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CAS No. : | 287714-35-6 | MDL No. : | MFCD08690330 |
Formula : | C6H5ClN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VJOKXLBQCKCWLV-UHFFFAOYSA-N |
M.W : | 172.57 | Pubchem ID : | 12627752 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 38.32 |
TPSA : | 52.08 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) : | -6.65 cm/s |
Log Po/w (iLOGP) : | 1.76 |
Log Po/w (XLOGP3) : | 0.99 |
Log Po/w (WLOGP) : | 0.92 |
Log Po/w (MLOGP) : | 0.15 |
Log Po/w (SILICOS-IT) : | 1.38 |
Consensus Log Po/w : | 1.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.81 |
Solubility : | 2.7 mg/ml ; 0.0157 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.67 |
Solubility : | 3.67 mg/ml ; 0.0213 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.34 |
Solubility : | 0.789 mg/ml ; 0.00457 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.47 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
44.4% | Stage #1: With hydrogenchloride; zinc(II) chloride In dichloromethane at 5 - 20℃; for 0.5 h; Stage #2: at 5 - 10℃; for 2 h; |
Step 3a. 2-Chloro-pyrimidine-5-carboxylic acid methyl ester (compound 1001-7) The above intermediate (7 g, 0.046 mol) was added to a mixture of concentrated hydrochloric acid (15.2 mL) and CH2Cl2(60 mL). After cooling, ZnCl2 (18.6 g, 0.138 mol) was added at 15-20° C. The mixture was stirred at 15-20° C. for 0.5 h and cooled to 5-10° C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internal temperature 5-10° C. The reaction was continued for 2 h. The reaction mixture was poured into ice-water (50 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×2). The combined organic extracts were concentrated to afford crude product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60° C. for 30 minutes and filtered. The filtrate was concentrated to afford the titled compound 1001-7 (3.5 g, 44.4percent) as an off-white solid. LCMS: m/z 214.1 [M+42]+. 1HNMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 9.15 (s, 2H |
44.4% | Stage #1: With hydrogenchloride; zinc(II) chloride In dichloromethane; water at 15 - 20℃; for 0.5 h; Cooling Stage #2: With sodium nitrite In dichloromethane; water at 5 - 10℃; for 2 h; |
Step g: Methyl 2-chloropyrimidine-5-carboxylate (Compound R-2-2) Compound 207 (7 g, 0.046 mol) was added to a mixture of concentrated hydrochloric acid (15.2 mL) and CH2Cl2 (60 mL). After cooling, ZnCl2 (18.6 g, 0.138 mol) was added at 15-20° C. The mixture was stirred at 15-20° C. for 0.5 h and cooled to 5-10° C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internal temperature 5-10° C. The reaction was continued for ˜2 h. The reaction mixture was poured into ice-water (50 mL). The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL*2). The combined organic extracts were concentrated to afford crude product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60° C. for 30 minutes and filtered. The filtrate was concentrated to afford the title compound R-2-2 (3.5 g, 44.4percent) as an off-white solid. LCMS (m/z): 214.1[M+42]+. 1HNMR (400 MHz, CDCl3): δ 4.00 (s, 3H), 9.15 (s, 2H). |
44.4% | Stage #1: With hydrogenchloride; zinc(II) chloride In dichloromethane; water at 15 - 20℃; for 0.5 h; Stage #2: With sodium nitrite In dichloromethane at 5 - 10℃; for 2 h; |
Compound 207 (7 g, 0.046 mol) was added to a mixture of concentratedhydrochloric acid (15.2 mL) and CH2C12(60 mL). After cooling, ZnC12 (18.6 g, 0.138mol) was added at 15-20 °C. The mixture was stirred at 15-20 °C for 0.5 h and cooled to 5-10 °C. NaNO2 (9.5 g, 0.138 mol) was added portion wise while keeping the internaltemperature 5-10 °C. The reaction was continued for 2 h. The reaction mixture was poured into ice-water (50 mL). The organic layer was separated and the aqueous phase was extracted with CH2C12 (30 nL*2) The combined organic extracts were concentrated to afford cmde product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60 °C for 30 minutes and filtered. The filtrate was concentrated to afford the title compound R-2-2 (3.5 g, 44.4 percent) as an off-white solid. LCMS (m/z): 214.1[M+42f. ‘H1’MR (400 MHz, CDC13): ö 4.00 (s, 3H), 9.15 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
720 mg | at 20℃; for 0.5 h; | 2-Chloropyrimidine-5-carboxylic acid (1.00 g)Trimethylsilyl diazomethane (2 M hexane solution, 9.46 mL) was added to a methanol (15 mL) and benzene (37 mL) solution, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (720 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3.5h; | A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.033 mol) in DCM(80ml) was added at room temperature to a solution of 4-piperidinemethanol (0.066mol) and jV-ethyldiisopropylamine (0.083 mol) in DCM (100ml) under N2 flow. Themixture was stirred at room temperature for 3 hours and 30 minutes, poured out into icewater and extracted with DCM. The organic layer was separated, dried (MgSCu),filtered and the solvent was evaporated. The residue was taken up in pentane. Theprecipitate was filtered off and dried, yielding 7.88g (95%) of intermediate 49. |
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3.5h; | A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.033 mol) in DCM (80ml) was added at room temperature to a solution of 4-piperidinemethanol (0.066 mol) and N-ethyl-N-(l-methylethyl)- 2-propanamine (0.083 mol) in DCM (100ml) under N2 flow. The mixture was stirred at room temperature for 3 hours and 30 minutes, poured into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was taken up in pentane. The precipitate was filtered off and dried, yielding 7.88g (95%) of intermediate 18. |
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 3.5h; | a) Preparation of intermediate 12 A solution of 4-piperidinemethanol (0.033 mol) in CH2Cl2 (80ml) was added at room temperature to a solution of <strong>[287714-35-6]2-chloro-5-pyrimidinecarboxylic acid methyl ester</strong> (0.066 mol) and DIPEA (0.083 mol) in CH2Cl2 (100ml) under N2 flow. The mixture was stirred at room temperature for 3 hours and 30 minutes, poured onto ice water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was taken up in pentane. The precipitate was filtered off and dried, yielding 7.88g (95%) of intermediate 12. |
83% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h; | To a stirred solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (I, 2.5 g, 14.53 mmol) in DMF (25 mL) was added piperidin-4-ylmethanol (2 g, 17.44 mmol) and potassium carbonate (4.01 g, 29.07 mmol) and stirred for 5 hours at room temperature. Progress of reaction followed TLC, after completion of reaction, the reaction mixture was concentrated and quenched with water (100 niL) extracted with ethyl acetate (2 x 150 niL). The organic portion was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to afford the crude product which was purified by column chromatography using methanol-dichloromethane gradient to afford the titled product as off-white solid (II, 3.6 g, 83%). LC-MS m/z calcd for C12H17N3O3, 251.1, found 252.1[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 1.5h; | A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.058 mol) in DMA(80ml) was added dropwise to a solution of 4-piperidinemethanamine (0.116 mol) andjV-ethyldiisopropylamine (0.145 mol) in DMA (150ml) under NI flow. The mixture wasstirred at room temperature for 1 hour and 30 minutes, poured out into ice water andextracted with EtOAc, then with DCM. The organic layer was washed with water, dried(MgSOa), filtered and the solvent was evaporated. The residue was crystallized fromDIPE. The precipitate was filtered off and dried, yielding lOg (65%) of intermediate45. |
65% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 1.5h; | A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.058 mol) in DMA (80ml) was added dropwise to a solution of 4-piperidinemethanamine (0.116 mol) and TV-ethyWV-(l-methylethyl)- 2-propanamine (0.145 mol) in DMA (150ml) under N2 flow. The mixture was stirred at room temperature for 1 hour and 30 minutes, poured into ice water and extracted with EtOAc, then with DCM. The organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 1Og (65%) of intermediate 31. |
65% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 1.5h; | Example A6; a).Preparatipn.of intermediate 32; A solution of 2-chloro-5-pyrimidinecarboxylic acid, methyl ester (0.058 mol) in /V5TV- dimethyl- acetamide (80ml) was added dropwise to a solution of 4- piperidinemethanamine (0.116 mol) and TV-ethyl -TV-(I -methyl ethyl)- 2-propanamine (0.145 mol) in TV^N-dimethyl- acetamide (150ml) under N2 flow. The mixture was stirred at room temperature for 1 hour and 30 minutes, poured out into ice water and extracted with EtOAc, then with DCM. The organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 1Og (65%) of intermediate 32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile;Heating / reflux; | The indicated chloropyrimidine (0.11 g, 0.63 mmol) and Et3N (0.88 mL, 6.3 mmol) were added to a solution of the amine (prepared according to the procedure of Example 6, 0.8 g, 2.52 mmol) in CH3CN (5 mL). The reaction mixture was heated at reflux overnight. The solvent was evaporated in vac and the residue was chromatographed on silica gel using ethyl acetate:hexanes (2:8) to give the titled compound. Aqueous NaOH (1N, 90.0 muL) was added to the aminopyrimidine (prepared according to the procedure of Example 26 Step 2, 20.0 mg, 0.24 mmol) in MeOH (1.0 mL) and THF (0.5 mL). The mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and neutralized with acetic acid. The solvent was evaporated in vac and the residue chromatographed on silica gel using ethyl acetate:hexanes (40:60) 2.5% acetic acid to give the titled compound. 1H NMR (CDCl3) delta8.85 (m, 2H), 7.58 (d, 1H, J=8.5 Hz), 7.05 (d, 1H, J=9.0), 4.19 (t, 2H, J=5.5), 3.99 (t, 2H, J=7.0), 3.32 (s, 3H), 2.97 (t, 2H, J=7.5), 2.24 (m, 2H), 1.77 (m, 2H), 1.02 (t, 3H, J=7.5). MS: m/z=439 (M+H). | |
With triethylamine; In acetonitrile;Heating / reflux; | The indicated chloropyrimidine (0.11 g, 0.63 mmol) and Et3N (0.88 mL, 6.3mmol) were added to a solution of the amine (prepared according to the procedure of Example 6, 0.8 g, 2.52 mmol) in CH3CN (5 mL). The reaction mixture was heated at reflux overnight. The solvent was evaporated in vac and the residue was chromatographed on silica gel using ethyl acetate : hexanes ( 2 :8) to give the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared as described in example 2, step 1 , replacing the ethyl (6-chloro-pyridin-3-yl)-acetate by <strong>[287714-35-6]methyl 2-chloro-pyrimidine-5-carboxylate</strong> that was prepared from 2-chloro-pyrimidine-5-carboxylic acid as described in example 3, step 1. MS: m/z 445.4 (ESI+). Alternatively, the title compound was prepared from 2-chloropyrimidine-5- carboxylic acid, 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-{4-[2- (trifluoromethyl)phenoxy]piperidin-l-yl}pyridine (1.4 equiv.), NaHCO3 (1.5 equiv.), (Ph3P)4Pd (0.1 equiv) in DMF/H2O (1/1) (0.1M) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.3% | With triethylamine; In isopropyl alcohol; at 100℃; for 0.166667h;Microwave irradiation;Product distribution / selectivity; | Methyl 2-chloropyrimidine-5-carboxylate (0.863 g, 5.0 mmol), N,N-diethylethanamine (0.697 ml, 5.00 mmol) and 1-methylpiperazine (0.565 ml, 5.09 mmol) were suspended in 2-propanol (10.00 ml) and sealed into a microwave tube. The reaction was heated to 100 C. for 10 mins in the microwave reactor and cooled to room temperature. The precipitate was collected by filtration, washed with EtOH (5 mL) and dried under vacuum to afford methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.405 g, 34.3%) as a white solid, which was used without further purification. MS: m/z 237 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 6h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (300 mg, 1.74 mmol) in DCM (4.70 mL) was added to a stirred solution of 2-(methoxymethyl)piperazine (226 mg, 1.74 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35 mmol) in DCM (4.00 mL) at 25 C. under nitrogen. The resulting solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and diluted with MeOH. The resulting mixture was filtered. The filtrate was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (346 mg, 75%) as a yellow solid. This was used directly with no further purification. 