1-en-1-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2(5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was sparged with Ar for 15 min and then 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached, and the reaction was warmed to 90 C in an oil bath and stirred under N2for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL) and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl-2-(prop-1-en-1- yl)pyrimidine 466.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid.1H NMR (300 MHz, CDCl3) delta 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). LCMS (ESI pos.) m/z: 135.2 (M+H)+. |
100% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | To a 500 mL round bottomed flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop-1-en-1-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added. A reflux condenser was attached, and the reaction was warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl- 2-(prop-1-en-1-yl)pyrimidine 103.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. 1H NMR (300MHz, CDCl3) delta 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). LCMS (ESI pos.) m/z: 135.2 (M+H)+. |
100% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | To a (0712) 500 mL round bottomed flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop-l-en-l-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then l,l-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached, and the reaction was warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL) and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgS04), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl- 2-(prop-l-en-l-yl)pyrimidine 83.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. NMR (300MHz, CDC13) delta 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). LCMS (ESI pos.) m/z: 135.2 (M+H)+. |
100% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | To a 500 mL RBF was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)trifluoro(prop-1-en-1-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 mm and then 1,1 -bis [(di-t-butyl-p-methylaminophenyljpalladium(II) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached, and the reaction warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL) and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5 -methyl-2-(prop- 1-en-i - yl)pyrimidine 373.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. 1H NMR (300MHz, CDC13) oe 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd,J= 6.8, 1.6 Hz, 3H). LCMS (ESI pos.) mlz: 135.2 (M+H)t |
100% | With potassium phosphate; In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | To a500 mL round bottom flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop- 1-en-i -yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 mm and then 1,1 -bis [(di-t-butyl-p-methylaminophenyljpalladium(II) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached, and the reaction was warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5-methyl- 2-(prop-i-en-i-yl)pyrimidine 29.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. 1H NMR (300 MHz, CDC13) oe 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). LCMS-ESI (pos.) m/z:135.2 (M+H)t |
100% | With potassium phosphate; 1,1-bis[di-t-butyl-p-methylaminophenyl]palladium(II) chloride; In 1,4-dioxane; at 90℃; for 16.5h;Inert atmosphere; | To a 500 mL round bottomed flask were added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop-l-en-l-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane (200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then l,l-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (commercially available from Strem, 2.64 g, 3.73 mmol) was added. A reflux condenser was attached, and the reaction was warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL) and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSC ) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes to afford Example 24.11 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. NMR (300MHz, CDC13) delta 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (d = 6.8, 1.6 Hz, 3H). LCMS-ESI (pos.) m/z: 135.2 (M+H)+. |
100% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | (E)-5-Methyl-2-(prop-l-en-l-yl)pyrimidine, Intermediate 5.5.1 To a 500 mL round bottomed flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol), potassium (E)-trifluoro(prop-l-en-l-yl)borate (17.27 g, 117 mmol), and potassium phosphate (59.4 g, 280 mmol). The flask was pinged with N2 (5x), then 1,4-dioxane (200 ml), and water (20.00 ml) were added. The resulting yellow suspension was bubbled with Ar for 15 min and then l,l-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added. A reflux condenser was attached and the reaction was warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extraxted with EtOAc (2x250 mL). The organic layers were combined, dried (MgSCb), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtO Ac/hexanes) to afford Intermediate 5.5.1 (12.96 g, 97 mmol, 100 % yield) as a yellow/orange oily solid. NMR (300MHz, CDC13) d 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 1H). MS (ESI pos. ion) m/z: 135.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.62 g | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In 1,4-dioxane; water; at 100℃; for 24h;Inert atmosphere; | [01332j 2-(3,4-Dihydro-2H-pyran-6-yl)-5-methylpyrimidine, Example643.1. A mixture of 2-chloro-5-methylpyrimidine (1.2 g, 9.33 mmol), 3,4-dihydro-2h- pyran-6-boronic acid pinacol ester (2.94 mL, 14.0 mmol), tricyclohexyiphosphine (0.524 g, 1.87 mmol) and tris-(dibenzylideneacetone) dipalladium (0) (0.855 g, 0.93 mmol) inflask was degassed and backfilled with argon. To this mixture were added 1,4-dioxane (16 mL) and potassium phosphate tribasic (6.45 g, 28.0 mmol) in water (2.0 mL). A stream of argon was bubbled through the resulting mixture for an additional 5 minutes, and the mixture was stirred at 100 C under a balloon of argon for 24 hours. The mixture was cooled to RT, filtered, and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by Isco CombiFlash on a RediSep 80 g silica gel column using 0-100% EtOAc gradient in heptane as the eluent to give Example 643.1 (1.62 g). ?H NMR (400 MI-Tz, CDC13) 8.48 (s, 2H), 6.26 (t, J= 4.1, 4.1 Hz, 1H), 4.21- 4.24 (m, 2H), 2.20-2.26 (obscured m, 2H), 2.25 (s, 3H), 1.9 (dd, J= 5.6, 4.8 Hz, 2H). LCMS (pos.)m/z: 177.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | [013551 (Z)-2-(But-2-en-2-yl)-5-methylpyrimidine, Example 671.2. A round bottom flask was charged with IPA (600 mL) and purged with argon for 1-2 h at 25-30C. 2-Chloro-5-methylpyrimidine (30.0 g, 0.23 3 mol) was charged into the flask, and the mixture was stirred for 5-10 mm followed by addition of potassium phosphate tribasic (98.9 g, 466 mol), (E)-but-2-en-2-ylboronic acid Example 671.1 (34.9 g, 0.349 mol), 2- dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (4.2 g, 8.8 mmol) and Pd2(dba)3 (2.13 g, 2.32 mmol). The reaction was stirred for 10-15 mm under argon atmosphere and then heated to 75-80 C for 12-16 h. The reaction was cooled to 0-5 C. Water (300.0 mL) and MTBE (180.0 mL) were then added slowly. The aqueous and organic layers were separated. The aqueous layer was extracted with MTBE (60.0 mL). The combined organic layers were washed with brine (60.0 mL) twice. The organic layer was concentrated in vacuo to afford the initial product which was diluted with heptane (150.0 mL) and MTBE (75.0 mL). The above mixture, was extracted three times with aq. hydrochloric acid. The combined aqueous layers were washed with heptane (30.0 mL), made basic with sodium hydroxide solution until pH 10 was obtained, and extracted with heptane (90.0 mL). The aqueous and organic layers were separated and the aqueous layer was extracted with heptane (30.0 mL). The combined organic layers were washed with brine (60.0 mL), dried over sodium sulfate, and concentrated in vacuo to afford (Z)-2- (but-2-en-2-yl)-5 -methylpyrimidine, Example 671.2 in 68% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuryl dichloride; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 