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CAS No. : | 4983-28-2 | MDL No. : | MFCD09743796 |
Formula : | C4H3ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BOGPIHXNWPTGNH-UHFFFAOYSA-N |
M.W : | 130.53 | Pubchem ID : | 14595700 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 29.06 |
TPSA : | 46.01 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) : | -6.52 cm/s |
Log Po/w (iLOGP) : | 1.08 |
Log Po/w (XLOGP3) : | 0.81 |
Log Po/w (WLOGP) : | 0.84 |
Log Po/w (MLOGP) : | -0.45 |
Log Po/w (SILICOS-IT) : | 1.22 |
Consensus Log Po/w : | 0.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.71 |
Solubility : | 2.52 mg/ml ; 0.0193 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.36 |
Solubility : | 5.72 mg/ml ; 0.0439 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.66 |
Solubility : | 2.88 mg/ml ; 0.0221 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.43 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
62% | Stage #1: With boron tribromide In dichloromethane at 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water |
2-Chloro-5-methoxypyrimidine (0.46 g, 3.18 mmol) in methylene chloride (10 mL) was treated with 1.0 N boron tribromide (16 mL, 16 mmol) at room temperature. The solution was stirred overnight. After this time the reaction was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extraxted with additional DCM. The combined organic layers were dried (MgSO4), filtered, and concnetrated. The residue was purified by flash column chromatography on silica gel to give 0.26 g of compound 112A (62percent): 1H NMR (DMSO-D6): δ 10.03 (s, IH), 8.30 (s, 2H), ESI (-)/MS: 129 (M-H)-. |
61% | With boron tribromide In dichloromethane at 20℃; for 20 h; | Intermediate 4: 2-Chloro-5-hydroxypyrimidineTo a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.7g, 61percent).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). |
55% | Stage #1: With boron tribromide In dichloromethane at -78 - 20℃; for 20 h; Stage #2: With methanol In dichloromethane at -78℃; Stage #3: With sodium hydroxide In methanol; water |
Intermediate 4: 2-Chloro-5-hydroxypyrimidine To a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.0g, 55percent).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). |
27% | With boron tribromide In dichloromethane at 0 - 20℃; for 16 h; | Boron tribromide (30mL) was slowly added to a solution of 2-chloro-5-methoxypyrimidine (2g, 13.83mmol) in DCM (lOmL) at 0 °C. Allowed the reaction mass to stir at room temperature for 16h. Then the reaction mixture was slowly quenched with ice cold water, warmed to room temperature and diluted with DCM (lOOmL). The aqueous layer was separated and extracted with DCM (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford desired title compound (0.5g, 27percent) as a solid. LCMS: m/z = 129.0 (M-H)+ (Negative mode). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With sulfuric acid In water for 2 h; Reflux | Example 8 Synthesis of 2-chloropyrimidine-5-ol Compound 41 Referring to the reaction scheme of , Compound 40 (40 g, 0.31 mol) in 2N sulfuric acid was refluxed for 2 hrs. After cooling to r.t., the reaction mixture was extracted with EtOAc using continuous overnight liquid-liquid extraction. The combined EtOAc layers were washed with brine, dried over magnesium sulfate, and filtered. After solvent removal in vacuo and recrystallization with EtOH, 10 g (25percent) yellow solid 41 was obtained. 1H NMR (DMSO-d6) δ 10.93 (brs, 1H), 6.45 (t, J=4.88 Hz, 1H), 3.57 (t, J=4.4 Hz, 4H), 2.01-1.98 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In methanol at 20℃; for 14 h; | Example 9 Synthesis of 2-chloro-5-benzyloxy-pyrimidine Compound 31 Referring to the reaction scheme of , potassium carbonate (11.6 g, 84.3 mmol) was added to 10 g of the alcohol 40 (76.6 mmol) in 500 mL of MeOH, followed by benzyl bromide (10.1 mL, 84.3 mmol). After 14 hrs stirring at r.t., the reaction was stopped by addition of water (300 mL). MeOH was evaporated and the remaining aqueous layer was extracted with CHCl3. The combined CHCl3 layers were washed with brine, dried over magnesium sulfate, and filtered. Removal of the solvent followed by silica gel chromatography using 100:1 CHCl3:MeOH as eluent gave 15 g (89percent) of 2-amino-5-benzyloxy-pyrimidine (31) as a white solid. 1H NMR (CDCl3) δ 8.27 (s, 2H), 7.37-7.30 (m, 5H), 5.09 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; | To a solution of 2-chloro-5-hydroxypyrimidine (4.13 g) in DMF (40 mL) were added ethyl 2-bromo-2,2-difluoroacetate (12.83 g) and cesium carbonate (20.59 g), and the mixture was reacted at 80°C overnight. The reaction solution was cooled to room temperature, and then poured into water. The mixture was extracted with ethyl acetate thrice. The organic layer was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 80:20 to 60:40) to give the titled compound (2.16 g) as a colorless liquid (yield 38percent). MS(APCI)m/z; Not detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1 h; | To a solution of 93 mg (0.71 mmol) of 4-hydroxy-1-methyl piperidine in 1.0 ml of N,N-dimethylformamide, 0.28 g (0.86 mmol) of cesium carbonate and 0.32 mg (2.2 mmol) of methyl chlorodifluoroacetate were added, and the reaction solution was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to provide 55 mg of the title compound as a colorless oil (yield: 43percent). 1H-NMR spectrum (500 MHz, CDCl3) δ ppm: 8.53 (2H, s), 6.62 (1H, t, J=71 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.7% | at 90℃; for 24 h; | Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine 2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2-difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90° C. for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30percent ethyl acetate/hexanes) to afford 2-chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7percent yield) as a pale yellow oil. MS (LC/MS) R.T.=1.32; [M+H]+=181.14. |
39.7% | at 90℃; for 24 h; | Step A: 2-Chloro-5-(Difluoromethoxy)pyrimidine2-Chloropyrimidin-5-ol (1 g, 7.66 mmol) and sodium 2-chloro-2,2- difluoroacetate (3.50 g, 22.98 mmol) in N,N-dimethylformamide (20 mL) and water (0.2 mL) were heated to 90 °C for 24 hours and concentrated in vacuo. The residue was purified by column chromatography (5-30 percent ethyl acetate/hexanes) to afford 2- chloro-5-(difluoromethoxy)pyrimidine (549 mg, 3.04 mmol, 39.7 percent yield) as a pale yellow oil. MS (LC/MS) R.T. = 1.32; [M+H]+ = 181.14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
659 mg | With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 20℃; | A) 2-chloro-5-(cyclopropylmethoxy)pyrimidine To a solution of cyclopropylmethanol (276 mg), 2-chloropyrimidin-5-ol (500 mg) and triphenylphosphine (1.51 g) in toluene (20 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (659 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.49 (2H, m), 0.49-0.69 (2H, m), 1.07-1.46 (1H, m), 4.00 (2H, d, J=7.2 Hz), 8.53 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; at 40℃; | (2) Potassium carbonate (2.54 g) was added to a solution of 5-bromovaleric acid tert-butyl ester (4.3 g) obtained in Reference Example 1(1) above and 2-chloro- pyrimidin-5-ol (2 g) in dimethylsulfoxide (8.6 ml) and the mixture was stirred at 400C overnight. The reaction mixture was cooled to room temperature, water and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; hexane:ethyl acetate = 49:1-->9:1) to give 5-(2-chloropyrimidin-5-yloxy)valeric acid tert-butyl ester (3.82 g). MS (m/z): 287/289 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; | Intermediate Production Example 1 Production of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine Used in Production Example 1 A mixture of 0.17 g of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, 0.22 g of methyl 2-bromopropionate, 0.20 g of anhydrous potassium carbonate and 2.6 ml of N,N-dimethylformamide was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, then, poured into water, and extracted with t-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine. 1H-NMR(CDCl3/300 MHz) delta(ppm): 1.68 (d, 3H, J=6.6 Hz),3.79(s, 3H), 4.82 (q, 1H, J=6.7 Hz), 8.27(s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogen bromide; DL-methionine; In acetic acid; for 5h;Reflux; | Prepare 1L four-necked flask with a stirring device and thermometer.Add 100 g of 2-chloro-5-methoxypyrimidine,300 mL of acetic acid was added to the reaction flask,Stir well, then add 153g of 48% hydrobromic acid and 1g of methionine.Warming up to reflux reaction for 5 h,Sampling HPLC controlled until the end of the reaction, product content 96%, dihydroxy by-product 0.5%;After dropping to room temperature, 300 mL of water was added to the reaction solution, and the mixture was extracted three times with 300 mL of dichloromethane.The organic phases were combined and washed with saturated sodium bicarbonate solution.Then, it is dried over anhydrous sodium sulfate, and after filtration, the organic phase is concentrated under reduced pressure to give a crude product;The crude product was recrystallized from the crude product to give a pale yellow solid, 82 g.The yield was 91% and the purity was 98%. |
62% | 2-Chloro-5-methoxypyrimidine (0.46 g, 3.18 mmol) in methylene chloride (10 mL) was treated with 1.0 N boron tribromide (16 mL, 16 mmol) at room temperature. The solution was stirred overnight. After this time the reaction was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extraxted with additional DCM. The combined organic layers were dried (MgSO4), filtered, and concnetrated. The residue was purified by flash column chromatography on silica gel to give 0.26 g of compound 112A (62%): 1H NMR (DMSO-D6): delta 10.03 (s, IH), 8.30 (s, 2H), ESI (-)/MS: 129 (M-H)-. | |
61% | With boron tribromide; In dichloromethane; at 20℃; for 20h; | Intermediate 4: 2-Chloro-5-hydroxypyrimidineTo a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.7g, 61%).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). |
55% | Intermediate 4: 2-Chloro-5-hydroxypyrimidine To a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.0g, 55%).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). | |
27% | With boron tribromide; In dichloromethane; at 0 - 20℃; for 16h; | Boron tribromide (30mL) was slowly added to a solution of 2-chloro-5-methoxypyrimidine (2g, 13.83mmol) in DCM (lOmL) at 0 C. Allowed the reaction mass to stir at room temperature for 16h. Then the reaction mixture was slowly quenched with ice cold water, warmed to room temperature and diluted with DCM (lOOmL). The aqueous layer was separated and extracted with DCM (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford desired title compound (0.5g, 27%) as a solid. LCMS: m/z = 129.0 (M-H)+ (Negative mode). |
