Structure of 4983-28-2
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CAS No. : | 4983-28-2 |
Formula : | C4H3ClN2O |
M.W : | 130.53 |
SMILES Code : | ClC1=NC=C(C=N1)O |
MDL No. : | MFCD09743796 |
InChI Key : | BOGPIHXNWPTGNH-UHFFFAOYSA-N |
Pubchem ID : | 14595700 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from |
46.01 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.08 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.45 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.22 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.7 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.71 |
Solubility | 2.52 mg/ml ; 0.0193 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.36 |
Solubility | 5.72 mg/ml ; 0.0439 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.66 |
Solubility | 2.88 mg/ml ; 0.0221 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.52 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.43 |
* 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 |
---|---|---|
90% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | <strong>[4983-28-2]2-Chloro-5-hydroxypyrimidine</strong> 34a (0.50 g, 3.8 mmol) was dissolved in N,N-dimethylformamide (5 mL).Benzyl bromide (0.55 mL, 4.6 mmol) and potassium carbonate (0.79 g, 5.7 mmol) were added, and the mixture was reacted at room temperature for 18 hours.The reaction was quenched with water (10 mL).It was extracted with ethyl acetate (20 mL) and the organic phase was washed with saturated sodium chlorideDry over anhydrous sodium sulfate, concentrate by suction filtration, and the residue obtained was purified by silica gel column chromatography[ethyl acetate/petroleum ether (v/v) = 1/10] purified,Get the title compound34b (0.76 g, yield 90percent) as a white solid. |
89% | With potassium carbonate; In methanol; at 20℃; for 14h; | 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) delta 8.27 (s, 2H), 7.37-7.30 (m, 5H), 5.09 (s, 2H). |
A solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (70percent purity, 7.5g, 40mmol) in DMF (15mL, 190mmol), under argon, was cooled to 0°C. Cesium Carbonate (14. Og, 43mmol) was added, portionwise, and the mixture was stirred for 5min at 0°C then lOmin at r.t.. The mixture was cooled back back down to 0°C and benzyl bromide (5.1mL, 43mmol) was added, portionwise. The reaction was stirred at 0°C for 15min, then allowed to warm to r.t. and stirred for a further 90min. The solvent was removed in vacuo and the residue partitoned between EtOAc and water. The organic phase was separated, washed with water:brine(l : 1), dried (MgS04), and the solvent removed in vacuo. Trituration from a combination of Et20 and IH, and further trituration of the motherliquer after concentration in vacuo, afforded the title compound in two crops: RT = 3.54 min; m/z (ES ) = 221.0 [M+ H]+. |
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 |
---|---|---|
39.7% | In water; N,N-dimethyl-formamide; at 90℃; for 24h; | 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% | In water; N,N-dimethyl-formamide; at 90℃; for 24h; | 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 |
---|---|---|
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 |
---|---|---|
25% | With sulfuric acid; In water; for 2h;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) delta 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 |
---|---|---|
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 |
---|---|---|
69% | To a stirred solution of (3-bromopyridin-4-yl)methanol (2.377 g, 12.64 mmol) and triethylamine (3.52 mL, 25.28 mmol) in dichloromethane (52.6 mL) was added a solution of methanesulfonyl chloride (1.034 mL, 13.27 mmol) in dichloromethane (5.26 mL) at 5° C.-10° C. When the addition was completed the mixture was stiffed at 5° C.-10° C. for 2 hours, treated with acetonitrile (52.6 mL), and then the dichloromethane evaporated in vacuo to leave a solution of the mesylate in acetonitrile, which was treated with <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (1.500 g, 11.49 mmol) and potassium carbonate (4.76 g, 34.47 mmol) and the stirred mixture heated under reflux at 85° C. overnight. The mixture was cooled to ambient temperature and the acetonitrile evaporated in vacuo to a residue which was partitioned between water (50 mL) and ethyl acetate (100 mL), and filtered through a filtration aid. The ethyl acetate layer washed with brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica with 50percent ethyl acetate in isohexane as eluant to give a solid which was crystallised from ethyl acetate/isohexane to give 5-((3-bromopyridin-4-yl)methoxy)-2-chloropyrimidine (2.370 g, 69percent). 