60 - 70℃; for 1.16667h; | A.a.a.1 Synthesis of amine salt a.1 To a mixture of 2-chloro-5-methyl-pyrimidine (100 g, 780 mmol) in 450 ml of CCU was added azobisisobutyronitrile (AIBN) (6.386 g, 39 mmol) and the mixture was heated to 60°C. Then a solution of SO2CI2 in 50 ml CCU was added in a dropwise manner. After the gas evolution started, the rate of the addition of the SO2CI2 solution was adjusted to allow minimal gas evolution, the addition of the solution required an addition 40 minutes. Heating was then continued for another 30 min at 70°C. The reaction mixture was cooled to room temperature, and slowly poured into ice-water (ca. 200 mL) and the pH was adjusted to 6 through the addition of NaHCC>3. The layers were separated and the aqueous layer was extracted with (200 mL). The combined organic layers were washed with water (4x 100 mL) and dried over Na2S04, filtered, and concentrated in vacuo to afford a residue. The residue was analyzed by 1H-NMR and the mixture was found to consist of 65% w/w product, 18% w/w dichlorinated pyrimidine and 17% w/w starting material. The product was used in the next step without purification (total yield of the mixture: 124 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | 5-Methylpyrimidine-2-carbonitrile, Example 13.1 A solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (500 g, 3889 mmol, 1.0 equivalent) in DMF (5000 mL) was degassed with N2 for 20 min and dppf (108 g, 194 mmol, 0.05 equivalent) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equivalent) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equivalent) was added, and the reaction mixture was heated at 100 C. for 16 h. The reaction was quenched with water (5000 mL) and stirred for 10 min. The reaction mixture was then filtered through a pad of Celite brand filter agent. The filtrate was diluted with water (4 L) and extracted with EtOAc (2*4 L). The combined organic layers were washed with brine (4 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10% EtOAc in hexanes to obtain Example 13.1 (330 g, 71%) as off white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h; | A solution of 2- chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv.) in DMF (5 L) was degassed with N2 for 20 min and dppf (108 g, 194 mmol, 0.05 equiv.) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv.) were added to the reaction mixture. Zn(CN)2(685 g, 5834 mmol, 1.5 equiv.) was then added, and the reaction mixture was heated at 100 C for 16h. The reaction was quenched with water (5 L) and stirred for 10 min. The reaction mixture was then filtered through a pad of Celite brand filter agent. The filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na2SO4,filtered and concentrated under reduced pressure to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexanes to obtain Example 468.1 (330 g, 71 %) as an off white solid.1H NMR (400 MHz, DMSO-d6) delta 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | A solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (500 g, 3889 mmol, 1.0 equiv) in DMF (5000 mL) was degassed with N2 for 20 mm and dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was added, and the reaction mixture was heated at 100 C for 16h. The reaction was quenched with water (5 L) and stirred for 10 mm. The reaction mixture was then filtered through a pad of Celite brand filter aid. Filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na2SO4, filtered and concentrated in vacuo to give the initial product which was further purified by column chromatography using silica gel (60-120mesh) and 0-10 % EtOAc in hexanes to obtain Example 31.1 (330 g, 71 %) as and off white solid. 