With boron tribromide; In methanol; dichloromethane; carbon dioxide; | Reference Example 25 To a solution of 2-chloro-5-methoxypyrimidine (1.90 g) which is previously prepared by a method disclosed in J. Chem, Soc., 4590 (1960) in methylene chloride (30 ml) is added dropwise boron tribromide (4.97 ml) over a period of 15 minutes in a dry ice/acetone bath. The mixture is stirred at room temperature for 22 hours, and thereto is added dropwise methanol (30 ml) in a dry ice/acetone bath. The reaction mixture is concentrated under reduced pressure, and the pH value thereof is adjusted to pH 5 with aqueous sodium hydroxide solution. The mixture is extracted twice with ethyl acetate, and the extract is washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The resulting crystals are washed with n-hexane to give 2-chloro-5-hydroxypyrimidine (1.47 g) as colorless crystals. M.p. 194-195 C. | |
Example 152(S)-2-(1-(5-(2,4-dichlorobenzyloxy)pyrimidin-2-yl)pyrrolidin-2-yl)acetic acid 152A. (S)-methyl 2-(1-(5-(2,4-dichlorobenzyloxy)pyrimidin-2-yl)pyrrolidin-2-yl)acetate: To a round bottom flask was added 2-chloro-5-methoxypyrimidine (250 mg, 1.73 mmol) and CH2Cl2 (1 mL). The reaction mixture was cooled to -78 C. and 1N BBr3 (4 eq) was added slowly over 15 min. The reaction mixture was slowly warmed to rt and was stirred ovn. The mixture was cooled to 0 C. and 1N BBr3 (4 eq) was added. The reaction was slowly warmed to rt and then stirred for 24 h. The reaction was quenched via addition of methanol at 0 C., and the mixture was evaporated to dryness. The residue was dissolved in water (1 mL) and the pH of the solution was adjusted to 5 using 1N NaOH solution. The resulting mixture was extracted with EtOAc (2×25 mL), and the combined organics were washed successively with water (20 mL) and brine (20 mL), and the organic layer was dried (MgSO4) and concentrated to give 2-chloropyrimidin-5-ol (170 mg, 75% yield). The crude product was dissolved in DMF (3 mL) and 2,4-dichloro-1-(chloromethyl)benzene (0.215 mL, 1.57 mmol), K2CO3 (270 mg, 1.96 mmol) were added. The reaction mixture was stirred at 60 C. for 4 h. The resulting solution was diluted with EtOAc (50 mL), and the organic layer was washed successively with water (4×30 mL) and brine (30 mL), and the organic layer was dried (MgSO4) and concentrated. The residue was purified via silica gel chromatography to give 2-chloro-5-(2,4-dichlorobenzyloxy)pyrimidine (310 mg, 81% yield) as white solid containing 50% of 2-bromo-5-(2,4-dichlorobenzyloxy)pyrimidine. The material was used as is in the subsequent step. To a microwave vial was added 2-chloro-5-(2,4-dichlorobenzyloxy)pyrimidine (54 mg, 0.19 mmol), (S)-methyl 2-(pyrrolidin-2-yl)acetate (80 mg, 0.56 mmol), Hunig's Base (0.16 mL, 0.93 mmol) and DMF (1.2 mL). The reaction was heated in a microwave at 180 C. for 30 min. The reaction mixture was diluted with MeOH, and the mixture was purified via preparative RP-HPLC to give 152A (clear oil, 40 mg, 0.101 mmol, 54.1% yield). LC-MS Anal. Calc'd for C18H19Cl2N3O3: 396.27. found [M+H] 396.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; water; | (2) A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (200 mg), 3-chloromethylthiophene (610 mg), potassium carbonate (635 mg) and dimethylformamide (3 ml) is stirred at 50° C. for one hour. After the reaction is complete, to the reaction mixture is added water, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate=20:1-->20:3), and evaporated to remove the solvent to give 2-chloro-5-(3-thienylmethoxy)pyrimidine (345 mg) as colorless needles. M.p. 73°-76° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In N-methyl-acetamide; water; | EXAMPLE 8 To a mixture of 4.50 g. of 1-(beta-napthylmethyl)piperazine(as prepared in Example 7), 2.5 g. of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> in 30 ml. of dimethylformamide is added 2.0 g. of sodium bicarbonate and the mixture is refluxed for six hours. The mixture is cooled and filtered and the filtrate concentrated to a small volume in vacuo. The concentrate is diluted with 100 ml. of water and the insoluble material is washed with water and hexane to yield 1-(beta-napthylmethyl)-4-(5-hydroxy-2-pyrimidinyl)piperazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | Reference Example 142-Chloropyrimidin-5-ol (3.89g) is dissolved in N,N- dimethylformamide (50ml) and thereto are added potassium carbonate (4.98g) and tert-butyl 4-bromo-butyrate (7.36g) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl <n="169"/>acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane : ethyl acetate - 24: 1-->4: 1) to give tert-butyl 4-(2-chloropyrimidin-5-yloxy)bromobutyrate (6.22g). MS (m/z): 273 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.6% | With potassium carbonate; In N,N-dimethyl-formamide; | Step A: 2-Chloro-5-(cyclopentyloxy)pyrimidine A mixture of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1 g, 7.66 mmol), chlorocyclopentane (2.39 mL, 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) in N,N-dimethylformamide were heated at 65° C. for 16 h at ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-25percent ethyl acetate/hexanes) to afford 2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6percent yield) as a white solid. MS (LC/MS) R.T.=2.32; [M+H]+=199.23. |
54.6% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 16h; | A mixture of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1 g, 7.66mmol), chlorocyclopentane (2.39 ml., 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) in N,N-dimethylformamide were heated at 65° C. for 16 h at ambient temperature.Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo.The residue was purified by colunm chromatography (0-25percentethyl acetate/hexanes) to afford 2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 24h; | A combination of (R)-methanesulfonic acid-3-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]butyl ester (Preparation 3, 560mg, 1.62mmol), <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (423mg, 3.24mmol) and potassium carbonate (447mg, 3.24mmol) in DMF (4mL) was heated to 700C for 24h. The reaction mixture was diluted with water (75mL) and extracted with EtOAc (2 x 75mL). The combined organic fractions were washed with IM NaOH solution, then brine, and dried (MgSO4). Removal of the solvent in vacuo afforded the title compound: RT = 4.14 min; mlz (ES+) = 380.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | A combination of (R)-methanesulfonic acid-3-[l-(5-chloropyrimidin-2-yl)piperidin-4- yl]butyl ester (Preparation 2, 641mg, 1.85mmol), <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (480mg, 3.69mmol) and potassium carbonate (510mg, 3.69mmol) in DMF (4mL) were heated at 800C until the reaction was complete. The mixture was diluted with water and extracted into EtOAc (x 3), then the organic fractions were combined, washed with IM NaOH solution, brine, and dried (MgSO4). Removal of the solvent in vacuo afforded the title compound: RT = 4.72 min; m/z (ES+) = 382.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-(2-hydroxy-l-methylethyl)piperidine-l -carboxylic acid isopropyl ester (Preparation 111, 400mg, 1.74mmol) in DCM (8mL), under argon, was added triethylamine (316muL, 2.27mmol) and the mixture was cooled to 00C. Methanesulfonyl chloride (163muL, 2.09mmol) was added before stirring the reaction at this temperature for Ih. The mixture was diluted with DCM (5OmL), washed with IM HCl solution (5OmL), sat. NaHCO3 solution (5OmL), then brine (5OmL), and dried (MgSO4). Removal of the solvent in vacuo afforded the intermediate product 4-(2-methanesulfonyloxy-l-methylethyl)piperidine-l- carboxylic acid isopropyl ester: RT = 3.49 min; mlz (ES+) = 308.1 [M + H]+. To a solution of the product in THF (8mL), under argon, was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (249mg, 1.91mmol) followed by potassium carbonate (600mg, 4.34mmol), and the reaction was warmed to 500C for 16h. DMF (2mL) was added and the reaction heated to 55°C for 3 h. A further portion of DMF(2mL) was added and heating continued at 600C for 3 h. Further DMF (2mL) was added and the reaction stirred at 500C for 1Oh before being cooled to r.t. and the solvent removed in vacuo. The crude residue was partitioned between EtOAc (5OmL) and water (10OmL) and the organic phase was separated. The aqueous phase was extracted with EtOAc (5OmL) then the organic fractions were combined, washed with sat. NaHCO3 solution (5OmL), brine (5OmL), and dried(MgSO4). Removal of the solvent in vacuo afforded the title compound: 1H NMR deltaH (400MHz, CDCl3): 8.29 (s, 2H), 4.98 - 4.88 (m, IH), 4.29 - 4.12 (m, 2H), 4.02 - 3.86 (m, 2H), 2.78 - 2.64 (m, 2H), 1.96 - 1.84 (m, IH), 1.70 - 1.59 (m, 3H), 1.37 - 1.319 (m, 8H), 1.04 (d, /= 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 72h;Sealed tube; | A combination of 4-((R)-3-methanesulfonyloxy-l-methylpropyl)piperidine-l- carboxylic acid isopropyl ester (Preparation 16, 300mg, 1.56mmol), 2-chloro-5- hydroxypyrimidine (213mg, 1.63mmol) and potassium carbonate (430mg, 3.11mmol) in DMF (5.OmL) were heated in a sealed tube to 700C for 72h. The reaction mixture was partitioned between EtOAc and brine and organic phase separated and dried (Na2SO4). Removal of the solvent in vacuo afforded the title compound: RT = 4.14 min m/z (ES+) = 356.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; | A combination of methanesulfonic acid (R)-3-[l-(3-ethyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]butyl ester (Preparation 20, 2.22g, 6.71mmol), <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (0.96g, 7.38mmol) and potassium carbonate (2.78g, 20.13mmol) in DMF (3OmL) was heated to 500C until the reaction was complete. The mixture was diluted with water (4OmL) and extracted into EtOAc (3 x 3OmL). The organic fractions were combined, washed with brine (7OmL), and dried (MgSO4). Removal of the solvent in vacuo and purification by column chromatography(IH:EtOAc, 70:30, 60:40) afforded the title compound: RT = 3.84 min; mlz (ES+) = 366.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | To a solution of 3-[l-(5-chloropyrimidin-2-yl)piperidin-4-yl]propan-l-ol (Preparation 22, 766mg, 3.0mmol) in DCM (25mL) was added triethylamine (0.5OmL, 3.6mmol) and the mixture was cooled to 00C. Methanesulfonyl chloride (0.23mL, 3.0mmol) was added and the reaction warmed to r.t. over 15 min. IM HCl was added and the resulting mixture poured into EtOAc. The organic layer was separated, washed with IM HCl, brine, dried (MgSO4), and the solvent removed in vacuo. To a solution of the material in DMF (1OmL) was added 2-chloro-5- hydroxypyrimidine (390mg, 3.0mmol) and potassium carbonate (828mg, .Ommol), and the mixture was heated to 800C for 16h. DMF was removed in vacuo and the residue was re- dissolved in EtOAc. The organic solution was washed with brine (x 2), dried (MgSO4), and solvent removed in vacuo. Recrystalisation from the minimal volume of MeOH afforded the title compound: RT = 4.53 min mlz (ES+) = 368.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | A stirred mixture of <strong>[4983-28-2]2-chloro-5-pyrimidinol</strong> (107) (1.00 g, 7.66 mmol) and chloromethyl ethyl ether (1.75 mL, 18.9 mmol) in anhydrous DMF (2.5 mL) was treated with K2CO3 (2.15 g, 15.6 mmol). After stirring at room temperature for 16 h, the mixture was added to ice/aqueous NaHCO3 (100 mL) and extracted with 50% Et2O/petroleum ether (5×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% Et2O/petroleum ether firstly gave foreruns, and then further elution with 1-10% Et2O/petroleum ether gave 2-chloro-5-(ethoxymethoxy)pyrimidine (108) (1.27 g, 88%) as an oil; 1H NMR (CDCl3) delta 8.43 (s, 2H), 5.27 (s, 2H), 3.74 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3 H); HRESIMS calcd for C7H10ClN2O2 m/z [M+H]+ 191.0396, 189.0425, found 191.0397, 189.0426. |