1H NMR (400.13 MHz, CDCl3) 5.1 (2H, s), 7.4 (1H, d), 8.3 (2H, s), 8.5 (1H, d), 8.7 (1H, s). m/z (ES+) (M+MeCN)+=343. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; | To a solution of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (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 |
---|---|---|
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 |
---|---|---|
With potassium carbonate; In tetrahydrofuran; at 20℃;Reflux; | Intermediate 8: 2-Chloro-5-benz loxypyrimidine To a stirred mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (2.0g, 0.01532mol), K2C03 (4.23g, 0.0307mol) in dry THF (30mL) was added benzyl chloride (2.6mL, 0.023mol) dropwise at room temperature. The mixture was heated at reflux overnight. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to provide 2-chloro-5-benzyloxypyrimidine (1.3g) which was of sufficient purity to use directly in the synthesis of Intermediate 9.Mass: (ES+) 221 (M+H) + | |
With potassium carbonate; In tetrahydrofuran;Reflux; | Intermediate 26: 2-Chloro-5-benz loxypyrimidineTo a stirred mixture of 2-chloro 5-hydroxy pyrimidine (2.0g, 0.01532mol), K2C03 (4.23g, 0.0307mol) in dry THF (30mL) was added benzyl chloride (2.6mL, 0.023mol) dropwise at room temperature. The mixture was heated at reflux overnight. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to provide 2-chloro-5-benzyloxypyrimidine (1.3g) which was of sufficient purity to use directly in the next step.Mass: (ES+) 221 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With copper diacetate; triethylamine; In dichloromethane; for 72h;Molecular sieve; Air conditions; | Intermediate 7: 2- Chloro-5- (3- (pyrrolidin- 1 -yl)phenoxy)pyrimidineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (2.69g, 0.0206mol), 3-(pyrrolidin-l- yl)phenylboronic acid (3.95g, 0.0206mol), copper (II) acetate (3.75 g, 0.0206mmol), triethylamine (14.40mL, 0.0721mol) and powdered 4A molecular sieves in dichloromethane (70mL) was stirred under air for 3 days. The 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 column chromatography on silica (ethyl acetate:hexane, 1: 1) to afford 2-chloro-5-(3-(pyrrolidin-l-yl)phenoxy)pyrimidine as colourless oil (1.3g, 18percent).Mass: (ES+) 275 (M+H) + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With copper diacetate; triethylamine; In dichloromethane; for 72h;Molecular sieve; Air conditions; | Intermediate 6: 4-[3-(2-Chloro-pyrimidin-5-yloxy)phenyl]morpholineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (12.6 lg, 0.097mol), 3-morpholinylphenyl boronic acid (20. Og, 0.097mol), copper (II) acetate (19.28g, 0.097mmol), triethylamine (47.13mL, 0.34mol) and powdered 4A molecular sieves in dichloromethane (600mL) 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 column chromatography on silica (ethyl acetate:hexane, 1: 1) to afford 4-{3-[(2-chloropyrimidin-5-yl)oxy]phenyl}morpholine (5.0g, 18percent) as colourless oil. Mass: (ES+) 292 (M+H)+ NMR: deltaEta ( 6-DMSO) 3.15 (4H, m), 3.84 (4H, m), 6.50 (1H, d), 6.58 (1H, s), 6.75 (1H, d), 7.28 (1H, t) and 8.35 (2H, s). |
With copper diacetate; triethylamine; In dichloromethane; | Intermediate 9: 4-[3-(2-Chloropyrimidin-5-yloxy)phenyl]morpholineA mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (15g, 0.115mol), 3-morpholinylphenyl boronic acid (24g, 0.115mol), copper (II) acetate (21g, 0.115mol), triethylamine(79.5mL, 0.402mol) and powdered 4A molecular sieves in dichloromethane (600mL) 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 column chromatography on silica (ethyl acetate:hexane 1: 1) to afford 4-[3-(2-chloropyrimidin- 5-yloxy)phenyl]morpholine (8.0g, 24percent) as colourless oil.Mass: (ES+) 292 (M+H)+ NMR: deltaEta ( 6-DMSO) 3.15 (4H, m), 3.84 (4H, m), 6.50 (1H, d), 6.58 (1H, s), 6.75 (1H, d), 7.28 (1H, t) and 8.35 (2H, s). |
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). |
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