1H NMR (399.9 MHz, CDCl3) delta 2.72-2.79 (2H, m), 2.84-2.90 (1H, m), 2.99-3.07 (2H, m), 3.25-3.30 (1H, m), 3.31 (3H, s), 3.38-3.42 (1H, m), 3.80 (3H, s), 4.61-4.68 (2H, m), 8.76 (2H, s). MS: m/z 267 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 3h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (535 mg, 3.10 mmol) in dichloromethane (7.50 ml) was added to a stirred solution of (2S,6R)-2,6-dimethylpiperazine (354 mg, 3.10 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (1.35 ml, 7.75 mmol) in dichloromethane (7.24 ml) at room temperature under nitrogen. The resulting solution was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford the desired compound (740 mg, 95%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) delta 1.02-1.04 (6H, m), 2.33 (1H, s), 2.43-2.46 (2H, m), 2.64-2.69 (2H, m), 3.81 (3H, s), 4.62-4.66 (2H, m), 8.77 (2H, s). MS: m/z 251 (MH+). |
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 12h; | General procedure: To a mixture of 5a (5.0g, 32.44 mmol, 1 equiv) and (2S,6R)-2,6-dimethylpiperazine (3.7g, 32.44 mmol, 1 equiv) in 60 mL DMSO was added K2CO3 (8.97g, 64.88 mmol, 2 equiv). The mixture was heated at 110 C for 12 h. The reaction mixture was diluted with 120 mL ice water. Ethyl acetate was added and the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silica gel chromatography to give ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate as a white solid (7.25g, 90%). 1H NMR (300 MHz, CDCl3) delta 7.85 (d, J=9.0Hz, 2H), 6.79 (d, J=9.0Hz, 2H), 4.26 (q, J=7.1Hz, 2H), 3.60 (d, J=12.0Hz, 2H), 2.96-2.88 (m, 2H), 2.32 (t, J=11.3Hz, 2H), 1.30 (t, J=7.1Hz, 3H), 1.08 (d, J=6.3Hz, 6H). The obtained methyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate was dissolved in dichloromethane (DCM) and stirred for 15 min after adding 1 N NaOH (aq) (32.12 mL, 32.12 mmol, 1.1 equiv). Then a solution of di-tert-butyl dicarbonate ester in DCM was added dropwise. The reaction mixture was stirred at room temperature until the starting material was consumed completely. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silica gel chromatography to give 6a as colorless oil. (10.00 g, 98%). 1H NMR (300 MHz, CDCl3) delta 7.77 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 4.20-4.08 (m, 4H), 3.44 (d, J = 12.5 Hz, 2H), 2.87 (dd, J = 12.4, 3.8 Hz, 2H), 1.35 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 6.8 Hz, 6H). To a solution of 6a (10.00 g, 28.70 mmol, 1 equiv) dissolved in MeOH was added 1 N NaOH (aq) (57.40 mL, 57.40 mmol, 2 equiv). The mixture was heated at 60 C for 4 h and allowed to cool down to room temperature. The reaction mixture was acidified with 2 N HCl (aq) to adjust PH to 5-6. The resulting precipitate was collected by filtration, washed with water and dried to a constant weight to afford 4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)benzoic acid (9.79 g, 98%). 1H NMR (300 MHz, DMSO) delta 7.76 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 4.18-4.05 (m, 2H), 3.75 (d, J = 12.8 Hz, 2H), 2.98 (dd, J = 12.9, 4.3 Hz, 2H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 6H). The obtained acid (9.79 g, 29.28 mmol, 1 equiv) was dissolved in dry DCM and allowed to cool down to 0 C. DMF (22.57 mL, 292.8 mmol, 10 equiv) and thionyl chloride (4.25 mL, 58.56 mmol, 2 equiv) dissolved in dry DCM were added dropwise to the mixture above. Then the reaction mixture was allowed to warm up to room temperature slowly and left to stir for 2 h. The solvent was removed under reduced pressure at room temperature. Then the residue was redissolved in dry DCM, and was added to the DCM solution of NH4OH (11.28 mL, 292.8 mmol, 10 equiv), which was cooled down to 0 C already. The ice-bath was removed and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silicagel chromatography to give 7a as a white solid (4.88 g, 50%). 1H NMR (300 MHz, CDCl3) delta 7.67 (d, J = 8.5 Hz,2H), 6.81 (d, J = 8.7 Hz, 2H), 5.87 (s, 2H), 4.29-4.10 (m, 2H), 3.50 (d, J = 12.3 Hz, 2H), 2.97 (dd, J = 12.3, 3.8 Hz, 2H), 1.43 (s, 9H), 1.25 (d, J = 6.8 Hz, 6H). 14 (8.0 g, 26.69 mmol, 1 equiv), methylamine hydrochloride (2.7 g, 40.04 mmol, 1.5 equiv), EDCl (7.68 g, 40.04 mmol, 1.5 equiv), HOBt (3.61 g, 26.69 mmol, 1.0 equiv) and DIPEA (11.02 mL, 66.72 mmol, 2.5 equiv) were dissolved in dry DCM and the reaction mixture was left to stir at room temperature overnight. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silica gel chromatography to give 15 as white solid (8.0 g, 95.8%). 1H NMR (300 MHz, CDCl3) delta 8.40 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.51-7.42 (m, 2H), 7.24 (dd, J = 9.3, 2.3 Hz, 1H), 6.78 (d, J = 7.6 Hz, 2H), 6.05 (d, J = 4.0 Hz, 1H), 3.05 (d, J = 4.9 Hz, 3H). 7a (100 mg, 0.30 mmol, 1 equiv) and 15 (112.56 mg, 0.36 mmol, 1.2 equiv) were dissolved in 10 mL dry dioxane. Then Pd2(dba)3 (27.47 mg, 0.03 mmol, 0.1 equiv), Xantphos (34.72 mg, 0.06 mmol, 0.2 equiv) and Cs2CO3 (195.49 mg, 0.60 mmol, 2 equiv) were added to the mixture above. The reaction mixture was left to stir at 110 C for 5 h under nitrogen atmosphere. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 18h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-ethyl-1,4-diazepane (149 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25 C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-ethyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (268 mg, 87%) as a cream oil which crystallised on standing. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 0.98 (3H, t), 1.81-1.87 (2H, m), 2.45-2.50 (2H, m), 2.55 (2H, m), 2.70-2.72 (2H, m), 3.81 (3H, s), 3.82 (2H, q), 3.86-3.89 (2H, m), 8.79 (2H, s). MS: m/z 265 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | A solution of <strong>[287714-35-6]methyl-2-chloropyrimidine-5-carboxylate</strong> (900 mg, 5.22 mmol) in dichloromethane (7.50 ml) was added to a stirred suspension of 1-cyclopropylpiperazine, 2HCl (1038 mg, 5.22 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (4.10 mL, 23.47 mmol) in dichloromethane (13 mL) at room temperature under nitrogen. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was poured onto ice (100 mL), extracted with dichloromethane (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford white solid. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford the desired compound (880 mg, 64%) as a white solid. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 0.36-0.39 (2H, m), 0.45-0.47 (2H, m), 1.65-1.68 (1H, m), 2.61 (4H, t), 3.81 (3H, s), 3.81-3.84 (4H, t), 8.79 (2H, s). MS: m/z 263 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 18h; | A solution of (2S)-2-propan-2-ylpiperazine (223 mg, 1.74 mmol) in dichloromethane (4.40 mL) was added to a stirred solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (300 mg, 1.74 mmol) in dichloromethane (4.30 mL) at 25 C. N-Ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35 mmol) was added. The resulting solution was stirred at room temperature for 18 h under a nitrogen atmosphere. The reaction mixture was concentrated and diluted with methanol. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford the desired compound (456.1 mg, 99%) as a yellow oil. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 0.94-0.96 (6H, m), 1.58-1.66 (1H, m), 2.25-2.30 (1H, m), 2.56-2.63 (1H, m), 2.68-2.74 (1H, m), 2.95-3.02 (2H, m), 3.81 (3H, s), 4.56-4.60 (1H, m), 4.64-4.68 (1H, m), 8.78 (2H, s). MS: m/z 265 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With water; sodium hydrogencarbonate;palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; at 25 - 80℃; for 4h; | Saturated aqueous sodium hydrogen carbonate solution (25.00 ml) was added to <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.863 g, 5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (1.855 g, 6.00 mmol), palladium(II) acetate (0.056 g, 0.25 mmol) and triphenylphosphine (0.262 g, 1.00 mmol) in 1,2-dimethoxyethane (25.00 ml) at 25 C. under nitrogen. The resulting mixture was stirred at 80 C. for 4 h. The cooled reaction mixture was taken up in water (50 mL), washed with EtOAc (50 mL) and then the aqueous layer was acidified to pH1 with 2N HCl. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organics washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (1.280 g, 84%) as a yellow solid. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 1.44 (9H, s), 2.65 (2H, q), 3.56 (2H, t), 4.15 (2H, m), 7.36 (1H, s), 9.18 (2H, s), 13.6 (1H, s). MS: m/z 304 (M-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 18h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (209 mg, 1.21 mmol) in dichloromethane (4.00 ml) was added to a stirred solution of 1-propan-2-yl-1,4-diazepane (172 mg, 1.21 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.523 ml, 3.02 mmol) in dichloromethane (4.00 ml) at 25 C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (267 mg, 79%) as a cream oil which crystallised on standing. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 0.92-0.94 (6H, m), 1.74-1.80 (2H, m), 2.71 (2H, t), 2.82-2.89 (1H, m), 3.81 (3H, s), 3.80-3.85 (4H, m), 8.78-8.78 (2H, m), 1× (2H, m) obscured by DMSO peak. MS: m/z 279 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In dichloromethane; at 20 - 25℃; for 4h; | A solution of 1-methylpiperazin-2-one (198 mg, 1.74 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (300 mg, 1.74 mmol) in dichloromethane (4.70 mL) at 25° C. The resulting solution was stirred at room temperature for 4 h under nitrogen. The reaction mixture was concentrated and dissolved in ethyl acetate (25 ml) and NaOH (50 ml, 1M aqueous solution). The organic layer was washed with ethyl acetate (25 ml). The organic layers were combined and washed with brine (50 ml), dried using MgSO4, filtered and evaporated to dryness to afford methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 57percent) as a cream solid. 1H NMR (399.9 MHz, DMSO-d6) delta 2.91 (3H, s), 3.44 (2H, t), 3.83 (3H, s), 4.09 (2H, t), 4.35 (2H, s), 8.86 (2H, s). MS: m/z 501 (2MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 5h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (500 mg, 2.90 mmol) in dichloromethane (7.50 ml) was added to a stirred solution of 1,2-dimethylpiperazine (331 mg, 2.90 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (1.26 ml, 7.24 mmol) in dichloromethane (7.25 ml) at room temperature under nitrogen. The resulting solution was stirred at ambient temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford the desired compound (713 mg, 98%) as a yellow solid. 1H NMR (399.9 MHz, DMSO-d6) delta 1.04-1.06 (3H, m), 1.98-2.05 (1H, m), 2.06-2.13 (1H, m), 2.21 (3H, s), 2.78-2.84 (2H, m), 3.14-3.21 (1H, m), 3.81 (3H, s), 4.46-4.55 (2H, m), 8.78 (2H, s). MS: m/z 251 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 18h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-cyclopropyl-1,4-diazepane (247 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25 C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (312 mg, 97%) as a cream solid. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 0.28-0.31 (2H, m), 0.40-0.45 (2H, m), 1.80-1.84 (2H, m), 1.85-1.89 (1H, m), 2.71 (2H,m), 2.85-2.88 (2H, m), 3.81 (3H, s), 3.82-3.88 (4H, m), 8.79 (2H, s). MS: m/z 277 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20 - 25℃; for 18h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-prop-2-enyl-1,4-diazepane (163 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.501 mL, 2.90 mmol) in dichloromethane (4.00 mL) at 25 C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeCN (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford the desired compound (304 mg, 95%) as a cream oil which crystallised on standing. This was used directly with no further purification. 