31.2% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere; | Weigh out 5.0 g (38.31 mmol, 1.0 eq) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> and 10.6 g (76.61 mmol, 2.0 eq) of K2CO3 in a 100 mL eggplant bottle.Under the protection of nitrogen atmosphere, add 20 mL of anhydrous DMF and stir.Then chloromethyl ethyl ether 9 mL (95.76 mmol, 2.5 eq) was added. Stir at room temperature and react for 1 h.About 60 mL of saturated NaHCO 3 solution was poured into the reaction, and the reaction solution was stirred, and 150 mL of ethyl acetate and 150 mL of saturated NaHCO 3 solution were added.After the mixture was uniformly mixed, the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL×2), washed with saturated saturated NaCl (200 mL×2);It was filtered, and the solvent was evaporated under reduced pressure.Purification by flash column chromatography (10percent EA/PE),A colorless transparent liquid of 2.23 g was obtained; the yield was 31.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h; | To a solution of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (1.00 g) in dimethylformamide (15 mL) were added potassium carbonate (1.59 g) and ethyl iodide (1.84 mL), and the mixture was stirred at 50°C for 1 hour. To the reaction mixture was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate = 99/1 to 78/22) to give the titled compound (1.07 g) as a colorless solid (yield: 88percent). MS(APCI)m/z; 159/161[M+H]+. |
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h; | 2-Chloropyrimidin-5-ol (13.0 g, 100 mmol) was dissolved in DMF (130 mL) (solution) and K2C03 (27.5 g, 199 mmol) was added (suspension), followed by iodoethane (16.1 mL, 199 mmol). The reaction mixture was stirred at 50°C for 4 hr and subsequently cooled to ambient temperature and stirred overnight. The reaction mixture was partitioned between EtOAc (650 mL) and 10percent aqueous NaCl (650 mL). The organic layer was washed with 10percent aqueous NaCl (650 mL). The first aqueous layer was extracted with EtOAc (325 mL). The combined organic layers-were driedOver Na2S0 , filtered, and concentrated in vacuo. The crude mixture was diluted with D'CM-to a final volume of 40 mL and purified by flash chromatography (MPLC, 5-4percent EtOAc-Hexanes) to provide 2-chloro-5-ethoxypyrimidine as a white solid.LRMS (EST) calc'd fbr C6K8C1N02 [M+H]+: 159; Found: 159 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With copper diacetate; triethylamine; In dichloromethane; | Intermediate 25: 2-Chloro-5-(3-methoxyphenoxy)pyrimidine A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (l .Og, 7.66mmol), 3-methoxyphenyl boronic acid (1.16g, 7.66mmol), copper (II) acetate (1.39g, 7.66mmol), triethylamine(5.34mL, 7.66mmol) and powdered 4A molecular sieves in dichloromethane (30mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The reaction mixture was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04), the solvent removed under reduced pressure and the crude product was purified by flash chromatography, using 0-15percent ethyl acetate:hexane as eluent, to provide 2-chloro-5- (3-methoxyphenoxy)-pyrimidine (0.448g, 25percent) as yellow oil.Mass: (ES+) 237 (M+H)+ NMR: deltaEta (CDC13) 3.82 (3H, s), 6.63 (2H, m), 6.81 (IH, br d), 7.33 (IH, t) and 8.39 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper diacetate; triethylamine; In dichloromethane; | Intermediate 32: 2-Chloro-5-( -N,N-dimethylaminophenoxy)pyrimidineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (l.Og, 0.00766mol), 3-N,N- dimethylamino-phenyl boronic acid (1.26g, 0.00766mol), copper (II) acetate (1.39g, 0.00766mol), triethylamine (5.34mL, 0.00766mol) and powdered 4A molecular sieves in dichloro-methane (30mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using 0-15percent ethyl acetate: hexane as eluent to obtained 2-chloro-5-(3-N,N-dimethylaminophenyl)pyrimidine (0.448, 25percent) as a yellow oil.Mass: (ES+) 250 (M+H)+ HPLC: 99.8percentNMR: 5H (CDC13) 2.98 (6H, s), 6.35 (1H, dd), 6.40 (1H, m), 6.60 (1H, dd), 7.25 (1H, t) and 8.38 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With copper diacetate; triethylamine; In dichloromethane; | Intermediate 16: l-[3-(2-Chloropyrimidin-5-yloxy)phenyl]-4-methylpiperazineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (0.71 lg, 0.00545mol), 3-(4-methyl- piperazin-l-yl)phenyl boronic acid (1.5g, 0.00545mol), copper (II) acetate (0.99g,0.00545mol), triethylamine (3.8mL, 0.0272mol) and powdered 4A molecular sieves in dichloromethane (40mL) was stirred under air for 3 days. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluting with dichloromethane:methanol (19:1) to afford l-[3-(2-chloropyrimidin-5-yloxy)phenyl]- 4-methylpiperazine (0.68g, 41percent) as colourless oil.Mass: (ES+) 305 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With copper diacetate; triethylamine; In dichloromethane; | Intermediate 25 (S)-4-[3-(2-Chloropyrimidin-5-yloxy)phenyl]-3-methyl-A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (0.250g, 0.00191mol), R-3-(3-methyl- morpholin-4-yl)phenyl boronic acid (0.423 g, 0.00191mol), copper (II) acetate (0.347g, 0.00191mol), triethylamine (1.33mL, 0.0096mol) and powdered 4A molecular sieves in dichloromethane (30mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography, using 0-15percent ethyl acetate:hexane as eluent, to afford (S)-4-[3-(2-chloropyrimidin-5-yloxy)phenyl]-3- methylmorpholine (0.175g, 30percent) as brown oil.Mass: (ES+) 305 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper diacetate; triethylamine; In dichloromethane; | Intermediate 21: (R)-4-[3-(2-Chloropyrimidin-5-yloxy)phenyl]-3-methyl- morpholineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (0.295g, 2.261mmol), (S)-3-(3-methyl- morpholin-4-yl)phenylboronic acid (0.5g, 2.261mmol), copper (II) acetate (0.410g,2.261mmol), triethylamine (1.6mL, 11.3mmol) and powdered 4A molecular sieves in dichloromethane (50mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The suspension was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by flash chromatography, using 0-15percent ethyl acetate:hexane as eluent, to give (R)-4-{3-[(2-chloropyrirnidin-5-yl)oxy]phenyl}3-methylmorpholine (0.258g) as a brown oil.Mass: (ES+) 305 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.05% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; | Under nitrogen atmosphere, potassium carbonate (74.12 g, 536.28 mmol) was added into a solution of intermediate 7A (94.40 g, 321.77 mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (35.00 g, 268.14 mmol) in DMF (1.00 L). The reaction solution was left at 80 C. for 16 hours, and thin layer chromatography was used to detect the completion of the reaction. Then the reaction solution was cooled to room temperature and concentrated, then water (500 mL) was added into the residue and extracted with ethyl acetate (300 mL*3). The organic phase was washed with brine (400 mL*2) and dried over anhydrous sodium sulfate, then filtered and concentrated. Then the residue was purified by column chromatography to give the intermediate 7B (pale yellow solid, 84.00 g, 95.05% yield). LCMS (ESI) m/z: 327.7 (M+1). 1HNMR (400 MHz, DMSO-d6) delta ppm 1.08-1.25 (m, 2H) 1.40 (s, 9H) 1.69-1.78 (m, 2H) 1.88-2.03 (m, 1H) 2.58-2.88 (m, 2H) 3.89-4.05 (m, 4H) 8.50-8.57 (m, 2H) |
94% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h; | tert-Butyl 4-((methylsulfonyloxy)methyl)piperidin-l-carboxylate (Step 2 of Intermediate 1, 2.00 g, 6.82 mmol) was dissolved in DMF (80 mL). K2C03 (3.33 g, 10.23 mmol) was added thereto, followed by stirring for 5 minutes. 2-Chloropyrimidin-5-ol (890 mg, 6.82 mmol) was added thereto, followed by stirring at 80 C for 5h. To the reaction mixture, water was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated NH4C1 aqueous solution, dried with anhydrous MgS04, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc hexane = 30 % ~ 70 %) to obtain white solid (2.10 g, 94%). |
94% | t-butyl 4-((methylsulfonyloxy)methyl)piperidin-1-carboxylate (the product of synthesis step 2 of compound 431; 2.00 g, 6.82 mmol) was dissolved in DMF (80 mL). K2CO3 (3.33 g, 10.23 mmol) was added thereto, and stirred for 5 minutes. <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (890 mg, 6.82 mmol) was added thereto, following with stirring at 80 C. for 5 hours. The reaction mixture was added with water, and extracted with EtOAc. The organic layer was washed with saturated NH4Cl aqueous solution, dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (EtOAchexane=30%?70%) to yield the title compound as white solid (2.10 g, 94%) |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | To a solution of 4-methanesulfonyloxymethylpiperidine-l-carboxylic acid tert-butyl ester (Preparation 23, 1.47g, 5.0mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (0.65g, 5.0mmol) in DMF (80mL) was added potassium carbonate (0.83g, 6.0mmol) and the reaction was heated to 80C until complete. The solvent was removed in vacuo, and the resulting residue was re- dissolved in EtOAc (300mL). The solution was washed with 1M NaOH solution (200mL), brine (200mL), then dried (MgS04) and the solvent was removed in vacuo. Purification by column chromatography (IH:EtOAc, 70:30) afforded the title compound: lH NMR delta?