1H NMR (400 MHz, DMSO-d6) oe 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | A solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (500 g, 3889 mmol, 1.0 equiv) in DMF (5 L) was degassed with N2 for 20 min and dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was next added, and the reaction mixture was heated at 100 C for 16h. The reaction was then quenched with water (5 L) and stirred for 10 min. The reaction mixture was then filtered through Celite filter aid. The filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexanes to obtain Example 104.01 (330 g, 71 %) as off white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | A solution of 2- chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv) in DMF (5000 mL) was degassed with N2 for 20 min and dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was then added, and the reaction mixture was heated at 100 C for 16h. The reaction was quenched with water (5000 mL) and stirred for 10 min. The reaction mixture was then filtered through Celite brand filter agent pad. The filtrate was diluted with water (4000 mL) and extracted with EtOAc (2 x 4000 mL). The combined organic layers were washed with brine (4000 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexane to obtain Example 85.1 (330 g, 71 %) as an off white solid. NMR (400 MHz, DMSO-d6) delta 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | A solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (500 g, 3889 mmol, 1.0 equiv) in DMF (5000 mL) was degassed with N2 for 20 mm and then dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was added, and the reaction mixture was heated at 100 C for 16 h. The reaction was quenched with water (5 L) and stirred for 10 mm. The reaction mixture was filtered through Celite brand filter aid pad. The filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na2SO4, filtered, and concentrated in vacuo to give the initial productwhich was further purified by column chromatography using silica gel (60-120 mesh) and0-10 % EtOAc in hexane to obtain Example 374.01 (330 g, 71 %) as an off white solid.1H NMR (400 MHz, DMSO-d6) oe 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | A solution of 2- chloro-5-methylpyrimidine (500 g, 3889 mmol, 1.0 equiv) in DMF (5 L) was degassed with N2 for 20 min and dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)3 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was added, and the reaction mixture was heated at 100 C for 16h. The reaction was quenched with water (5 L) and stirred for 10 min. The reaction mixture was filtered through a Celite brand filter aid pad. Filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexanes to obtain Example 31.1 (330 g, 71 %) as an off white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | A solution of 2- chloro-5-methylpyrimidine (500 g, 3889 mmol) in DMF (5.0 L) was degassed with N2 for 20 min and l,l'-ferrocenediyl-bis(diphenylphosphine) (108 g, 194 mmol) and Pd2(dba)3 (178 g, 194 mmol) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol) was added and the reaction mixture was heated at 100 C for 16 h. The reaction was quenched with water (5 L) and stirred for 10 min. The reaction mixture was then filtered through a pad of Celite brand filter aid. The filtrate was diluted with water (4 L) and extracted with EtOAc (2 x 4 L). The combined organic layers were washed with brine (4 L), dried over Na2S04, filtered and concentrated in vacuo to give the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10 % EtOAc in hexanes to obtain Example 4.13 (330 g, 71 %) as an off white solid. NMR (40 -d6) delta 8.89 (s, 2H), 2.39 (s, 3H). |
71% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 100℃; for 16h;Inert atmosphere; | 5-Methylpyrimidine-2-carbonitrile, Intermediate 5.7.1. A solution of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (500 g, 3889 mmol, 1.0 equiv) in DMF (5.0 L) was degassed with N2 for 20 min and dppf (108 g, 194 mmol, 0.05 equiv) and Pd2(dba)2 (178 g, 194 mmol, 0.05 equiv) were added to the reaction mixture. Zn(CN)2 (685 g, 5834 mmol, 1.5 equiv) was added, and the reaction mixture was heated at 100 C for 16 h. The reaction was quenched with water (5.0 L) and stirred for 10 min. The reaction mixture was then fdtered through a pad of Celite brand fdter agent. The filtrate was diluted with water (4.0 L) and extracted with EtOAc (2x 4.0 L). The combined organic layers were