1H NMR (399.9 MHz, DMSO-d6) delta 1.81-1.87 (2H, m), 2.55 (2H, m), 2.70-2.72 (2H, m), 3.06-3.09 (2H, m), 3.81 (3H, s), 3.80-3.89 (4H, m), 5.09-5.13 (1H, m), 5.13-5.19 (1H, m), 5.76-5.86 (1H, m), 8.79 (2H, d). MS: m/z 277 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 18h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (900 mg, 5.22 mmol) in dichloromethane (7.50 ml) was added to a stirred suspension of 2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, HCl (1106 mg, 6.26 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (3.19 mL, 18.25 mmol) in dichloromethane (13.00 mL) at room temperature under nitrogen. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was poured onto ice (50 mL), extracted with DCM (3×50 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow solid. The crude product was purified by crystallisation from IPA to afford the title compound (591 mg, 41%) as a white solid. The filtrate still contained some product and was purified by silica column chromatography, eluting with a gradient of 0 to 10% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford a further sample of the title compound (402 mg, 28%) as a white solid. 1H NMR (399.9 MHz, DMSO-d6) delta 1.14-1.30 (2H, m), 1.46-1.55 (1H, m), 1.61 (2H, d), 1.72 (1H, d), 1.81 (1H, t), 1.95 (1H, m), 2.06 (1H, m), 2.67-2.70 (1H, m), 2.80 (2H, d), 3.05-3.12 (1H, m), 3.81 (3H, s), 4.59 (1H, m), 4.68 (1H, d), 8.79 (2H, s). MS: m/z 277 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20 - 25℃; for 4h; | A solution of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (300 mg, 1.74 mmol) in dichloromethane (4.30 ml) was added to a stirred solution of 1-ethyl-2-methylpiperazine (223 mg, 1.74 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.75 ml, 4.35 mmol) in dichloromethane (4.40 ml) at 25 C. under nitrogen. The resulting solution was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and diluted with MeOH (10 mL). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and was evaporated to dryness to afford impure product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 3% 7M NH3/MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford the desired compound (382 mg, 83%) as a colourless oil. 1H NMR (399.9 MHz, DMSO-d6) delta 0.98 (3H, t), 1.02 (3H, d), 2.20-2.27 (1H, m), 2.33-2.38 (1H, m), 2.40-2.45 (1H, m), 2.71-2.79 (1H, m), 2.81-2.85 (1H, m), 3.06-3.11 (1H, m), 3.35-3.42 (1H, m), 3.81 (3H, s), 4.28-4.35 (2H, m), 8.78 (2H, s). MS : m/z 265 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 100℃; for 14h; | Example 4E257 258 259Part A:2-chloro-5-carboxymethyl pyrimidine 257 (0.5 g) was dissolved in Morpholine and heated at 1000C for 14 hours. Removal of excess morpholine and passing through the column provided the product, 2-morpholino-5-carboxymethylpyrimidine 258. Mass calculated for compound 258 is 223.22, observed LCMS m/z 224.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a dry flask was added <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (17 mg) and THF (5 mL). The mixture was cooled to -780C and a solution of DIBAL-H in hexane (1 M, 1.2 mL) was added slowly. The resulting mixture was stirred at -780C to it overnight, then quenched with saturated aqueous Na2SO4. The solution was filtered. Solvents were removed under reduced pressure to give (2-chloropyrimidin-5-yl)methanol. MS calcd. for [M+H]+ CsH6ClN2O: 145.1; found: 145.1. | ||
A solution of <strong>[287714-35-6]2-chloropyrimidine-5-carboxylic acid methyl ester</strong> (l .Og, 5.8mmol) in THF (30mL), under argon, was cooled to -78°C. To the solution was added a solution of DIBAL-H in DCM (1.0M, 20.3mL, 20.3mmol), slowly over 40min. The reaction was allowed to warm to r. t. before continuing to stir for a further 16 h. A solution of sat. sodium potassium tartrate (lOOmL) was slowly added, followed by EtOAc, and the mixture was stirred vigorously for 2 h. The organic phase was separated then a further portion of EtOAc was added to the aquoues phase before stirring vigorously for lh. The organic phase was removed and the aqueous phase was washed with a mixture of EtOAc and THF (1 :1). All organic fractions were combined and washed with sat. sodium potassium tartrate solution, water, then brine, and dried (MgS04). The solvent was removed in vacuo to afford the title compound: RT = 1.62 min; mlz (ES+) = 145.0 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.333333h;microwave irradiation; | To a microwave reaction vessel was added <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (138 mg), 2-(methylsulfonyl)-6-(3- (piperidin-4-yl)propoxy)-l,2,3,4-tetrahydroisoquinoline (175 mg), DMF (3 mL) and Cs2CO3 (350 mg). The mixture was irradiated in microwave reactor at 160 0C for 20 min. It was cooled and EtOAc (20 mL) was added. The mixture was washed with brine (10 mL), dried over Na2SO4 and filtered. Removal of solvents under reduced pressure and purification of the crude on silica gel (EtOAc: Hexanes = 1: 1) gave desired product. MS calcd. for [M+H]+ C26H35N2O5S: 487.2; found: 487.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; at 60℃; | Water (2 mL) was added to a stirred suspension of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.306 g, 1.77 mmol), (2-tert-butyl-1-ethynyl)diisopropoxyborane (0.45 mL, 1.91 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.111 g, 0.14 mmol) and potassium carbonate (0.770 g, 5.57 mmol) in tetrahydrofuran (8 mL) and the resulting mixture was heated at 60 C. over night. Water and ethyl acetate was added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using 0-10% methanol in dichloromethane as the eluent, gave 0.082 g (21% yield) of the title compound.1H NMR (400 MHz, DMSO-d6) delta ppm 9.16 (s, 2H) 3.91 (s, 3H) 1.33 (s, 9H). |
21% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In tetrahydrofuran; water; at 60℃; | Water (2 mL) was added to a stirred suspension of methyl 2-chloropyrimidine-5- carboxylate (0.306 g, 1.77 mmol), (2-tert-butyl-l-ethynyl)diisopropoxyborane (0.45 mL, 1.91 mmol), [l,r-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.111 g, 0.14 mmol) and potassium carbonate (0.770 g, 5.57 mmol) in tetrahydrofuran (8 mL) and the resulting mixture was heated at 600C over night. Water and ethyl acetate was added. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using 0-10% methanol in dichloromethane as the eluent, gave 0.082 g (21% yield) of the title compound. 1H NMR (400 MHz, DMSO-J6) delta ppm 9.16 (s, 2 H) 3.91 (s, 3 H) 1.33 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate; In acetonitrile; at 20℃; for 3h;Inert atmosphere; | Under N2 at room temperature, <strong>[287714-35-6]2-chloro-pyrimidine-5-carboxylic acid methyl ester</strong> (4.75g, 0.028 mol) was added portionwise to a solution of 3-aza-bicyclo[3.1 ,0]hex-6- ylamine (3g, 0.0306 mol) and potassium carbonate (6.327g, 0.046 mol) in acetonitrile (80 mL). The solution was stirred at room temperature for 3 hours. The solution was poured out into cooled water, the product was extracted with DCM, the organic layer was dried over MgSO4, filtered and evaporated to dryness. The residue (3g) was purified by column chromatography over silica gel (15-40mum) (eluent: DCM/MeOH/ NH4OH 97/3/0.5). The pure fractions were collected and the solvent was evaporated till dryness. The residue (1.6Og) was taken up with diethyl ether. The precipitate was filtered and dried, yieldingl.55g (22%) of intermediate 4, melting point : 149C. 1H NMR (400MHz, d6-DMSO) 1.55 (s, 2H); 1.9 (br s, 2H); 1.95 (s, IH); 3.5-3.6 (m, 2H); 3.7 (d, J=I 1.6Hz, 2H); 3.8 (s, 3H); 8.75 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine; In propan-1-ol; at 20℃; for 48h; | A solution of (R)-(trans-1-hydroxy-4-adamantyl) 3-aminopyrrolidine-1- carboxylate (159 mg, 0.57 mmol), <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (1 15 mg, 0.67 mmol), i-Pr2NEt (0.2 mL, 1.13 mmol) and n-PrOH (4 mL) was stirred at rt for 2 days. The mixture was concentrated and the residue was chromatographed on a 12- g silica cartridge eluted with a 0-100% EtOAc in hexanes gradient to afford the title compound (124 mg, 52%) as a white solid. LC-MS Method 1 tR = 1.37 min, m/z = 417; 1H NMR (CDCI3) 1.42 (m, 2H), 1.65-2.40 (13H), 3.39 (m, 1 H), 3.58 (m, 2H), 3.83 (m, 1 H), 3.88 (s, 3H), 4.64 (m, 1 H), 4.83 (s, 1 H), 5.90 (1 H), 8.83 (br s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 116 2-{3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-pyrimidine-5-carboxylic acid methyl ester The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and <strong>[287714-35-6]methyl-2-chloropyrimidine-5-carboxylate</strong> [CAS Reg. No. 287714-35-6]. MS (m/e)=502.1 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.678 g | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 25h; | To a solution of 20 (0.5 g, 3.33 mmol) in anhydrous DMF (15 mL) were added K2CO3 (1.382 g, 10.0 mmol) and <strong>[287714-35-6]2-chloro-pyrimidine-5-carboxylic acid methyl ester</strong> (0.575 g, 3.33 mmol) at room temperature. After stirring at room temperature for 25 h, the reaction mixture was cooled to 0 °C diluted with water (20 mL) and acidified to pH 2 using diluted hydrochloric acid. The white precipitate was collected, washed with water and dried to give 0.678 g of 23; mp 117-118 °C. |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 25h; | To a solution of 3H-benzo[c][1,2]oxaborole-1,6-diol (0.5 g, 3.33 mmol) in anhydrous DMF (15 mL) were added K2CO3 (1.382 g, 10.0 mmol) and <strong>[287714-35-6]2-chloro-pyrimidine-5-carboxylic acid methyl ester</strong> (0.575 g, 3.33 mmol) at room temperature. After stirring at room temperature for 25 h, the reaction mixture was cooled to 0° C. diluted with water (20 mL) and acidified to pH 2 using diluted hydrochloric acid. The white precipitate was collected, washed with water and dried to give 0.678 g of pure product. Mp 117-118° C. 1HNMR (400 MHz, DMSO-d6) delta 9.26 (s, 1H), 9.08 (s, 2H), 7.44-7.57 (m, 2H), 7.31-7.40 (m, 1H), 5.03 (s, 2H), 3.88 (s, 3H). MS (ESI) m/z=287 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 120℃;Inert atmosphere; Microwave; | Step A Methyl 2-[4-(propyloxy)-2-(trifluoromethyl)phenyl]-5-pyrimidinecarboxylate A 20 mL microwave vial was charged with 0.500 g (2.90 mmol) of methyl-2-chloropyrimidine-5-carboxylic acid, 0.934 g (3.77 mmol) of [4-(propyloxy)-2-(trifluoromethyl)phenyl]boronic acid and 1.23 g (5.79 mmol) of K3PO4 followed by 9 mL of 8:1 dioxane/water. The mixture was deoxygenated by bubbling nitrogen through for 5 minutes, treated with 0.10 g (0.087 mmol) of Pd(Ph3P)4 and the vessel sealed. The mixture was subjected to microwave heating at 120 C. for 20 minutes. This same procedure was repeated twice. The crude mixtures from all three reactions were combined and partitioned between EtOAc and water. The phases were separated and the aqueous phase extracted with EtOAc (3*). The combined EtOAc solutions were washed with water (1*), saturated brine (1*), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude residue was purified by flash chromatography (silica gel, gradient elution from hexane to EtOAc) to afford 1.70 g (58%) of methyl 2-[4-(propyloxy)-2-(trifluoromethyl)phenyl]-5-pyrimidinecarboxylate as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 9.27 (s, 2H) 7.79 (d, J=8.6 Hz, 1H) 7.22-7.40 (m, 2H) 4.06 (t, J=6.5 Hz, 2H) 3.89 (s, 3H) 1.73 (sxt, J=7.0 Hz, 2H) 0.96 (t, J=7.4 Hz, 3H). LCMS m/z 341 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.5h;Microwave irradiation; | Intermediate 10BA mixture of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.75g, 4.35mmol), 3-methoxyazetidine hydrochloride (0.8 l g, 6.5mmol) and DIPEA (2.27mL, 13.0mmol) in acetonitrile (5mL) was microwaved at 140 C for 30 min. The reaction was then diluted with EtOAc (40mL) and Na2C03 (sat. aq., 15mL). The phases were separated and the aqueous phase extracted with EtOAc (2 x 15mL). The combined organic phases were washed with brine (15mL), dried (MgS04), filtered and concentrated. Purified by Biotage Si column, 20-100% EtOAc / petrol to give methyl 2-(3-methoxyazetidin-l-yl)pyrimidine-5-carboxylate (908 mg, 94 %). NMR (400 MHz, CD3OD) delta ppm 8.78 (s, 2 H) 4.28 - 4.52 (m, 3 H) 3.96 - 4.13 (m, 2 H) 3.89 (s, 3 H) 3.37 (s, 3 H). MS (ES+) 224 |
94% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 140℃; for 0.5h;Microwave irradiation; | Intermediate 10B; A mixture of <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.75 g, 4.35 mmol), 3-methoxyazetidine hydrochloride (0.81 g, 6.5 mmol) and DIPEA (2.27 mL, 13.0 mmol) in acetonitrile (5 mL) was microwaved at 140 C. for 30 min. The reaction was then diluted with EtOAc (40 mL) and Na2CO3 (sat. aq., 15 mL). The phases were separated and the aqueous phase extracted with EtOAc (2×15 mL). The combined organic phases were washed with brine (15 mL), dried (MgSO4), filtered and concentrated. Purified by Biotage Si column, 20-100% EtOAc/petrol to give methyl 2-(3-methoxyazetidin-1-yl)pyrimidine-5-carboxylate (908 mg, 94%).1H NMR (400 MHz, CD3OD) delta ppm 8.78 (s, 2H) 4.28-4.52 (m, 3H) 3.96-4.13 (m, 2H) 3.89 (s, 3H) 3.37 (s, 3H).MS (ES+) 224 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,2-dichloro-ethane; at 20℃; for 16h; | Preparation 79: 2-[(3i?,45)-3-feri-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl]-pyrimidine-5-carbox lic acid methyl esterTo a solution of <strong>[287714-35-6]2-chloro-pyrimidine-5-carboxylic acid methyl ester</strong> (2.1 g, 12mmol) and [(3R,45')-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 193, 4.0g, 13mmol) in DCE (l OOmL) was added triethylamine (3.3mL, 23mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (200mL), washed with water (200mL) and brine (400mL), dried (MgS04), filtered and concentrated in vacuo. The remainder was triturated with MeOH and the solid collected by filtration to afford the title compound: RT = 3.95 min; mlz (ES ) = 435.18 [M+ H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-2-{4-[4-(1-Acetylamino-ethyl)-phenyl]-piperidin-1-yl}-pyrimidine-5-carboxylic acid To 1.52 g (8.5 mmol) <strong>[287714-35-6]2-chloropyrimidine-5-carboxylic acid methyl ester</strong> in 80 mL NMP are added 2.1 g (8.5 mmol (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 2.9 mL (17.1 mmol) DIPEA and the mixture is stirred for 4 h at 100 C. The solvent is removed in vacuo. The residue is treated with 100 mL MeOH and 10 mL 4N sodium hydroxide solution is added. The mixture is stirred for 1 h at 60 C. After cooling to rt 4N HCl solution is added until the pH is acidic. The precipitate is collected and dried to yield the desired product. C20H24N4O3 (M=368.4 g/mol); ESI-MS: 369 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 3h; | Example 1.4 (+/-)-3-(2-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrimidine-5-carboxamido)propanoic acid A solution of 3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (307 mg, 1 mmol), prepared as in example 1.1 using racemic 2-methylpropane-2-sulfinamide, <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (186 mg, 1 mmol) and diisopropylethylamine (516 mg, 4 mmol) in 2-propanol (3 mL) was heated to 100 C. for 3 hours. The mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography to give methyl 2-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrimidine-5-carboxylate (500 mg, 87.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium acetate; In methanol; at 150℃; for 1h;microwave irradiation; | A microwave reaction vessel was charged with 3-(methoxy-phenyl)-propylamine (1.44g,8.7mmol), <strong>[287714-35-6]2-chloro-pyrimidine-5-carboxylic acid methyl ester</strong> (Maybridge, lg, 5.8mmol), potassium acetate (1.62g, 16.5mmol) and methanol (10ml). The mixture was heated to 150C for lh in a microwave oven, then cooled to rt and quenched with cold water (4ml). The precipitate was collected by filtration and washed with water and cold methanol to afford the desired product (1.73g, 99% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 50℃; for 12h;Inert atmosphere; | 4H-[l,2,4]triazolo[4,3-a][l,5]benzodiazepine, 5,6-dihydro-l-methyl-8-(5-(methoxy carbonyl)pyrimidin-2-yl)-6-(4-chloro-phenyl) (Step 2). A mixture of 4H-[l,2,4]triazolo[4,3- a][l,5]benzodiazepine,5,6-dihydro-lmethyl-8- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6- (4-chloro-phenyl) (75 mg, 0.17 mmol), <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (36 mg, 0.21 mmol), Tetrakis(triphenylphosphine)palladium(0)(20 mg) and potassium carbonate (50 mg, 0.36 mmol) in N,N-Dimethylformamide (8 mL) degassed by nitrogen three times, and then the mixture was heated at 50C for 12 hours. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with brine (10 mL x 2). The separated organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and the residue was purified by preparative-TLC (silica gel, dichloromethane/methanol = 10:1) to yield 4H-[l,2,4]triazolo[4,3-a][l,5]benzodiazepine,5,6-dihydro-l-methyl-8-(5- (methoxycarbonyl)pyrimidin-2-yl)-6-(4-chloro-phenyl) as a white solid (30 mg, 39%). LRMS (M+H)+: calcd 446.13; found 446. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 10h;Inert atmosphere; | To a solution of <strong>[287714-35-6]methyl-2-chloropyrimidine-5-carboxylate</strong> (2.084 g, 12.08 mmol) and tributyl(vinyl)tin (3.635 g, 11.46 mmol) in toluene (15 ml) was added triphenylphosphine (94.9 mg, 0.362 mmol) followed by tetrakis(triphenylphosphine) palladium(O) (418.5 mg, 0.362 mmol). The mixture was stirred at 11O0C for 10 h under anhydrous argon. After evaporation of solvent, the residue was purified by flash chromatography (hexanes-ethyl acetate = 4:1, then 1:1) to give the title compound (0.842 g) as a white solid. Mass spectrum (ESI) 166.2 (M+l). 1H NMR (500 MHz, CDCI3) delta 9.26 (s, 2H), 6.95-7.01 (m, IH), 6.82 (dd, IH, J=1.4, 17.2 Hz), 5.92 (dd, IH, J=I.4, 10.5 Hz), 4.01 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diazomethyl-trimethyl-silane; In hexane; benzene; at 20℃; for 0.5h; | To a solution 2-chloropyrimidine-5-carboxylic acid (1.63g, 10.28 mmol) in a mixture of methanol (20 ml) and benzene (50 ml) was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 10 ml) at room temperature. The mixture was stirred for 30 min, and then was concentrated to give the title compound (1.77 g) as a yellow solid. Mass spectrum (ESI) 173.2 (M+l). 