(400MHz, CDCI3): 8.30 (s, 1H), 4.18 (br. s., 2H), 3.92 (dd, J=6.25, 3.51 Hz, 2H), 2.78 (t, J=12.30 Hz, 2H), 2.09 - 1.95 (m, 1H), 1.84 (d, J=12.89 Hz, 2H), 1.49 (s, 9H), 1.41 - 1.24 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | To a solution of the intermediate in DMF (50mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (0.78g, 6.0mmol) and potassium carbonate (1.38g, lO.Ommol), and the reaction was heated to 80°C for 16 h. The reaction solvent was concentrated in vacuo and the resulting residue was re-dissolved in EtOAc (300mL). The solution was washed with 1M NaOH solution (2 x 300mL), brine, then dried (MgSC^), and the solvent was removed in vacuo to afford the title compound: RT = 3.55 min, m/z (ES+) = 338.1 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 570mg, 2.38mmol) and triethylamine (390muEpsilon, 2.86mmol) in DCM(42mL), cooled to 0°C, was added methanesulfonyl chloride (204muEpsilon, 2.86mmol) and the reaction was allowed to warm to r.t. over 1 h. Further portions of methanesulfonyl chloride (92muEpsilon, 1.19mmol) and triethylamine (199muEpsilon, 1.43mmol) were added and stirring continued for 16 h. The mixture was partitioned between DCM (lOOmL) and 1M HCl (250mL), then the organic phase was separated and concentrated in vacuo. To a solution of the residue in DMF (15mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (373mg, 2.86mmol) and potassium carbonate (985mg, 7.34mmol), and the mixture was heated to 80°C for 48 h. The reaction solvent was concentrated in vacuo, then azeotroped once from toluene. The residue was dissolved in EtOAc, washed with brine, dried (MgS04), and the solvent removed in vacuo. Recrystallisation from MeOH, followed by column chromatography (IH:EtOAc, 70:30) afforded the title compound: RT = 3.82 min; mlz (ES+) = 352.1 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;microwave irradiation; | A combination of methanesulfonic acid-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethyl ester (Preparation 52, 440mg, 1.51mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (270mg, 1.81mmol) and potassium carbonate (417mg, 3.02mmol) in DMF (20mL) was heated to 100°C in a microwave reactor for 2 h. The reaction solvent was concentrated in vacuo and the resulting residue was dissolved in EtOAc. The solution was washed with 1M NaOH solution (x 2), brine, then dried (MgS04), before removal of the solvent in vacuo.Purification by column chromatography (DCM:MeOH, 95:5) afforded the title compound: 1H NMR deltaEta (400MHz , CDC13): 8.27 (s, 1H), 8.25 (s, 1H), 4.26 - 4.15 (m, 2H), 3.95 - 3.85 (m, 2H), 3.15 - 3.00 (m, 2H), 2.62 - 2.50 (m, 2H), 2.15 - 2.01 (m, 1H), 1.97 - 1.85 (m, 2H), 1.52 - 1.38 (m, 2H), 1.30 - 1.19 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 2.5h;Inert atmosphere; | To a solution of 4-(5-hydroxyrnethyl-[l,2,4]oxadiazol-3-yl)piperidine-l-carboxylic acid isopropyl ester (Preparation 67, 103mg, 0.38mmol) in THF (5mL), in an oven-dried flask, under argon, was added <strong>[4983-28-2]2-chloro-pyrimidin-5-ol</strong> (50mg, 0.38mmol), followed by triphenylphosphine (150mg, 0.57mmol), and the mixture was cooled to 0°C. DIAD (112muIota,, 0.57mmol) was added, dropwise, and the resulting mixture was stirred at r.t. for 2.5 h. The reaction solvent was removed in vacuo, and the residue was re-dissolved in EtOAc (lOOmL). The solution was washed with water (50mL), then brine, and dried (MgS04), before removal of the solvent in vacuo. IH was added, followed by a minimal volume of Et20, and a precipitate formed. The solvent was decanted and concentrated in vacuo. Purification of the resulting residue by column chromatography (IH:EtOAc, 50:50, 40:60) afforded the title compound: RT = 3.43 min; mlz (ES+) = 382.1 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 16h; | To a solution of 4-((i?)-l-methanesulfonyloxyethyl)piperidine- 1-carboxylic acid tert- butyl ester (Preparation 114, 1.77g, 5.76mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (0.75g, 5.75mmol) in NMP (20mL) was added potassium carbonate (l .lg, 8.10mmol) and the reaction was heated to 80°C for 16 h. The reaction mixture was partitioned between TBME and water, and the aqueous layer was separated and washed with further TBME. The organic fractions were combined, washed with water, then brine, and dried (MgS04). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 100:0 - 70:30) afforded the title compound: 1H NMR deltaEta (400MHz, CDC13): 8.26 (s, 2H), 4.25 - 4.19 (m, 3H), 2.74 - 2.64 (m, 2H), 1.90 - 1.65 (m, 3H), 1.47 (s, 9H), 1.39 - 1.25 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride; In ISOPROPYLAMIDE; at 60℃; for 168h; | To a solution of 4-((i?)-l-methanesulfonyloxy-ethyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 182, 27.6g, 80.8mmol) in DMA (800mL) was added 2-chloro- pyrimidin-5-ol (10.9g, 130mmol) and cesium fluoride (12.7g, 83.4mmol) and the resulting reaction mixture stirred at 60°C for 96 h. Further cesium fluoride (7.50g, 49.7mmol) was added and stirring at 60°C continued for 72 h. Upon cooling, the reaction mixture was poured into water (1500mL) and diluted with EtOAc (lOOOmL) and brine (500mL). The layers were separated and the aqueous extracted with EtOAc (2 x 750mL). The combined organics were washed with watenbrine (1 : 1 , 4 x 500mL), dried (Na2S04), filtered and concentrated in vacuo. Purification by column chromotograpy (DCM:MeOH, 99: 1 to 97.5:2.5) followed by further purification by column chromotograpy (Heptane:EtOAc, 3: 1 to 2:1) afforded the title compound: RT = 0.87 min; mlz (ES+) = 376.1 [M+ H]+ (LCMS - method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | To a solution of 4-((5)-l-methanesulfonyloxyethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 28, 1.85g, 6.30mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (0.69g, 5.25mmol) in DMF (40mL) was added potassium carbonate (1.45g, 10.50mmol) and the reaction was heated to 100°C until complete. The mixture was poured into a combination of water (300mL) and brine (300mL), then the aqueous mixture was extracted with EtOAc (4 x lOOmL). The organic fractions were combined, washed with brine (lOOmL), dried (MgS04) and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 2: 1) afforded the title compound: RT = 3.75 min; m/z (ES+) = 328.1 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With triethylamine;copper diacetate; In 1,4-dioxane; dichloromethane; at 20 - 80℃;Molecular sieve; | Example 66Preparation of N-(2,6-difluorobenzyl)-5-(2-(trifluoromethyl)phenoxy)pyrimidin-2-amine (126)<strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (100 mg, 0.77 mmol), [2-(trifluoromethyl)phenyl]boronic acid (213 mg, 1.12 mmol), copper (II) acetate (140 mg, 0.219 mmol), triethylamine (386 mg, 3.83 mmol) and 4-angstrom molecular sieves (750 mg) were combined in methylene chloride (9 mL) and stirred vigorously at room temperature overnight.Dioxane (5 mL) and approximately 3 equivalents each of [2-(trifluoromethyl)phenyl]boronic acid, copper (II) acetate and triethylamine were added and the mixture was heated to 80° C. for 20 minutes then cooled to room temperature while stirring overnight.The mixture was filtered and concentrated to give 263 mg of a dark brown oil which was purified by silica gel chromatography (0-15percent ethyl acetate:hexane) to afford 125 as a clear colorless oil (19 mg, 9percent). MS (M+H)=275. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere; | j0399j 2-Chloropyrimidin-5-ol (200 mg, 1.53 mmol), 1-bromo-2-methoxyethane (0.158 mL, 1.69 mmol) and potassium carbonate (423.5 mg 3.06 mmol) were suspended in anhydrous NN-dimethylformamicle (5 mL) and heated 10 50 °C in a nitrogen almosphere for 16 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL), the aqueous was extracted with ethyl acetate (2 x 30 niL) and the conbilled organics washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 244 mg (yield 85percent) as off-white translucent crystals. &i NMR (500 MHz, DMSO) 8.55 (s, 2F1), 4.37 ?4.21 (m, 2H), 3.78 ? 3.59 (m, 2H), 3.30 (s, 3H). Tr(METCRI278) = 1.36 mill, (Est) (M+Na)t 189. |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 26h; | To a stirred solution of 2-chloropyrimidm-5-ol (Intermediate No.86 Step 2, 17.5 g, 134 mmol) in DMF (90 mL was added 2-bromoethyl methyl ether (17.6 mL, 1-87 mmol) followed by K2C03 (24.0 g, 174 mmol). The. resulting suspension was heated at 60 °C for 18 hr. In order to drive the reaction to completion, additional 2-bromoethyl methyl ether (16.0 mL, 170 mmol) and K2C03 (18.5 g, 134 mmol) were added, and- the heating was continued for approximately 8 hr. The reaction mixture was cooled and partitioned between 10percent aqueous sodium chloride (250 mL) and EtOAc (500 mL). The layers were separated and the organic layer was washed with 10percent aqueous sodium chloride (250 mL). The first aqueous layer was extracted with EtOAc (250 mL). The second aqueous layer was salted with solid NaCl, and extracted with EtOAc (250-mL). The combined organic layers were driecLover Na2S04, filtered, andconcentrated to a crude oil that was taken up into a minimal amount of DCM and purified by silica gel chromatography to afford 2-chIoro-5-(2-methoxyethoxy)pyrimidine as a white solid. LRMS (ESI) calc'd for C7H10C1N2O2 [M+Hf: 189. ; found 189. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | 2-Chloropyrimidin-5-ol (Intermediate No.86 Step 2, 200 mg,. 1.5 mmol) was dissolved in THF (5 mL) and triphenylphosphine (600 mg, 23 mmol) and 1,4-dioxa- spiro[4.5]decan-8-ol (365 mg, 2.30 mmol) was added, followed by DIAD (0.45 mL, 2.3 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHC03> and the aqueous phase was extracted with. EtOAc. The combined organic extracts were dried over Na2S04, filtered, dry loaded onto silica gel and the cpade residue was purified by flash chromatography (MPLC, 2-20percentDCM-hexane followed-by 5-60percent EtOAc-hexane) to give a crude residue which was further purified by reverse phase preparative HPLC (0-80percent MeCN-H20, 0.05percent TFA). Fractions containing the pure compound were collected and the free base was liberated by an EtOAc extraction and sat.NaHC03 wash to give 2-c oro-5-(l ,4-dioxaspiro[4.5]dec-8-yloxy)pyrimidine as a solid.LRMS (ESI) calc'd for C12H16C1N203 [M+H] +: 271 , Found: 271 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 60℃; for 24h; | To a pressure vial equipped with a stir bar was added rt-butyl 4- (bromomethyl)piperidine-1-carboxylate (4.95 g, 17.8 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong>(Intermediate No.86 Step 2, 2.3 g, 17.8 mmol) and DMF (59 mL). Sodium hydride (60 wtpercent, 0.47 g, 19.6 mmol) was added and the vial was sealed and heated to 60 °C for 24 hours. The crude reaction mixture was diluted with ethyl acetate and filtered through a column pre-packed with Celite. The filtrate was concentrated in vacuo and the residue purified by flash chromatography (MPLC, 0-50percent EtOAc-hexanes) to give tert-butyl 4-[(2-chloropyrimidin-5- y l)oxy]methyl } piperidine- 1 -carboxylate.LRMS (ESI) calc'd for CI 1H15C1N303 [M+H]+: 272, Found: 272 (carbamic acid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 76h; | 2- Chloropyrimidin-5-ol (intermediate No.86 Step 2, 5.0 g, 38.3 mmol), K2C03 (10.6 g, 77 mmol) and 2,2-dimethyloxirane (6.81 mL, 77 mmol) were stirred in DMF (50 mL) at 50 °C for 4 hours followed by 65"°C for 3 days. Water was added, followed by saturated NH4C1 and EtOAc. The resulting emulsion was filtered through Celite. The organic phase was separated and the aqueous portion extracted again with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. Purification of the residue by flash chromatography (MPLC, 12-100percent EtOAc-hexanes) gave l-[(2-chloropyrimidin- 5-yl)oxy]-2-methylpropan-2-ol as a white solid.LRMS (ESI) calc'd for C8H12C1N202 [M+H]+: 203; found 203 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | To a solution of 100 mg (0.766 mmol) of 4-hydroxy-1-methyl piperidine in 1.5 ml of tetrahydrofuran, 155 mg (1.53 mmol) of di-tert-butyl azocarboxylic acid, 402 mg (1.53 mmol) of triphenylphosphine and 0.170 ml (1.53 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the reaction solution was extracted with 1 N hydrochloric acid. 1 N sodium hydroxide aqueous solution was added to the aqueous layer to make its pH 10 and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to provide 152 mg of the title compound as a white solid (yield: 87percent). 1H-NMR spectrum (400 MHz, CDCl3) delta ppm: 8.22 (2H, s), 4.33 (1H, tt, J=7.5, 3.8 Hz), 2.65-2.57 (2H, m), 2.30-2.22 (5H, m), 2.01-1.93 (2H, m), 1.85-1.75 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | To a solution of 9.50 g (72.8 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> in 100 ml of N,N-dimethylformamide, 26.1 g (80.1 mmol) of cesium carbonate and 24.3 g (102 mmol) of 5-(methanesulfonyloxymethyl)-2,2,5-trimethyl-1,3-dioxane, which was synthesized by the method described in V. W. Gash, Journal of Organic Chemistry, 1972, Vol. 37, pp. 2197-2201, were added, and the reaction solution was stirred at 90° C. for 24 hours. After completion of the reaction, the insoluble material was filtered off and washed with ethyl acetate, and then 0.5 N sodium hydroxide aqueous solution was added to the filtrate and separation was performed. The obtained aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the precipitate was obtained by filtration and washed with toluene and n-heptane to provide 6.00 g of the title compound as a white solid (yield: 30percent). [0822] 1H-NMR spectrum (300 MHz, CDCl3) delta ppm: 8.34 (2H, s), 4.16 (2H, s), 3.73 (4H, s), 1.47 (3H, s), 1.41 (3H, s), 0.94 (3H, s). |
30% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 24h; | To a solution of 9.50 g (72.8 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> in 100 ml of N,N-dimethylformamide, 26.1 g (80.1 mmol) of cesium carbonate and 24.3 g (102 mmol) of 5-(methanesulfonyloxymethyl)-2,2,5-trimethyl-1,3-dioxane, which was synthesized by the method described in V.W. Gash, Journal of Organic Chemistry, 1972, Vol. 37, p. 2197-2201, were added, and the mixture was stirred at 90°C for 24 hours. After completion of the reaction, the insoluble material was filtered off and washed with ethyl acetate, and then 0.5 N sodium hydroxide aqueous solution was added to the filtrate and separation was performed. The obtained aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the precipitate was obtained by filtration and washed with toluene and n-heptane to provide 6.00 g of the title compound as a white solid (yield: 30percent). 1H-NMR spectrum (300 MHz, CDCl3) deltappm: 8.34 (2H, s), 4.16 (2H, s), 3.73 (4H, s), 1.47 (3H, s), 1.41 (3H, s), 0.94 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | 295 mg (1.72 mmol) 1-bromomethyl-2,2-difluorocyclopropane and 318 mg (2.30 mmol) K2CO3 are added to a mixture of 150 mg (1.15 mmol) <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> in 2 mL DMF. The mixture is stirred at 80° C over night. Then the reaction mixture is quenched by the addition of water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3).C8H7ClF2N2O (M= 220.6 g/mol)ESI-MS: 221 [M+H]+ Rt(HPLC): 1.21 min(methodV) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | 2-Chloro-5-((2,2-difluorocyclopropyl)methoxy)pyrimidine 295 mg (1.72 mmol) 1-bromomethyl-2,2-difluorocyclopropane and 318 mg (2.30 mmol) K2CO3 are added to a mixture of 150 mg (1.15 mmol) <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> in 2 mL DMF. The mixture is stirred at 80° C. over night. Then the reaction mixture is quenched by the addition of water and extracted with DCM. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by HPLC (MeOH/H2O/NH3). C8H7ClF2N2O (M=220.6 g/mol) ESI-MS: 221 [M+H]+Rt (HPLC): 1.21 min (method V) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | The mixture of 150 mg (1.15 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, 295 mg (1.72 mmol) of 1-bromoethyl-2,2-difluorocyclopropane and 318 mg (2.30 mmol) of K2CO3 in 3 ml DMF is stirred at 80° C. over night. The reaction mixture is extracted with water and DCM. The organic layer is dried, filtered and the solvent is removed in vacuo. The residue is purified by prep. HPLC-MS (MeOH/H2O/NH4OH). C8H7ClF2N2O (M=220.1 g/mol). ESI-MS: 221 [M+H]+, Rt (HPLC): 1.21 min (method G). |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | The mixture of 150 mg (1 .15 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, 295 mg (1 .72 mmol) of 1 -bromoethyl-2,2-difluorocyclopropane and 318 mg (2.30 mmol) of K2C03 in 3 ml DMF is stirred at 80 °C over night. The reaction mixture is extracted with water and DCM. The organic layer is dried, filtered and the solvent is removed in vacuo. The residue is purified by prep. HPLC-MS (MeOH/H20/NH4OH). C8H7CIF2N20 (M = 220.1 g/mol) ESI-MS: 221 [M+H]+ R, (HPLC): 1 .21 min (method G) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With copper diacetate; triethylamine; In dichloromethane; | To a stirred solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1.50 g, 1 1.6 mmol) in dichloromethane (20 mL) was added 4-fluorophenylboronic acid (3.30 g, 23.2 mmol), copper(II) acetate (2.49 g, 13.9 mmol) and triethylamine (8.0 mL, 57 mmol). The mixture was left open to the air and stirred overnight. The suspension was then filtered through a pad of Celite and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford 2-chloro-5-(4-fluorophenoxy)pyrimidine as a light yellow solid (0.400 g, 17percent). Exchanging 2-chloro-4-(4-fluorophenyl)pyrimidine for this intermediate, ethyl piperidine-4-carboxylate for ethyl 4-fluoropiperidine-4-carboxylate hydrochloride and Intermediate 5 for Intermediate 1 , the final three steps of Example 41 were used to prepare the title compound. 1H NMR (400 MHz, CD3OD) delta 8.20 (s, 2H), 7.09-6.99 (m, 4H), 4.70-4.66 (m, 2H), 3.33-3.16 (m, 3H), 2.90-2.83 (m, 5H), 2.30-2.01 (m, 3H), 1.92-1.89 (m, 4H), 1.70-1.50 (m, 5H) ppm. 13C NMR (100 MHz, CD3OD) delta 172.4, 172.2, 159.8, 158.5, 157.4, 154.4, 150.0, 143.3, 1 18.2, 1 18.1 , 1 16.1 , 1 15.8, 95.7, 93.8, 60.7, 52.8, 45.6, 45.5, 39.6, 31.5, 31.4, 31.3, 31.2, 29.3, 23.0, 21.8, 21.3 ppm. Purity: > 99percent LCMS (214 nm & 254 nm); retention time 1.39 min; (M+H+) 458.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h; | Potassium carbonate (1.05g, 7.6 mmol) was slowly added to a stirred solution of 2- chloropyrimidin-5-ol (0.5g, 3.8 mmol) in DMF (5mL) followed by the addition of 3- (bromomethyl)-l,5-dimethoxybenzene (0.97g, 4.2 mmol) at 0 °C. The reaction mass was stirred at room temperature for lh then the reaction mixture was quenched with ice cold water. The solid that separated was filtered and dried under reduced pressure to afford desired title compound (0.9 83percent). LCMS: m/z = 281.2 (M+H)+. |
360 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 7h;Cooling with ice; | Preparation Example 13 A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (278 mg), potassium carbonate (453 mg), and N,N-dimethylformamide (3 mL) was ice cooled, and 3,5-dimethoxybenzyl bromide (541 mg) was added thereto followed by stirring at room temperature for 7 hours. To the reaction mixture, water was added followed by extraction with ethyl acetate. An organic layer obtained was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2-chloro-5-[(3,5-dimethoxybenzyl)oxy]pyrimidine (360 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.53 g | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h; | Preparation Example 19 To a mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (4.38 g), potassium carbonate (9.27 g), and N,N-dimethylformamide (79 mL), 2,6-difluoro-3,5-dimethoxybenzyl methanesulfonate (7.89 g) was added followed by stirring at 60 C. for 1 hour. To the reaction mixture, water was added, and the resulting solid was collected by filtration, washed with water, and then dried under reduced pressure to give 2-chloro-5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidine (8.53 g). |
8.53 g | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h; | (4) To a mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (4.38 g), 2,6-difluoro-3,5-dimethoxybenzylmethanesulfonate (7.89 g), and N,N-dimethylformamide (78.9 mL) was added potassium carbonate (9.27 g), followed by stirring at 60 C. for 1 hour. To the reaction mixture was added water, followed by stirring for 30 minutes under ice-cooling. The resulting solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain 2-chloro-5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidine (8.53 g). MS (APCl/ESI+): 317 [(M+H)+]. |
8.53 g | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h; | (4) To a mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (4.38 g), potassium carbonate (9.27 g), and N,N-dimethylformamide (79 mL), 2,6-difluoro-3,5-dimethoxybenzyl methanesulfonate (7.89 g) was added, followed by stirring at 60 C. for 1 hour. To the reaction mixture was added water. The generated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain 2-chloro-5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidine (8.53 g). |
With caesium carbonate; In acetonitrile; for 2h;Inert atmosphere; Reflux; | A mixture of (2,6-difluoro-3,5-dimethoxy-phenyl)methyl methanesulfonate (440 mg, 1.56 mmol, 1.00 eq) , <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (203 mg, 1.56 mmol, 1.00 eq) and Cs2CO3 (762 mg, 2.34 mmol, 1.50 eq) in CH3CN (8.0 mL) was heated to reflux for 2 hours. LC-MS showed reaction was complete. The reaction mixture was quenched by addition of water (5 mL) at 0 C, and then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO;12 g SepaFlash Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient 30 mL/min). Compound 2-chloro-5-[(2,6-difluoro-3,5-dimethoxy-phenyl)methoxy]pyrimidine (188 mg, 528 umol, 34% yield, 89% purity) was obtained as a white solid. LCMS (ESI) m/z: 316.9, 318.9 [M+H]+. | |
188 mg | With caesium carbonate; In acetonitrile; for 2h;Reflux; | To a solution of the crude control example 6C (440 mg, 1.56 mmol) and 2-chloro-5-hydroxypyridine (203.48mg, 1.56 mmol) in CH3CN (8.00 ml) was added CS2CO3 (762.42 mg, 2.34 mmol) as a solid, then the reaction solutionwas heated to reflux and stirred for 2 hours. LCMS showed that the raw materials have been converted completely, with products being generated. When the reaction solution was cooled to room temperature, the reaction was quenched with(5 ml), partitioned, and the aqueous phase was extracted with ethyl acetate (2310 ml). The organic phases werecombined and washed with saturated saline (10 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated at reduced pressure to give a crude product, which was purified over a flash silica gel column (mobilephase: 0?20% ethyl acetate/petroleum ether) to give a white solid compound control example 6D (188.00 mg, yield:33.87%). LCMS (ESI) m/z: 316.9, 318.9[M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