washed with brine (4 L), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give the product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-10% EtOAc in hexanes to obtain Intermediate 5.7.1 (330 g, 71%) as off white solid. NMR (400 MHz, DMSO-cfe) d 8.89 (s, 2H), 2.39 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To (1 -(3-(i , 1 -difluoroethyl)-4-fluorophenyl)-5-methyl-i H-i ,2,3-triazol-4-yl)methanol (25 mg, 0.09 mmol) stirring in THF (0.8 mL) was added NaH (60% dispersion in mineral oil, 12.5 mg, 0.31 mmol) and the reaction was stirred for 5 mi 2-Chloro-5-methylpyrimidine was then added and the reaction was stirred at rt overnight. The reaction was quenchedwith H20, then concentrated under a stream of air. Purification (FCC, 5i02, EtOAc/hexanes 0 - 80%) afforded the title compound (20 mg, 60%). MS (ESI):mass calcd. for C17H15F3N50, 363.1; mlz found, 364.0 [M+H]. 1H NMR (500MHz, CDCI3) O 8.37 (5, 2H), 7.66 (dd, J = 6.3, 2.6 Hz, 1 H), 7.53 (ddd, J = 8.5, 4.1, 2.6 Hz, 1H), 7.32 (t, J= 9.4 Hz, 1H), 5.56 (s, 2H), 2.42 (s, 3H), 2.25 (s,3H), 2.11 -1.96 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; for 24h;Inert atmosphere; Reflux; | To a 3-neck flask, 5.18 g (40.3 mmol) of 2-chioro- 5-methylpyrimidine, 9.26 g (46.8 mmol) of 3-biphenylboronic acid, 95 ml of 2 M aqueous solution of potassium carbonate, and 70 ml of 1 ,2-dimethoxyethane were added, and after purge with argon gas, 2.25 g (1.95 mmol) of tetrakis (triphenylphosphine) palladium (0) was added and refluxed with heating for 24 hours under argon atmosphere. The reaction solution was cooled to room temperature, the organic layer was then recovered, the solvent was removed by distillation under reduced pressure, and by performing purification using silica gel colunm chromatography (elution solution: dichloromethane), the ligand (L-b) was obtained. The obtained amount was 8.40 g (yield: 84.7%). Identification of the compound was carried out by using ?H-NMR. The analysis data of the ligand (L-b) are shown below. ?H-NMR (400 MHz/CDC13) oe: 8.66-8.68 (m, 3H),8.39 (d, 1H), 7.70-7.72 (m, 3H), 7.56 (t, 1H), 7.46 (t, 2H),7.37 (t, 1H), 2.36 (s, 3H). |
84.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; for 24h;Inert atmosphere; Reflux; | 5.18 g (40.3 mmol) of <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong>, 9.26 g (46.8 mmol) of 3-biphenylboronic acid, 95 ml of 2 M potassium carbonate aqueous solution and 70 ml of 1,2-dimethoxyethane were placed in a three- After passing argon gas, 2.25 g (1.95 mmol) of tetrakis (triphenylphosphine) palladium (0) was added thereto, and the mixture was heated under reflux for 24 hours under an argon atmosphere. After the reaction solution was cooled to room temperature, the organic layer was recovered, the solvent was distilled off under reduced pressure, and the ligand (Lb) was obtained by silica gel column chromatography (eluent: dichloromethane) It was. Yield 8.40 g (yield 84.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 130℃; for 3h; | To terf-butyl azetidin-3-ylcarbamate (649 mg, 3.1 1 mmol) in acetonitrile (10 mL) was added 2-chloro-5-methylpyrimidine (400 mg, 3.1 1 mmol) followed by N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). The mixture was heated in a microwave at 130 C for 3 h. The solvent was removed, and the residue was purified on silica gel eluting with a 30%-100% EtOAc in hexanes gradient. The appropriate fractions were combined, evaporated under reduced pressure and placed in vacuo to give the title compound as a white solid (373 mg, 45%). 1H NMR (400 MHz, CD3OD) delta 1 .47 (s, 9 H), 2.17 (s, 3 H), 3.92 (dd, J = 8, 6 Hz, 2 H), 4.34 (t, J = 8 Hz, 2 H), 4.43-4.58 (m, 1 H), 8.21 (s, 2 H); LC-MS (LC-ES) M+H = 265. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | at 135℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 16.5h;Inert atmosphere; | To a 500 mL round bottom flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (12 g, 93 mmol),potassium (E)-trifluoro(prop- 1-en-i -yl)borate (17.27 g, 117 mmol), and potassiumphosphate (59.4 g, 280 mmol). The flask was purged with N2 (5x) and then 1,4-dioxane(200 mL) and water (20 mL) were added. The resulting yellow suspension was bubbledwith Ar for 15 mm and then 1,1 -bis [(di-t-butyl-p-methylaminophenyljpalladium(II)chloride (Amphos, commercially available from Strem, 2.64 g, 3.73 mmol) was added, a reflux condenser was attached and the reaction was warmed to 90 C in an oil bath and stirred under N2 for 16.5 h. The reaction was then cooled to RT. The reaction was diluted with water (250 mL), and extracted with EtOAc (2 x 250 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 0-20% EtOAc/hexanes) to afford (E)-5- methyl-2-(prop-1-en-1-yl)pyrimidine 29.01 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid. 1H NMR (300 MHz, CDC13) oe 8.49 (s, 2H), 7.01-7.20 (m, 1H), 6.57 (dd, J= 15.6, 1.7 Hz, 1H), 2.29 (s, 3H), 1.97 (dd, J= 6.8, 1.6 Hz, 3H). LCMS-ESI (pos.) m/z: 135.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 4h;Sealed tube; | A 40 mL pressure vial was charged with Example 29.4 (71 mg, 0.16 mmol) which was then dissolved in DMSO (1.6 mL). To that solution was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (83 muL, 0.80 mmol) followed by Hunig's base (277 muL, 1.59 mmol). The vial was sealed and placed into a reaction block preheated to 100 C. After 4 h, the reaction was cooled to RT and diluted with DCM and water. The contents of the vial were transferred into a separatory funnel and the layers were separated. The organic layer was washed with water (x3). The aqueous layer was analyzed for product and showed a large presence of product. The aqueous layer was re-extracted using 3:1 EtOAc/EtOH (x3). The combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced and purified by flash chromatography: Redi-Sep Rf Gold 12g - CV = 16.8mL, eluting with EtOAc:EtOH 3:1 (v/v) in DCM 0% (2 CV), 0-40% (15 CV), 40% (5 CV) to provide Example 29.5 (54 mg, 0.10 mmol, 63 % yield) as an orange solid. LCMS-ESI (pos.) m/z: 538.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | Mixing 1-piperazincarboxylic acid tert-butyl ester (5.00 g, 26.8 mmol) in 30 mL of anhydrous DMF and anhydrous THF (1:1)Sodium hydride (1.29 g, 53.7 mmol) and anhydrous lithium bromide (2.80 g, 32.2 mmol) were gradually added at 0 C under argon, and stirred at 0 C for 4 h.2-Chloro-5-methylpyrimidine (3.45 g, 26.8 mmol) was gradually added at 0 C, stirred for 20 min, and the reaction was transferred to room temperature 25 C and stirred for 5 h. The reaction was completed, and the mixture was evaporated to dryness. The organic layer was concentrated under reduced pressure, and the obtained crude product was purified by silica gel (300-400 mesh) column chromatography eluting with methylene chloride-methanol (V:V=33:1) as eluent.Intermediate i, white solid 6.29g, yield 84.2% | |
With triethylamine; In ethanol; for 12h;Reflux; | General procedure: To a solution of 17a-f (7.78 mmol), 1-Boc-piperazine 13(7.78 mmol) in anhydrous ethanol (10 mL)was added triethylamine(15.56 mmol). The mixture was heated to reflux for 12 h. Aftercooling to the ambient temperature, ice-cold water (20 mL) wasadded. The precipitate was separated by filtration, washed withwater (10 mL) and dried to afford 18a-f. The compounds 18a-f wereused to the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In ethanol; water; at 78℃; for 48h;Inert atmosphere; | A mixture of naphthalen-l-ylboronic acid (15 g, 96 mmol), <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (9 g, 70 mmol), 2 M aq. potassium carbonate (58 mL, 116 mmol) and ethanol (300 mL) was sparged with nitrogen for 15 min. Siliacat DPP-Pd silica-based catalyst (3.87 g, 1.16 mmol, 0.17 equiv) was added and the reaction mixture heated at 78 C. for 48 h. The reaction mixture was cooled to room temperature (?22 C.) filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 0-20% ethyl acetate in heptanes to afford 5-methyl-2-(naphthalen-1-yl)pyrimidine (12.65 g, 82% yield, 99.8% UPLC purity) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | With potassium