1H NMR (500 MHz, CDCI3) delta 9.18 (s, 2H), 4.02 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 0℃; for 3h; | To an oven dried microwave vial equipped with a stir bar was added methyl 2- chloropyrimidine-5-carboxylate (516 mg, 2.99 mmol) and THF (30 mL). The reaction was cooled to 0 C. Methylmagnesium bromide (3 M in THF, 2.2 mL, 6.58 mmol) was added dropwise and the reaction was stirred for 3 hours. Saturated NaHC03 was added and the products extracted into ethyl acetate. The combined organics were concentrated in vacuo to give 2-(2-chloropyrimidin-5-yl)propan-2-ol.LRMS (ESI) calc'd for C7H10C1N2O [M+H]+: 173, Found: 173. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; triphenylphosphine;palladium diacetate; In 1,4-dioxane; at 100℃; for 5h; | To a 75 mL pressure vial was added sodium carbonate ( 1.23 g, 1 1.59 mmol), triphenylphosphine (300 mg, 1.159 mmol), palladium (II) acetate (52 mg, 0.232 mmol), <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (1.0 g, 5.79 mmol), (3-chlorophenyl)boronic acid (1.36 g, 8.69 mmol), and 1 ,4-dioxane (30 mL). The reaction vial was sealed and heated to 100 C for 5 hours. Saturated NH4C1 was added and the products extracted into EtOAc. The combined organics were concentrated in vacuo and the residue purified by flash chromatography (MPLC, 0-20% EtOAc-hexanes) to give methyl 2-(3-chlorophenyl)pyrimidine-5-carboxylate.LRMS (ESI) calc'd for C12H10N2O2 [M+H]+: 249, Found: 249. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
185 mg | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 6h;Cooling with ice; | [0831] Preparation Example 231: Preparation of methyl 2-(1,1-dioxo-1lambda6-isothiazolidin-2-yl)pyrimidine-5-carboxylate[0832][0833] Methyl 2-chloropyrimidine-5-carboxylate (173 mg) and isothiazolidine 1,1-dioxide (145 mg) were dissolved inN,N-dimethylformamide (1 mL), and sodium hydride (48mg, 60% in oil) was added under ice-cooling. After stirring atroom temperature for 6 hr, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated,diisopropyl ether and ethyl acetate were added, and the precipitated solid was collected by filtration to give thetitle compound (185 mg).MS(ESI)m/z:258(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3b. 2-[2-Chloro-5-(2-chloro-4-methanesulfonyl-benzoylamino)-phenyl]-pyrimidine-5-carboxylic acid methyl ester (compound 1002-7) A mixture of 1001-7 (200 mg, 1.1 mmol), 1-9 (756 mg, 1.6 mmol) and Pd(PPh3)4(60 mg, 0.05 mmol) in saturated NaHCO3 (2 mL) and DMSO (6 mL) was stirred at 100 C. for 3 h. After cooling to room temperature, NaOH (43 mg, 1.1 mmol) was added to reaction solution and stirred for 0.5 h. The reaction mixture was extracted with ethyl acetate. The aqueous layer was adjusted pH to 6 with 1.2 M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated to afford crude acid (300 mg) without further purification. The mixture of the crude acid (300 mg) in MeOH (15 mL) and H2SO4 (0.25 mL) was stirred at 85 C. for 1 h. After removal of solvent, the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4. The crude product was purified by column chromatography (hexanes/ethyl acetate: 1/1) to afford compound 1002-7 as a white solid (160 mg, 78% yield via two steps). LCMS: m/z 480.2 [M+1]+. 1H NMR: (400 MHz, CDCl3): delta 3.36 (s, 3H), 3.96 (s, 3H), 7.65 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.02 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.14 (d, J=1.2 Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 9.40 (s, 2H), 11.02 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 16h; | Step A: To a solution of (3ai?, 5K, 6aS) -5- (2- ( trifluoromethyl ) phenyl ) octahydrocyclopenta [c] yrrole hydrochloride (9, 0.050 g, 0.17 mmol) and Et3N (0.05 mL, 0.51 raraol) in DMF (10 mL) was added <strong>[287714-35-6]methyl 2-chloropyrimidine-5-carboxylate</strong> (0.029 g, 0.17 mmol) and the resulting solution was stirred at 60 C for 16 hours. The reaction was diluted with H20 (200 mL) and extracted with EtOAc (3 x 100 mL) . The combined organic extracts were washed with 0 (3 x 100 mL) , brine (100 mL) , dried over KfcSOa, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 30% EtOAc in hexanes) to give methyl 2- ( (3aR, 5r, 6aS) - 5- (2- (trifluoromethyl ) phenyl ) hexahydro-cyclopenta [c]pyrrol-2 ( IH) - yl)pyrimidine-5-carboxylate as an off-white solid (0.035 g, 52%): MS (ESI+) m/z 392 [M + H] + . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃; for 14h;Inert atmosphere; | a. Methyl 2-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidine-5- carboxylate (82). To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 74 (0.8047 g, 3.958 mmol), methyl 6-chioronicotinate (0.6897, 4.02 mmol), andpTsOH (0.8 101 g, 3.98 mmol) was added 1,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111C for 14 h. After cooling the reaction to r.t., the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL Si02, 10% ethyl acetate:hexanes to 12% ethyl acetate:hexanes) to give 82(1.0177 g, 75%) as a white crystalline solid, m.p. 143.2-149.3 C: ?H NMR (400 MHz, CDC13) 6 8.95 (s, 2H), 8.25 (br s, 1H), 7.47 (dd, J 8.4, 2.4, 1H), 7.42 (d, J 2.0, 111), 7.32 (d, J 8.4, 1H), 3.90 (s, 3H), 1.69 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H); ?3C NMR (100.6 MHz, CDC13) 6164.7, 161.4, 145.7, 141.1, 135.3, 127.1, 118.8, 118.7, 114.7, 51.9, 35.0, 34.3, 33.9, 31.8, 31.8; JR (neat) 3254, 2954, 1720, 1597, 1526, 1433, 1289, 1258, 1123 cm?; ES-MS (M+Na)+ calcd for C20H25N3O2Na 362.1844, found 362.1844. |
Tags: 287714-35-6 synthesis path| 287714-35-6 SDS| 287714-35-6 COA| 287714-35-6 purity| 287714-35-6 application| 287714-35-6 NMR| 287714-35-6 COA| 287714-35-6 structure
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H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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