415 mg | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 20 - 50℃; for 15h;Cooling with ice; | Preparation Example 15 A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (487 mg) and 1-(3,5-dimethoxyphenyl)ethanol (680 mg), tributylphosphine (1.37 mL), and tetrahydrofuran (14 mL) was ice cooled, and 1,1'-(azodicarbonyl)dipiperidine (1.4 g) was added thereto followed by stirring at room temperature for 12 hours and stirring at 50° C. for 3 hours. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2-chloro-5-[1-(3,5-dimethoxyphenyl)ethoxy]pyrimidine (415 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h; | [00222] To a mixture of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (700 mg, 5.4 mmol, 1.0 eq), octan-1-ol (1.05 g, 8.1 mmol, 1.5 eq), PPh3 (2.8 g, 10.8 mmol, 2.0 eq) and triethylamine (1.63 g, 16.2 mol, 3.0 eq) in THF (14 mL) was added dropwise DIAD (2.18 g, 10.8 mmol, 2.0 eq) at 0 °C. The mixture was allowed to warm up to rt and stirred for 16 h. The solvent was then removed under reduced pressure and the residue was purified by column chromatography on silica gel (PE/EA=10/1) to give the title compound as a yellow oil (847 mg, 65percent yield). LCMS mlz 243.1 [M+H] 1H NMR (CDC13, 400 MHz) 5: 8.28 (s, 2H), 4.05 (t, J= 6.8 Hz, 2H), 1.85-1.78 (m, 2H), 1.42-1.26 (m, 1OH), 0.90-0.86 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 100℃; | [00576j 1 70B. 2-Chloro-5 -(((3 ,4-trans)- 1 -(5 -chloro-2-methoxypyridin-4-yl)-3 - methylpiperidin-4-yl)oxy)pyrimidine: To a solution of 170A (335 mg, 1.00 mmol) in anhydrous DMF (3 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (100 mg, 0.766 mmol)followed by K2C03 (159 mg, 1.15 mmol). The reaction mixture was stirred atrt for 10 mm and then heated to 100 °C overnight. The reaction mixture was cooled to rt and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with sat. aq. NaHCO3, water (2x), and brine, dried (MgSO4), and concentrated. The crude productwas purified by silica chromatography to give 170B (75 mg, 0.19 mmol, 24percent yield) as a white solid. LC-MS Anal. Calc?d for C16H18C12N402: 369.25, found [M] 369.2. 1H NMR (400 MHz, CDC13) oe 8.31 (s, 2H), 8.01 (s, 1H), 6.27 (s, 1H), 4.06 (td, J=8.6, 4.2 Hz, 1H), 3.92 (s, 3H), 3.62 - 3.51 (m, 2H), 3.00 - 2.85 (m, 1H), 2.70 (dd, J12.4, 9.1 Hz, 1H), 2.31 - 2.15 (m, 2H), 1.89 (dtd, J=13.2, 9.6, 3.9 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | 0.80 mg (6.13 mmol) <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, 1.26 g (9.19 mmol) 1-bromo-2-methylpropane and 1.69 g (12.26 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.C8H11ClN2O (M=186.6 g/mol)ESI-MS: 187 [M+H]+Rt (HPLC): 1.04 min (method D) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | Example XII.1 (general route) -Chloro-5-/'so-butoxy-pyrimidine 0.80 mg (6.13 mmol) <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, 1 .26 g (9.19 mmol) 1-bromo-2- methylpropane and 1.69 g (12.26 mmol) K2C03 are added to 10 mL DMF and stirred at 80 °C over night. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. C8H11CIN2O(M= 186.6 g/mol) ESI-MS: 187 [M+H]+ Rt (HPLC):1.04 min (method D) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | A mixture of 3-(bromomethyl)-4-chloro-5-methoxybenzoate (600 mg, 2.04 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (320 mg, 2.45 mmol), Bu4NI (151 mg, 0.408 mmol) and K2C03 (564 mg, 4.08 mmol) in DMF (15 mL) was stirred at 60 °C for 2 h. The resulting mixture was partitioned between water (100 mL) and DCM (100 mL). Then the organic layer was concentrated to afford the title compound as a yellow solid (700 mg, quantative yield). MS (m/z): 343.0 (M+H)+. |
100% | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | A mixture of 3-(bromomethyl)-4-chloro-5-methoxybenzoate (600 mg, 2.04 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (320 mg, 2.45 mmol), Bu4NI (151 mg, 0.408 mmol) and K2C03 (564 mg, 4.08 mmol) in DMF (15 mL) was stirred at 60 °C for 2 h. The resulting mixture was partitioned between water (100 mL) and DCM (100 mL). Then the organic layer was concentrated to afford the title compound as a yellow solid (700 mg, quantative yield). MS (m/z): 343.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 6h;Microwave irradiation; | 600 mg (2.11 mmol) of example VII.1, 275 mg (2.11 mmol) <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> and 1.12 mL (6.53 mmol) DIPEA in 8 mL NMP are stirred at 150° C. for 6 h in a microwave oven. Afterwards the reaction mixture is directly purified by HPLC (MeOH/H2O/NH3).C18H22N4O3 (M=342.4 g/mol)ESI-MS: 343 [M+H]+Rt (HPLC): 1.04 min (method J) | |
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 6h;Microwave irradiation; | Example XXII.1 (general route) N-((S)-1-(4-((R)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yloxy)phenyl)ethyl) cetamide 600 mg (2.11 mmol) of example VII.1 , 275 mg (2.11 mmol) 2-chloro-5- hydroxypyrimidine and 1 .12 mL (6.53 mmol) DIPEA in 8 mL NMP are stirred at 150 °C for 6 h in a microwave oven. Afterwards the reaction mixture is directly purified by HPLC (MeOH/H20/NH3). ESI-MS: 343 [M+H]+ Rt (HPLC):1.04 min (method J) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h; | General procedure: 0.80 mg (6.13 mmol) <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, 1.26 g (9.19 mmol) 1-bromo-2-methylpropane and 1.69 g (12.26 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.For example XII.4 the reaction conditions are 100° C. for 30 min. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 0.5h; | The following compounds are prepared analogously to example XII.1 For example XII.4 the reaction conditions are 100 C for 30 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 3h; | c) 2.16 g (20.0 mmol) of the above mentioned product, 2.75 g (20 mmol) 1-chloro-5-hydroxypyrimidine and 6.56 g (25 mmol) triphenylphosphine are added to 20 ml THF and cooled to 0° C. Then 11.5 mL (25 mmol) diethylazocarboxylate (40percent in toluene) are added carefully at constant temperature. Then cooling is removed and the mixture is stirred at r.t. for 3 h. Afterwards the solvent is removed in vacuo, diethylether is added and the mixture is filtered. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica gel, PE/EtOAc)C8H7ClF2N2O (M=220.60 g/mol)ESI-MS: 221 [M+H]+Rt (HPLC): 0.91 min (method I) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
b) 7.2 g (59 mmol) R-2,2-difluoro-cyclopropanecarboxylic acid are added to 100 mL THF, chilled to 0°C and 35 mL (77 mmol) lithium aluminum hydride solution (2.2 M in 2-methyltetrahydrofuran) are added dropwise. The mixture is stirred at r.t. over night. After that the mixture is chilled to 0°C and quenched by the addition of 3 ml water and 3 ml aq. NaOH solution (c= 4 mol/L) slowly. The resulting mixture is stirred for 30 min, filtered, washed with THF and the filtrate is concentrated by evaporation. The residue is added to Et2O, dried over Na2SO4, filtered and the solvent is removed in vacuo. C4H4F2O(M= 108.1 g/mol) Rt (GC):15.4 min (method a) c) ) 2.16 g (20.0 mmol) of the above mentioned product, 2.75 g (20 mmol) 1-chloro-5- hydroxypyrimidine and 6.56 g (25 mmol) triphenylphosphine are added to 20 ml THF and cooled to 0 °C. Then 11.5 mL (25 mmol) diethylazocarboxylate (40 percent in toluene) are added carefully at constant temperature. Then cooling is removed and the mixture is stirred at r.t. for 3 h. Afterwards the solvent is removed in vacuo, diethylether is added and the mixture is filtered. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica gel, PE/EtOAc) C8H7CIF2N2O (M= 220.60 g/mol) ESI-MS: 221 [M+Hf Rt (HPLC): 0.91 min (method I) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2.5h; | (Reference Example 12) 5-[(tert-Butyldimethylsilyl)oxy]-2-chloropyrimidine To a solution of 20.2 g (0.154 mol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> in 150 ml of N,N-dimethylformamide, 15.8 g (0.232 mol) of imidazole and 26.8 g (0.178 mol) of tert-butyldimethylsilyl chloride were added, and the reaction mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with n-heptane three times. The obtained organic phases were combined, washed with 0.01 N sodium hydroxide aqueous solution, water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to provide 39.5 g of the title compound as a white solid (yield: 100percent). 1H-NMR spectrum (300 MHz, CD2 Cl2) delta: 8.21 (2H, s), 1.00 (9H, s), 0.25 (6H, s). Mass spectrum (EI, m/z): 244 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 70℃; for 3.5h; | (Reference Example 20) 2-Chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine To 2.53 g (19.4 mmol) of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong>, a solution of 5.95 g (19.8 mmol) of 5-(toluenesulfonyloxymethyl)-2,2-dimethyl-1,3-dioxane in 11 ml of N-methylpyrrolidone and 6.50 g (19.9 mmol) of cesium carbonate were added, and the reaction mixture was stirred at 70°C for 3.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate twice. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. tert-Butyl methyl ether was added to the obtained residue, and the precipitate was obtained by filtration to provide 3.72 g of the title compound as a white solid (yield: 74percent). 1H-NMR spectrum (300 MHz, CD2 Cl2) delta: 8.31 (2H, s), 4.22 (2H, d, J = 7.1 Hz), 4.11 (2H, dd, J = 12.5, 3.7 Hz), 3.82 (2H, dd, J = 12.5, 4.2 Hz), 2.05 (1H, ttt, J = 7.5, 3.8, 3.8 Hz), 1.44 (3H, s), 1.36 (3H, s). Mass spectrum (CI, m/z): 259 [M+ +1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h; | Step-1: Preparation of 2-chloro-5-((triisopropylsilyl)oxy)pyrimidine [0179] To a solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1.0 g, 7.67 mmol) in tetrahydrofuran (20 mL) was added triethylamine (2.15 mL, 15.34 mmol) and the reaction mixture was cooled to 0 °C. Chlorotriisopropylsilane (2.46 mL, 11.50 mmol) was added drop wise and the solution was stirred at room temperature for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 ml x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography using 5percent ethyl acetate in hexane to obtain the title compound 2-chloro-5-((triisopropylsilyl)oxy)pyrimidine (1.9 g, 86percent yield) as a colorless liquid. Calculated (M+H): 287.13; Found (M+l): 287.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With di-isopropyl azodicarboxylate; N-ethyl-N,N-diisopropylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 24h; | Step 1. 2-chloro-5-((6-phenylhexyl)oxy)pyrimidine. To a stirring solution of chlorohydroxypyrimidine (250 mg, 1.92 mmol), 6-phenylhexanol (444 mg, 2.5 mmol), in THF (5 mL) was added DIEA (1.0 mL, 5.76 mmol), PPh3 (1.0 g, 3.84 mmol) and the mixture was cooled to 0 °C and DIAD (0.756 mL, 3.84 mmol) was added dropwise. The mixture was allowed to warm to rt and stirred for 24h. The crude reaction mixture was concentrated, and purified by silica gel chromatography using 0-10percent EtOAc/hexanes to afford 2-chloro-5-((6-phenylhexyl)oxy)pyrimidine as a white solid (400 mg, 72percent): XH NMR (500MHz, CDCl3) delta ppm 8.26 (s, 2H), 7.15 - 7.30 (m, 5H), 4.03 (t, J= 6.3 Hz, 2H), 2.63 (t, J= 7.8 Hz, 2H), 1.81 (quin, J= 8.3 Hz, 2H), 1.66 (quin, J= 7.7 Hz, 2H), 1.49 (quin, J= 7.8 Hz, 2H), 1.40 (J= 7.8 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.6% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | To a mixture of 2- chloropyrimidin-5-ol (1 g, 7.6 mmol) and i-fluoro-2-iodoethane (1.73 g, 9.9 mmol) in DMF (2.9 mL) was added 052003 (3.2 g, 9.9 mmol). The mixture was stirred vigorously for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered, and the solid was washed with EtOAc (20 mL). Thefiltrate was washed with water (3x30 mL) and dried (Na2504) and concentrated. Purification (FCC, 5i02, DCM/EtOAc) afforded the title compound as a white solid (847 mg, 62.6percent). MS (ESI): mass calcd. for C5H5CIFN2O, 176.0; m/zfound, i7i.i[M+H]. |
27% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | Step A: 2-chloro-5-(2-fluoroethoxy)pyrimidine. To a vial charged with <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (300 mg, 2.23 mmol) and Cs2CO3 (0.97 g, 3.0 mmol), was added 1-fluoro-2-iodoethane (480 mg, 2.76 mmol) in DMF (5 mL). The mixture was stirred vigorously at rt for 3, then diluted with water, extracted with EtOAc, washed with brine. The organic layers were dried and concentrated. The residue was purified on a silica gel chromatography to afford 2-chloro-5-(2-fluoroethoxy)pyrimidine (111 mg, Yield 27percent). MS (ESI): mass calcd. for C5H6ClFN2O, 176.0; m/z found, 177.0 [M+H]+. 1H NMR (400 MHz, d-chloroform) delta 8.31-8.24 (s, 2H), 4.80-4.74 (m, 1H), 4.70-4.64 (m, 1H), 4.31-4.20 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.5% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 12h; | To a stirred solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (20 g, 153 mmol) in THF (100 mL) at 0 C was added (R)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (24.30 g, 184 mmol), triphenylphosphine (50.2 g, 192 mmol) followed by DEAD (30.3 mL, 192 mmol) and the reaction was stirred at RT for 12 h. (TLC eluting system: 70% EtOAc in pet ether; R/-0.5; UV active). The reaction mixture was quenched with water (100 mL) and extracted into EtOAc (200 mL). Organic layer was separated and dried over anhydrous Na2S04, filtered and filtrate was evaporated to give crude product. The crude was purified by chromatography (Silicagel, eluent: 35% EtOAc in hexane) to afford (R)-2-chloro-5-((2,2- dimethyl-l,3-dioxolan-4-yl)methoxy)pyrimidine (23 g, 91 mmol, 59.5 % yield) as a white solid. LCMS (m/z): 245.06; [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a stirred solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (13 g, 100 mmol) in THF (100 mL) at 0 C was added (,S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (13.16 g, 100 mmol), triphenylphosphine (32.7 g, 124 mmol) followed by DEAD (19.71 mL, 124 mmol) and reaction was stirred at RT for 4 h. (TLC eluting system: 30% EtOAc in pet ether; R/-0.5; UV active). The reaction mixture was quenched with water (50 mL) and extracted into EtOAc (2x75 mL). Organic layer was separated and dried over anhydrous Na2S04, filtered and filtrate was evaporated to give crude product. The crude was purified by chromatography (Silicagel, eluent: 20% EtOAc in hexane) to afford (,S)-2-chloro-5-((2,2- dimethyl-l,3-dioxolan-4-yl)methoxy)pyrimidine (20g, 79 mmol, 79 % yield) as an off white solid. LCMS (m/z): 245.10; [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.37% | With potassium carbonate; In acetonitrile; at 60℃; for 2h; | To a mixture of bromoacetonitrile (2.94 mL, 42.18 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong>(5 g, 38.30 mmol) in CH3CN (100 mL) is added potassium carbonate (7.94 g, 57.45mmol). The reaction mixture is heated to 60 °C for 2 hours. After cooling to roomtemperature, the solid is filtered and the filtrate is concentrated under reduced pressure.The residue is purified by silica gel flash chromatography eluting with a gradient of 100percentether to 1/1 ether/ethyl acetate to give the title compound (6 g, 35.38 mmol, 92.37percent) as awhite solid. Mass spectrum (mlz): 170 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h; | Potassium carbonate (1.51g, 11 mmol) was slowly added to a stirred solution of 2- chloropyrimidin-5-ol (0.58g, 4.4 mmol) in DMF (25mL) followed by the addition of 3- (bromomethyl)-2,4-difluoro-l,5-dimethoxybenzene (Example 506, step (b)) (1.2g, 4.4 mmol) at 0 °C. The reaction mass was stirred at room temperature for 12h. Then the reaction mixture was quenched with ice cold water. The solid separated and was filtered and dried under reduced pressure to afford desired title compound (1.2g, 85percent). LCMS: m/z = 316.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | Potassium carbonate (1.32g, 9.6 mmol) was slowly added to a stirred solution of 2- chloropyrimidin-5-ol (0.41g, 3.2 mmol) and 3-(l-bromoethyl)-2,4-difluoro-l,5- dimethoxybenzene (0.9g, 3.2 mmol) in DMF (lOmL) at 0 °C. The reaction mass was stirred at room temperature for lh. Then the reaction mixture was quenched with ice cold water and diluted with ethyl acetate. The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum to afford the title compound (0.98g, 92percent). LCMS: m/z = 331.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; for 18h;Inert atmosphere; | Step 1 : 2-Chloropyrimidin-5-ol (5.3 g) was dissolved under argon in acetone (144 ml). After addition of potassium carbonate (8.42 g) and 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (12.3 g) the mixture was stirred for 18 h. The mixture was diluted with -200 ml ether, stirred for 10 min and filtered. The filtrate was concentrated, taken up in dichloromethane, filtered again and concentrated to dryness to give 2-chloro-5-(2,2,3,3- tetrafluoropropoxy)pyrimidine (8.99g, not totally pure) as orange oil. MS: m/z = 245.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.12% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Cooling with ice; | Diisopropyl azodicarboxylate (0.8298 g, 4.104 mmol, 6.0 eq) under ice bath It was added dropwise to a solution of triphenylphosphine (1.0765 g, 4.104 mmol, 6.0 eq) in anhydrous tetrahydrofuran (13.5 ml).After reacting for 15 minutes in an ice bath, 1-(2,6-dichloro-3,5-dimethoxyphenyl)ethan-1-ol (0.171 g, 0.6840 mmol, 1.0 eq) of tetrahydrofuran (3.67) The ml, 5.36 ml/mmol solution was added dropwise to the reaction flask followed by <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (0.3571 g, 2.736 mmol, 4.0 eq).The ice bath was removed and reacted at room temperature for 12 h. A 1 M NaOH (2.8 ml) aqueous solution and water (6 ml) were added to the reaction flask.Extract with ethyl acetate and concentrate the organic phase.Column chromatography gave 0.1271 g of the desired product. Yield: 51.12percent. |
With tributylphosphine; diisopropyl diazenedicarboxylate; In tetrahydrofuran; at 0 - 27℃; for 16h;Inert atmosphere; | To a stirred solution of 1-(2,6-dichloro-3,5-dimethoxyphenyl)ethanol (800 mg, 3.19 mmol, 1.00 eq) and DIAD (968 mg, 4.79 mmol, 930 uL, 1.50 eq) in THF (6.0 mL) was added tributylphosphane (968 mg, 4.79 mmol, 1.18 mL, 1.50 eq) at 0 °C. To the resulting mixture, <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (625 mg, 4.79 mmol, 1.50 eq) was added as one portion. The mixture was warmed up to 27 °C and stirred for 16 hours, to which was added water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column size: 40 g, 100-200 mesh silica gel, ethyl acetate/petroleum ether = 0percent to 20percent) to yield a mixture of 2 and 3 (ratio, 1:2.3), which was carried to the next step without further purification. Calculated amount of desired product 3 in the mixture was 0.54 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.25% | With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; for 1h;Cooling with ice; | 2,6-Dichloro-3,5-dimethoxybenzyl bromide (6.3 g, 21 mmol) was added in a 250 ml flask.<strong>[4983-28-2]2-Chloro-5-hydroxypyrimidine</strong> (2.61 g, 20 mmol), tetra-tert-butylammonium iodide (1.48 g, 4 mmol), K2CO3 (5.53 g, 40 mmol) and 80 ml DMF.The reaction solution was poured into ice and stirred for 1 h, filtered with a Buchner funnel, and the filter cake was washed with water several times.Drying at 50 ° C in vacuo gave 6.31 g of solid, yield: 90.25percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate; In acetonitrile; at 80℃; for 16h;Inert atmosphere; | To a mixture of (3,5-dimethoxyphenyl)methyl methanesulfonate (3.90 g, 15.8 mmol, 1.00 eq) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (2.07 g, 15.8 mmol, 1.00 eq) in CH3CN (40.0 mL) was added Cs2CO3 (10.3 g, 31.7 mmol, 2.00 eq) in one portion under N2. The mixture was stirred at 80 °C for 16 hours. TLC showed the starting material was consumed and a new spot was detected. LC-MS showed the starting material was consumed and desired product was detected. The reaction mixture was filtered, then diluted with H2O (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, Petroleum ether/Ethyl acetate=1/0 to 7/3). Compound 2-chloro-5-[(3,5-dimethoxyphenyl)methoxy]pyrimidine (3.00 g, 10.7 mmol, 67percent yield) was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d): delta 8.33 (s, 2H), 6.53 (d, J = 2.3 Hz, 2H), 6.42-6.47 (m, 1H), 5.09 (s, 2H), 3.80 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.1% | With caesium carbonate; In acetonitrile; for 1h;Reflux; | The control example 5B (447.2 mg, 3.43 mmol), 4-chloro,5-hydroxy pyrimidine (447.2 mg, 3.43 mmol) andcesium carbonate (2.23 g, 6.85 mmol) were added into acetonitrile (15.00 ml). Then the reaction was heated to refluxin an oil bath. After the mixture was stirred for 1.0 h, LCMS detection showed that the reaction was completed. Thereaction solution was diluted with water (10 ml), with adjusting the pH to 9. The organic phase was washed with waterto neutral, then washed with saturated saline (10 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate wasconcentrated at reduced pressure to give the control example 5C (1.02 g, yield 85.1%). 1H NMR (400MHz, CHLOROFORM-d) delta 8.40 (s, 2H), 6.64 (s, 1H), 5.43 (s, 2H), 3.95(s, 6H). |