carbonate; In acetonitrile; at 80℃; for 23h; | To 50mLIn the round bottom flask<strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (0.150 g, 1.167 mmol), ciprofloxacin(0.387 g, 1.167 mmol) and potassium carbonate (0·193 g, 1 · 400 mmol),Add 10mL of acetonitrile,80 C.Under reflux 23 hours. After the reaction,The reaction mixture was concentrated under reduced pressure.Get a rough product.And use it as an eluent(methanol / dichloromethane,1/10, V/V)Purified by silica gel column chromatography,Get 0.259g.Compound I-7,Yellow solid. Yield: 61.2 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.8% | With potassium carbonate; In acetonitrile; at 80℃; for 23h; | To a 50 mL round bottom flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (0.150 g, 1.167 mmol), clinfloxacin.(0.427 g, 1.167 mmol) and potassium carbonate (0·193 g, 1 · 400 mmol), then 10 mL of acetonitrile, refluxed at 80 C 23 hours. After the reaction,The reaction mixture was concentrated under reduced pressure.Get a crude product,Use it again(methanol / dichloromethane,1/10, V/V) Purified by silica gel column chromatography,get 0.329g Compound III-2, a yellow solid.Yield: 71.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.7% | With potassium carbonate; In acetonitrile; at 80℃; for 24h; | To a 50 mL round bottom flask was added <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (0.150 g, 1. 167 mmomicron1), norfloxacin(0.373 g, 1.167 mmol) and potassium carbonate (0·193 g, 1 · 400 mmol), then 10 mL of acetonitrile, 80 CUnder reflux mixing 24hour.After the reaction,The reaction mixture was concentrated under reduced pressure.Get a crude product,Then use the eluent (methanol / dichloromethane,1/10, V/V) passedPurified by silica gel column chromatography to give 0.311 g of compound 1-2, a yellow solid.Yield: 75.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With bis-triphenylphosphine-palladium(II) chloride; disodium hydrogenphosphate; triethylamine; In 1,4-dioxane; water; at 95℃; for 15h;Inert atmosphere; | General procedure: To the stirred solution of the halogenated compound (0.39 mmol) in dioxane (10 mL), PdCl2(PPh3)2 (0.04 mmol), saturated solution of NaHPO4 (2 mL, 1.2 mmol) were addedand degassed using argon for 15 min. To this mixture, boronic acid (0.42 mmol) wasadded and degassing was continued for 15 more minutes following this TEA (4.0 equiv)was added to the turbid solution and degassed for additional 15 min. The reaction mixturewas heated at 95 C for 15 h. TLC revealed complete consumption of starting material.The reaction mixture was filtered using Hyflo bed and the bed was washed thoroughlyby ethyl acetate. The solvent mixture was evaporated under reduced pressure, and crudecompound was loaded on a column and eluted using the mixture of ethyl acetate andhexanes. The products were characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; at 90℃; for 5h;Inert atmosphere; Sealed tube; | A pressure tube was charged with benzophenone hydrazone (1.07 g, 5.4 mmol), <strong>[22536-61-4]2-chloro-5-methylpyrimidine</strong> (0.50 g, 3.9 mmol), sodium tert-butoxide (0.52 g, 5.4 mmol), JohnPhos (35 mg, 0.12 mmol), Pd2(dba)3 (36 mg, 0.04 mmol) and degassed toluene (6 mL). The suspension was degassed further with N2 and sealed. The reaction was heated at 90 oC for 5 h. The reaction was allowed to cool to room temperature and was quenched with water (10 mL). The reaction was neutralised with 1M HCl(aq). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by Biotage Isolera chromatography (silica gel, eluting with 0-30% EtOAc in heptane, to give 748 mg (67% yield) of the title compound as a yellow solid.1H NMR (500 MHz, Chloroform-d) d 8.32 (s, 1H), 8.29 (s, 2H), 7.68- 7.61 (m, 2H), 7.59- 7.54 (m, 2H), 7.54- 7.48 (m, 1H), 7.36- 7.34 (m, 1H), 7.34- 7.32 (m, 1H), 7.32- 7.29 (m, 3H), 2.19 (s, 3H). LCMS (Analytical Method D) Rt= 1.15, MS (ESIpos): m/z= 288.90 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: water; hydrogenchloride / 4 h / 100 °C / Inert atmosphere 2: potassium carbonate / acetone / 12 