With caesium carbonate; In acetonitrile; for 2h;Inert atmosphere; Reflux; | General procedure: A mixture of (2,6-difluoro-3,5-dimethoxy-phenyl)methyl methanesulfonate (440 mg, 1.56 mmol, 1.00 eq) , <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (203 mg, 1.56 mmol, 1.00 eq) and Cs2CO3 (762 mg, 2.34 mmol, 1.50 eq) in CH3CN (8.0 mL) was heated to reflux for 2 hours. LC-MS showed reaction was complete. The reaction mixture was quenched by addition of water (5 mL) at 0 C, and then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO;12 g SepaFlash Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient 30 mL/min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.57 g | With potassium phosphate; In N,N-dimethyl-formamide; at 50℃; for 2h; | A) tert-butyl 2-((2-chloropyrimidin-5-yl)oxy)acetate (0276) To a mixture of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (5.7 g), tert-butyl 2-bromoacetate (9.80 g) and DMF (75 mL) was added potassium phosphate (14.83 g) at room temperature, and the mixture was stirred at 50°C for 2 hr. The reaction mixture was quenched with water at room temperature, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.57 g). MS: [M+H]+ 245.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; | To a solution of (2R,5R)-tert-butyl 2-(hydroxymethyl)-5-methylmorpholine-4-carboxylate (1.2 g, 5.2 mmol) and <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1 g, 7.5 mmol), DIAD(1.5 g 7.5 mmol) in THF (30 mL) was added triphenylphosphine (2 g, 7.5 mmol) at 0 °C, then the reaction was stirred at room temperature for 12 hours. The reaction solution was evaporated to dryness and the residue was purified by flash column chromatography, eluting with ethyl acetate: petroleum ether = 1:3 to afford the title compound (0.52 g, 1.52 mmol, 29 percent yield). LCMS Method D RT= 1.54 min, ES+ve 287.9 (M-tBu+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h; | To a mixture solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (4.0 g, 30.8 mmol) and potassium carbonate (12.7 g, 92.0 mmol ) in DMF (50 mL) was added 1,2-dibromoethane (23.0 g, 122 mmol), and the reaction was stirred for 16 hours at 70 °C. The reaction mixture was poured into water, extracted with ethyl acetate (80 mL x3), the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The organic layers were concentrated to dryness and the residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (5:1) to afford the title compound (4.0 g, 17.0 mmol, 55percent yield). LCMS Method D RT= 1.47 min, ES+ve 236 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.3% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 42h;Inert atmosphere; | To a solution of 2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethanol (247 mg, 0.589 mmol) in THF (5 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (85 mg, 0.648 mmol), triphenylphosphine (232 mg, 0.883 mmol) and DIAD (0.172 mL, 0.883 mmol) and the reaction was stirred at 20 °C under an atmosphere of nitrogen for 42 hours. The reaction was concentrated, and the residue was subjected directly to purification by flash chromatography (60g pre-packed C-18 SNAP cartridge: 5percent to 30percent acetonitrile (0.1percent formic acid) in water (0.1percent formic acid)). The desired fractions were combined and concentrated to afford the title compound (167 mg, 0.31 mmol, 53.3 percent yield). LCMS RT= 0.73 min, ES+ve 532. |
53% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 42h;Inert atmosphere; | (0189) To a solution of 2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethanol (247 mg, 0.59 mmol) in THF (5 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (85 mg, 0.65 mmol), triphenylphosphine (232 mg, 0.88 mmol) and DIAD (0.172 mL, 0.88 mmol) and the reaction mixture was stirred at rt under an atmosphere of nitrogen for 42 hours. The reaction mixture was concentrated, and the residue subjected directly to purification by flash chromatography (60 g pre-packed C-18 SNAP cartridge: 5percent to 30percent acetonitrile (0.1percent formic acid) in water (0.1percent formic acid)). Desired fractions were combined and concentrated to afford the title compound (167 mg, 0.31 mmol, 53percent yield). LCMS RT=0.73 min, ES+ve 532. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; | To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (561 mg, 2.79 mmol) in THF (5 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (200 mg, 1.532 mmol), triphenylphosphine (548 mg, 2.089 mmol) and DIAD (0.406 mL, 2.089 mmol) and the reaction was stirred at 20 C under an atmosphere of nitrogen for 72 h. The reaction was concentrated, and the residue subjected directly to purification by flash chromatography (60g pre-packed C-18 SNAP cartridge:35% to 90% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). The desired fractions were combined and concentrated to afford the title compound (430 mg, 1.07 mmol, 77 % yield). LCMS T= 1.12 min, ES+ve 258 (M+H-tBu). |
77% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; | (0204) To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (561 mg, 2.8 mmol) in THF (5 mL) was added <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (200 mg, 1.53 mmol), triphenylphosphine (548 mg, 2.09 mmol) and DIAD (0.406 mL, 2.09 mmol) and the reaction mixture was stirred at 20 C. under nitrogen for 72 h. The reaction mixture was concentrated in vacuo, and the residue was subjected directly to purification by flash chromatography (60 g pre-packed C-18 SNAP cartridge using a gradien elution from 35-90% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). Desired fractions were combined and concentrated to afford the title compound (430 mg, 1.1 mmol, 77% yield). LCMS RT=1.12 min, ES+ve 258 (M+H-tBu). |
48% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate ( 2.5 g, 12.60 mmol) in THF (30 mL), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1.5 g, 11.4 mmol), TPP (7.4 g, 22.9 mmol) followed by di-tert- butyl azocarboxylate (DTAD, 5.2 g, 22.9 mmol) were added and the reaction mixture was stirred at RT overnight. Completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (5 mL), brine solution (5 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude material was purified by flash chromatography (Biotage Isolera, eluent: 50percent EtOAc in hexane) to afford the title compound. Yield: 48percent (1.8 g, yellow solid). LCMS: (Method A) 258.2 (M-f-butyl), Rt. 4.5 min, 96.8percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h; | Add K2CO3(5.71 g, 41.3 mmol) to a solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (5.01 g, 38.3 mmol) and tert-butyl N- [ (E) -2- (bromomethyl) -3-fluoro-allyl] carbamate (3.67 g, 13.7 mmol) in DMF (25 mL) . Stir the resulting solution at room temperature for 12 hours. Quench the reaction by adding water (80 mL) and EtOAc (100 mL) . Separate the organic and aqueous phases. Extract the aqueous phase with EtOAc (3×100 mL) . Combine all the organic extracts. Dry the combined organic extracts over Na2SO4, filter, and concentrate the filtrate under vacuum to provide a residue. Subject the residue to silicia gel flash chromatography eluting with a mixture of 30EtOAc in hexanes to give the title compound as a white solid (4.15 g, 13.1mmol, 96% yield) . ES/MS (m/z) : 340 (M+Na) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 6h;Inert atmosphere; Cooling with ice; | (0220) Under an atmosphere of nitrogen, an ice-cooled solution of a mixture of tert-butyl ((S)-1-(((S)-1-cyclohexyl-2-((2S,4R)-4-hydroxy-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (600 mg, 1.0 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (161 mg, 1.2 mmol) and triphenylphosphine (404 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was treated dropwise over 1 minute with DIAD (0.3 mL, 1.5 mmol). The mixture was then stirred at room temperature for 6 hours and subsequently treated with dichloromethane (40 mL) and water (10 mL). The organic phase was evaporated to dryness and the product was purified by chromatography on silica using a gradient elution from 0-100percent ethyl acetate in cyclohexane followed by 0-5percent methanol in ethyl acetate to afford the title compound (525 mg, 0.75 mmol, 73percent yield). LCMS RT=1.38 min, ES+ve 697. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.1% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2.08333h; | To a 50 mL round bottom flask equipped with a stir bar was added 2- chloropyrimidin-5-ol (250 mg, 1.9 15 mmol), 2-(4-fluorophenyl)ethanol (268 mg, 1.9 15 mmol), triphenylphosphine (603 mg, 2.298 mmol) and THF (10 mL). To the stirred solution was added DIAD (0.447 mL, 2.298 mmol). The solution warmed to a mildexotherm, then cooled within 5 minutes. The solution was stirred at r.t. for 2 hrs. The reaction solution was concentrated in vacuo and the resulting oil was purified via silica gel chromatography (40 g column, 5-40percent EtOAc:Hex) to afford the product 2-chloro-5- (4-fluorophenethoxy)pyrimidine (310 mg, 1.227 mmol, 64.1 percent yield) as a white solid. ?H NMR (500 MHz, CDC13) 8.28 (s, 2H), 7.25 (dd, J=8.7, 5.4 Hz, 2H), 7.08 - 7.02 (m,2H), 4.26 (t, J=6.7 Hz, 2H), 3.13 (t, J=6.7 Hz, 2H). LCMS (M+1) = 252.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.7% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 16h; | A suspension of tert-butyl 4-(((trifluoromethylsulfonyl)oxy)piperidine-1-carboxylate (6.2 g, 21.1 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (2.5 g, 19.2 mmol) and potassium carbonate ( 13.3 g, 96 mmol) in dimethylsulfoxide (100 mL) was stirred at llOoC for 16 hours. The reaction mixture was cooled to room temperature and dimethylsulfoxide was distilled off under reduced pressure. The residue was then treated with water (50 mL) and precipitate was formed, filtered off and purified by column chromatography eluting with hexanes: ethyl acetate mixture (3:2) by volume to afford the title compound (2.0 g, 31.7 %) as a white crystalline powder: |
31.7% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 16h; | [0545] A suspension of tert-butyl 4-(((trifluoromethylsulfonyl)oxy)piperidine-1-carboxylate (6.2 g, 21.1 mmol), <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (2.5 g, 19.2 mmol) and potassium carbonate (13.3 g, 96 mmol) in dimethylsulfoxide (100 mL) was stirred at 110 for 16 hours. The reaction mixture was cooled to room temperature and dimethylsulfoxide was distilled off under reduced pressure. The residue was then treated with water (50 mL) and precipitate was formed, filtered off and purified by column chromatography eluting with hexanes: ethyl acetate mixture (3:2) by volume to afford the title compound (2.0 g, 31.7 %) as a white crystalline powder: 1H NMR (400 MHz, DMSO-d6) delta 8.53 (s, 2H), 4.02 (d, J = 6.4 Hz, 2H), 3.96 (d, J = 12.4 Hz, 2H), 3.24- 3.23 (m, 1H), 2.74 (s, 2H), 2.02- 1.85 (m, 1H), 1.73 (d, J = 11.1Hz, 2H), 1.39 (s, 9H), 1.24- 1.02 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere; | Compound 3-(dimethylamino)propan-1-ol (825.28 mg, 8 mmol) and triphenylphosphine (2.517 g, 9.6mmol) were added successively to a suspension of 19 (1.044 g, 8 mmol) in THF (15 mL) under nitrogen.A solution of DIAD (1.67 g, 9.6 mmol) in THF (2 mL) was then slowly added dropwise with ice cooling.The resultant solution was stirred at room temperature for 12 hours. The aqueous phase wasextracted with dichloromethane (40 mL 3). The combined organic layer was washed with H2O (40 mL)and brine (20 mL), and then dried over anhydrous Na2SO4, filtered and evaporated in vacuo. Theresidue was purified by flash chromatography over silica gel (DCM/MeOH = 40:110:1) to give 20a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere; | General procedure: Compound 3-(dimethylamino)propan-1-ol (825.28 mg, 8 mmol) and triphenylphosphine (2.517 g, 9.6mmol) were added successively to a suspension of 19 (1.044 g, 8 mmol) in THF (15 mL) under nitrogen.A solution of DIAD (1.67 g, 9.6 mmol) in THF (2 mL) was then slowly added dropwise with ice cooling.The resultant solution was stirred at room temperature for 12 hours. The aqueous phase wasextracted with dichloromethane (40 mL 3). The combined organic layer was washed with H2O (40 mL)and brine (20 mL), and then dried over anhydrous Na2SO4, filtered and evaporated in vacuo. Theresidue was purified by flash chromatography over silica gel (DCM/MeOH = 40:110:1) to give 20a. |
Tags: 4983-28-2 synthesis path| 4983-28-2 SDS| 4983-28-2 COA| 4983-28-2 purity| 4983-28-2 application| 4983-28-2 NMR| 4983-28-2 COA| 4983-28-2 structure
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