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water at 105℃; for 20h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.7% | Stage #1: Norfloxacin hydrochloride With potassium carbonate In acetonitrile at 60℃; for 0.5h; Stage #2: 5-methyl-2-chloropyrimidine In acetonitrile at 80℃; for 24h; | 1.1.1 Synthesis of 1-ethyl-6-fluoro-4-oxo-7-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (1a) General procedure: A suspension of norfloxacin hydrochloride (427 mg, 1.31 mmol) and potassium carbonate (354 mg, 1.57 mmol) was stirred at 60 °C for 0.5 h in acetonitrile (20 mL). After cooling to room temperature, 2-chloropyrimidine (150 mg, 1.31 mmol) was added, then raised to 80 °C and kept for 24 h. The solvent was distilled under reduced pressure to give crude product, which was purified by column chromatography on silica gel (Eluent: Dichloromethane/methanol = 10/1, V/V) to afford yellow solid 1a (289 mg). |
75.7% | Stage #1: Norfloxacin hydrochloride With potassium carbonate In acetonitrile at 60℃; for 0.5h; Stage #2: 5-methyl-2-chloropyrimidine In acetonitrile at 80℃; for 24h; | 1.1.1 Synthesis of 1-ethyl-6-fluoro-4-oxo-7-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (1a) General procedure: A suspension of norfloxacin hydrochloride (427 mg, 1.31 mmol) and potassium carbonate (354 mg, 1.57 mmol) was stirred at 60 °C for 0.5 h in acetonitrile (20 mL). After cooling to room temperature, 2-chloropyrimidine (150 mg, 1.31 mmol) was added, then raised to 80 °C and kept for 24 h. The solvent was distilled under reduced pressure to give crude product, which was purified by column chromatography on silica gel (Eluent: Dichloromethane/methanol = 10/1, V/V) to afford yellow solid 1a (289 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | Stage #1: 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride With potassium carbonate In acetonitrile at 60℃; for 0.5h; Stage #2: 5-methyl-2-chloropyrimidine In acetonitrile at 80℃; for 24h; | 1.1.1 Synthesis of 1-ethyl-6-fluoro-4-oxo-7-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (1a) General procedure: A suspension of norfloxacin hydrochloride (427 mg, 1.31 mmol) and potassium carbonate (354 mg, 1.57 mmol) was stirred at 60 °C for 0.5 h in acetonitrile (20 mL). After cooling to room temperature, 2-chloropyrimidine (150 mg, 1.31 mmol) was added, then raised to 80 °C and kept for 24 h. The solvent was distilled under reduced pressure to give crude product, which was purified by column chromatography on silica gel (Eluent: Dichloromethane/methanol = 10/1, V/V) to afford yellow solid 1a (289 mg). |
61.2% | Stage #1: 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride With potassium carbonate In acetonitrile at 60℃; for 0.5h; Stage #2: 5-methyl-2-chloropyrimidine In acetonitrile at 80℃; for 24h; | 1.1.1 Synthesis of 1-ethyl-6-fluoro-4-oxo-7-(4-(pyrimidin-2-yl)piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (1a) General procedure: A suspension of norfloxacin hydrochloride (427 mg, 1.31 mmol) and potassium carbonate (354 mg, 1.57 mmol) was stirred at 60 °C for 0.5 h in acetonitrile (20 mL). After cooling to room temperature, 2-chloropyrimidine (150 mg, 1.31 mmol) was added, then raised to 80 °C and kept for 24 h. The solvent was distilled under reduced pressure to give crude product, which was purified by column chromatography on silica gel (Eluent: Dichloromethane/methanol = 10/1, V/V) to afford yellow solid 1a (289 mg). |
Tags: 22536-61-4 synthesis path| 22536-61-4 SDS| 22536-61-4 COA| 22536-61-4 purity| 22536-61-4 application| 22536-61-4 NMR| 22536-61-4 COA| 22536-61-4 structure
[ 1753-50-0 ]
2-Chloropyrimidine-5-carbonitrile
Similarity: 0.85
[ 1046816-75-4 ]
(2-Chloropyrimidin-5-yl)methanol
Similarity: 0.85
[ 933702-55-7 ]
2-Chloropyrimidine-5-carbaldehyde
Similarity: 0.85
[ 1753-50-0 ]
2-Chloropyrimidine-5-carbonitrile
Similarity: 0.85
[ 1046816-75-4 ]
(2-Chloropyrimidin-5-yl)methanol
Similarity: 0.85
[ 933702-55-7 ]
2-Chloropyrimidine-5-carbaldehyde
Similarity: 0.85
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :