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CAS No. : | 4430-75-5 | MDL No. : | MFCD01098257 |
Formula : | C8H16N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ONHPOXROAPYCGT-UHFFFAOYSA-N |
M.W : | 140.23 | Pubchem ID : | 2876391 |
Synonyms : |
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Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3267 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
60% | With hydrogen In methanol at 20℃; for 4 h; | 7. Synthesis of octahydro-1H-pyrido[1,2-a]pyrazine Into a 500 mL round-bottom flask was added benzyl hexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (8.5 g, 29.45 mmol). To this was added MeOH (200 mL). To the mixture was added Pd/C (15 g) followed by hydrogen. The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at r.t ° C. The reaction progress was monitored by TLC (CH2Cl2/MeOH=10:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 2.5 g (60percent) of octahydro-1H-pyrido[1,2-a]pyrazine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.7% | e) (R,S)-1,4-diazabicyclo[4.4.0]decane; 50.7% yield; bp 55 C., 100 millitorr. | |
A sample of this lactam (168 g, 1.1 mole) dissolved in 2 L of dioxane was added to a refluxing solution of LiAlH4 (40.0 g, 1.05 mole) in 1 L of dioxane over 2 hours. After refluxing the reaction overnight, it was cooled to room temperature and quenched with a mixture of 20% NaOH in dioxane. The resulting mixture was filtered through supercell and stripped of all solvent under reduced pressure. The residue was distilled to give 169 g of the desired octahydro-2H-pyrido[1,2]pyrazine. | ||
A sample of this lactam (168 g, 1.1 mole) dissolved in 2 L of dioxane was added to a refluxing solution of LiAlH4 (40.0 g, 1.05 mole) in 1 L of dioxane over 2 hours. After refluxing the reaction overnight, it was cooled to room temperature and quenched with a mixture of 20% NaOH in dioxane. The resulting mixture was filtered through supercell and stripped of all solvent under reduced pressure. The residue was distilled to give 169 g of the desired octahydro-2H-pyrido[1,2-a]pyrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tri-tert-butyl phosphine; sodium t-butanolate;palladium diacetate; In xylene; at 110℃; for 2h; | 8. Synthesis of 2-(1-(triisopropylsityl)-1H-indol-6-yl)-<strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 6-bromo-1-(triisopropylsilyl)-1H-indole (2 g, 5.40 mmol). To this was added <strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> (2.1 g, 14.25 mmol). Addition of t-BuONa (2 g, 20.83 mmol) was next. This was followed by the addition of (t-Bu)3P (200 mg, 0.99 mmol). This was followed by the addition of Pd(OAc)2 (50 mg, 0.22 mmol). To the mixture was added xylene (30 mL). The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at 110 C. in a bath of oil. The reaction progress was monitored by TLC (CH2Cl2MeOH=10:1). The resulting mixture was washed 1 time with 30 mL of H2O. The resulting solution was extracted three times with 100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed 1 time with 10 mL of NaCl(sat.). The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 2.15 g (80%) of 2-(1-(triisopropylsilyl)-1H-indol-6-yl)-<strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> as red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Step A 2-(Octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)acetonitrile 8 g of <strong>[4430-75-5]octahydro-2H-pyrido[1,2-a]pyrazine</strong> and 12 ml of acrylonitrile are refluxed for 48 hours in 150 ml of acetonitrile. The solvent is then removed in vacuo to yield 11 g of a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | Step A Ethyl 3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)propionate A solution of 7 g of <strong>[4430-75-5]octahydro-2H-pyrido[1,2-a]pyrazine</strong> and 15 ml of ethyl acrylate in 100 ml of acetonitrile is refluxed for 24 hours and then concentrated to dryness in vacuo to yield the expected product. | |
In acetonitrile; | Step A Ethyl 3-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)propanoate A solution of 3.5 g of <strong>[4430-75-5]octahydro-2H-pyrido[1,2-a]pyrazine</strong> and 8 ml of ethyl acrylate in 50 ml of acetonitrile is refluxed for 24 hours. The solvent is removed in vacuo to yield the expected product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; | EXAMPLE 1 2-(6-Chloro-2-pyrazinyl)-octahydro-2H-pyrido [1,2-a]pyrazine A solution of <strong>[4430-75-5]octahydro-2H-pyrido[1,2-a]pyrazine</strong> (4 gm, 0.029 moles), 2,6-dichloropyrazine (4.28 gm, 0.029 moles) and triethylamine (8 ml. 0.06 moles) in 75 ml of acetonitrile is heated under reflux for 4 hours. After cooling, the precipitate is filtered off and washed with a little acetonitrile. The filtrate is concentrated under reduced pressure and the resulting residue is partitioned between water and ether. The aqueous layer is made basic with potassium carbonate and extracted 3 times with 100 ml. portions of ether. The combined ether layer is washed with saline and dried over sodium sulfate. After filtering off the drying agent the clear filtrate is made acidic with dry hydrogen chloride gas. The precipitate is filtered off, washed with ether and dried. After two crystallizations from ethanol there is obtained a 4.5 gm (54 percent) yield of title compound, m.p. 298-301 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In methanol; at 120℃; for 0.0833333h;Microwave irradiation; | (a) 2-[l-(Diphenylmethyl)azetidin-3-yl]octahydro-2H-pyrido[l,2-a]pyrazine A mixture of octahydro-2/i'-pyrido[l,2-alpha]pyrazine (1.00 g, 7.1 mmol) and 1- (diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett; 13; 2003; 2191-2194, 1.5 s g, 6.5 mmol), methanol (13.5 mL) and acetic acid (1.5 mL) was devided into five test tubes (5 mL). To each tube was added (polystyrylmethyl) trimethylammonium cyanoborohydride (4.2 mmol/g, 0.3 g, 1.6 mmol) and each mixture was then heated for 5 min at 12O0C using microwave single node heating. The resins were filtered off and then the solutions were combined. The solvent was removed by evaporation. The product was EPO <DP n="56"/>purified by means of silica gel chromatography using a mixture of methanol and methylene chloride (2% - 4%). There was obtained 1.2 g (51%) of 2-[l-(diphenylmethyl)azetidin-3- yl]octahydro-2No.-pyrido[l,2-alpha]pyrazine. 1H NMR (500 MHz, CDCl3): 1.2-1.3 (m, 2H), 1.4-1.5 (d, IH), 1.6-1.8 (m, 4H), 2.0-2.2 (m, 3H), 2.3 (t, IH), 2.5 (d, IH), 2.6-3.0 (m, 6H), 3.4 (t, 2H), 4.4 (s, IH), 7.2 (t, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 362 (M+ 1) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | EXAMPLE 84 5-(3,4-Dimethoxybenzylamino)-2-(2-furyl)-8-(1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-ylmethyl)[1,2,4]triazolo[1,5-c]pyrimidine (Compound 84) The subject compound (92%) was obtained as a pale brown oily matter from 5-(3,4-dimethoxybenzylamino)-8-formyl-2-(2-furyl)[1,2,4]triazolo[1,5-c]pyrimidine and 1,3,4,6,7,8,9,9a-<strong>[4430-75-5]octahydropyrido[1,2-a]pyrazine</strong> in a manner similar to that in Example 1. 1H NMR (CDCl3, delta, ppm): 1.24-1.26 (m, 2H), 1.48-1.51 (m, 2H), 1.70-1.73 (m, 2H), 2.06-2.09 (m, 4H), 2.35-2.39 (m, 1H), 2.78-2.96 (m, 4H), 3.83 (s, 2H), 3.89 (s, 3H), 3.89 (s, 3H), 4.76 (d, J=5.6 Hz, 2H), 6.40 (t, J=5.6 Hz, 1H), 6.56 (dd, J=1.8, 3.6 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.95 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 7.21 (d, J=3.5 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.92 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.8 - 22.87% | With caesium carbonate;copper(l) iodide; 2-acetylcyclohexanone; In N,N-dimethyl-formamide; at 90℃; for 20h;Product distribution / selectivity; | Methyl 4-iodobenzoate (2.84 g, 10.86 mmol), cesium carbonate (7.07 g, 21.71 mmol), 2-acetylcyclohexanone (0.286 mL, 2.17 mmol) and copper(I) iodide (0.103 g, 0.54 mmol) were added to a stirred solution of 2,3,4,6,7,8,9,9a-<strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> (1.5224 g, 10.86 mmol) in DMF (30 mL) under nitrogen. The resulting suspension was stirred at 90 C. for 20 h. The reaction mixture was evaporated to dryness and dissolved in methanol. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford a brown gum. This was purified again by silica column chromatography, eluting with 5% MeOH (containing 0.1% ammonium hydroxide) in DCM. Pure fractions were evaporated to dryness to afford the desired compound (0.503 g, 16.8%) as an orange solid 1H NMR (399.9 MHz, CDCl3) delta 1.29-1.33 (1H, m), 1.26-1.40 (1H, m), 1.62 (1H, d), 1.64 (1H, d), 1.65-1.68 (1H, m), 1.69 (1H, s), 1.80-1.82 (1H, m), 2.04-2.10 (2H, m), 2.32-2.39 (1H, m), 2.61 (1H, d), 2.89 (2H, d), 3.01-3.08 (1H, m), 3.58-3.63 (1H, m), 3.70-3.75 (1H, m), 3.86 (3H, s), 6.83-6.87 (2H, m), 7.89-7.93 (2H, m). MS m/z=275 (MH+).; Methyl -4-iodobenzoate (2.84 g, 10.86 mmol), cesium carbonate (7.07 g, 21.71 mmol), 2-acetylcyclohexanone (0.286 mL, 2.17 mmol) and copper(I) iodide (0.103 g, 0.54 mmol) were added to a stirred solution of 2,3,4,6,7,8,9,9a-<strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> (1.5224 g, 10.86 mmol) in DMF (30 mL) under nitrogen. The resulting suspension was stirred at 90 C. for 20 h. The reaction mixture was evaporated to dryness. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and fractions were evaporated to dryness to afford the crude product as an impure brown gum. The crude product was purified by silica column chromatography, eluting with 5% MeOH, 0.1% aqueous ammonia in DCM. Pure fractions were evaporated to dryness to afford the desired compound (0.681 g, 22.87%) as an orange solid. 1H NMR (399.9 MHz, CDCl3) delta 1.29-1.33 (1H, m), 1.26-1.40 (1H, m), 1.62 (1H, d), 1.64 (1H, d), 1.65-1.68 (1H, m), 1.69 (1H, s), 1.80-1.82 (1H, m), 2.04-2.10 (2H, m), 2.32-2.39 (1H, m), 2.61 (1H, d), 2.89 (2H, d), 3.01-3.08 (1H, m), 3.58-3.63 (1H, m), 3.70-3.75 (1H, m), 3.86 (3H, s), 6.83-6.87 (2H, m), 7.89-7.93 (2H, m). MS: m/z 275 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In dimethyl sulfoxide; at 25 - 100℃; for 18h; | 2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido[1,2-a]pyrazine (477 mg, 3.40 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25 C. The resulting solution was stirred at 100 C. for 18 h. 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 to afford impure material. The concentrated eluant was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. The sample was then put through a basic HPLC system to obtain the free base. Fractions containing the desired compound were evaporated to dryness to afford the title compound (395 mg, 47%) as a cream solid. 1H NMR (500.133 MHz, DMSO) delta 1.19-1.35 (3H, m), 1.51-1.60 (1H, m), 1.64 (1H, t), 1.73-1.79 (1H, m), 1.93-2.08 (2H, m), 2.17-2.25 (1H, m), 2.73 (1H, dd), 2.81-2.93 (6H, m), 3.13 (1H, td), 3.73 (6H, s), 4.28-4.33 (1H, m), 4.37-4.42 (1H, m), 6.32 (1H, t), 6.38-6.41 (3H, m), 8.26 (1H, d), 8.70 (1H, d), 9.59 (1H, br s), 11.82 (1H, br s). MS: m/z 492 (MH+). Mean of n=1, FGFR Kinase assay-Caliper Echo Dosing, IC50 0.13 muM. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h; | HATU (36 mg, 0.094 mmol) was added to a stirring solution of acid (40 mg, 0.073 mmol) and <strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> (20 mg, 0.15 mmol) in DMF (0.5 mL) and TEA (0.06 mL, 0.4 mmol) and the reaction was stirred at rt for 1 h. The reaction mixture was diluted with MeOH (1 mL), filtered and purified by preparative HPLC (Xterra Prep MS C18 5u 30×100 mm, Eluent A: 5% acetonitrile/water with 10 mM ammonium acetate, Eluent B: 95% acetonitrile/water with 10 mM ammonium acetate, Flow Rate: 42 mL/min, linear gradient from 15% Eluent B to 100% Eluent B over 15 min) to yield 8-cyclohexyl-N-(dimethylsulfamoyl)-11-methoxy-1a-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide (38.5 mg, 0.057 mmol, 79% yield) as an off-white solid. The compound was isolated as a mixture of four stereoisomers. Partial (aromatic protons) 1HNMR (300 MHz, CDCl3) delta 6.86-7.10 (m, 2H), 7.26 (d, J=8.8 Hz, 0.6H), 7.27 (d, J=8.8 Hz, 0.4H), 7.43-7.64 (m, 1H), 7.83 (d, J=8.8 Hz, 0.4H), 7.84 (d, J=8.4 Hz, 0.6H), 7.96 (br s, 0.4H), 7.99 (br s, 0.6H). LC-MS retention time: 2.97 min; m/z 672 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h; | HATU (38 mg, 0.10 mmol) was added to a stirring solution of acid (40 mg, 0.077 mmol) and <strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> (21 mg, 0.15 mmol) in DMF (0.5 mL) and TEA (0.06 mL, 0.4 mmol), and the reaction was stirred at rt for 3 h. The reaction mixture was diluted with MeOH (1 mL), filtered and purified by preparative HPLC (Xterra Prep MS C18 5u 30×100 mm, Eluent A: 5% acetonitrile/water with 10 mM ammonium acetate, Eluent B: 95% acetonitrile/water with 10 mM ammonium acetate, Flow Rate: 42 mL/min, linear gradient from 15% Eluent B to 100% Eluent B over 15 min) to yield 8-cyclohexyl-11-methoxy-N-(methylsulfonyl)-1a-(octahydro-2H-pyrido[1,2-a]pyrazin-2-ylcarbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide (36.2 mg, 0.056 mmol, 73% yield) as a white solid. The compound was isolated as a mixture of four stereoisomers. Presents as a 1:3 mixture of rotamers or atrope isomers and 1:1 mixture of diastereomers. Partial 1HNMR (300 MHz, CDCl3) delta 3.36 (s, 3H), 3.84 (s, 0.75H), 3.84 (s, 2.25H), 6.81-7.09 (m, 2H), 7.15-7.29 (m, 1H), 7.46-7.78 (m, 1.2H), 7.83 (d, J=8.4 Hz, 0.38H), 7.84 (d, J=8.4 Hz, 0.38H), 7.97 (br s, 0.75H), 8.01 (br s, 0.25H). LC-MS retention time: 2.22 min; m/z 643 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrogen;palladium on activated charcoal; In methanol; at 20℃; for 4h; | 7. Synthesis of octahydro-1H-pyrido[1,2-a]pyrazine Into a 500 mL round-bottom flask was added benzyl hexahydro-1H-pyrido[1,2-a]pyrazine-2(6H)-carboxylate (8.5 g, 29.45 mmol). To this was added MeOH (200 mL). To the mixture was added Pd/C (15 g) followed by hydrogen. The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at r.t C. The reaction progress was monitored by TLC (CH2Cl2/MeOH=10:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 2.5 g (60%) of octahydro-1H-pyrido[1,2-a]pyrazine as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Step 12a:; A solution of acid 49 (50 mg, 0.125 mmol) in CH2C12 (2 mL) was treated with oxalyl chloride (100 muL, 1.16 mmol). After 20 min, the reaction mixture was concentrated in vacuo, diluted with CH2CI2 (1 mL) and treated with Et3N (130 muL, 1.20 mmol) followed by (+/-)-1,4-diazabicyclo[4.4.0]decane (140 mg, 1.0 mmol). After 18 h, the reaction mixture was diluted with saturated aqueous NH4CI and extracted with CH2CI2 (2x). The combined organic layers were washed with saturated aqueous NaHC03, dried over MgS04 and concentrated in vacuo. Preparative TLC (0.5:4.5:95 NH40H/MeOH/CH2CI2), afforded Example 40 (42.0 mg, 65%) as a yellow oil. Example 40: LCMS (ES): time 3.45 min, m/z 520.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 3-(chlorosulfonyl)benzoyl chloride (0.36 g 1.5 mmol) in anhydrous dichloromethane (50 mL) was added octahydro-lH-pyrido[l,2-alpha]pyrazine (0.21 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.32 g, 3 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 3 -(trifluoromethyl)aniline (2.9 g, 18 mmol) was added. The mixture was stirred at room temperature for 5 days, then sodium carbonate(0.32 g, 3 mmol) and methanol (5 mL) were added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (methanol/ethyl acetate = 1 : 10) to give the titled compound: 1U NMR (400 MHz, DMSO-J6) delta ppm 1.00-1.27 (m, 3H), 1.42-2.10 (m, 7H), 2.70-3.40 (m, 4H), 4.25-4.40 (m, IH), 7.40 (m, 3H), 7.50 (m, IH), 7.70 (m, 3H), 7.85 (m, IH), 10.80 (br s, IH); MS (ESI) m/z 468 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To 3-([4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid (4.35 g, 12.6 mmol) and 2-(3H-[l,2,3]triazolo[4,5-delta]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (5.27g, 13.9 mmol) in JV,iV-dimethylacetamide (30 mL) and 2- methyltetrahydrofuran (90 mL) was added l,4-diazabicyclo[4.4.0]decane (2.47 g, 17.6 mmol). The reaction was stirred at ambient temperature for 2.5 hours, and then it was diluted with 2-methyltetrahydrofuran (57 mL). The organic solution was washed with 6% NaHCOs/6% NaCl (35 niL), and the aqueous layer was extracted with 2- methyltetrahydrofuran (50 mL). The organic layer was washed with 6% NaHCOs/6% NaCl (50 mL) and 1 : 1 saturated NaCl/water (6chi50 mL), and then it was concentrated. The residue was concentrated from ethanol (2x50 mL) to give the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With triethylamine; In dichloromethane; at 0 - 20℃; for 1.16667h; | To a solution of <strong>[4430-75-5]octahydropyrido[1,2-a]pyrazine</strong> (50 mg, 0.38 mmol) and NEt3 (83 muL, 0.59 mmol) in DCM (15 mL) at 0 C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-8% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 132 (36 mg, 62%) as a white solid. LCMS: RT 2.90 min [M+H]+ 498.3. 1H NMR (DMSO, 400 MHz): delta 8.78 (1H, d, J=2.41 Hz), 8.01 (1H, s), 7.94 (1H, s), 7.63 (1H, dd, J=8.63, 2.42 Hz), 7.28 (1H, d, J=8.62 Hz), 5.73-5.72 (1H, m), 4.63-4.59 (4H, m), 3.53 (1H, d, J=11.02 Hz), 3.43 (1H, d, J=9.07 Hz), 2.70-2.68 (2H, m), 2.33-2.32 (1H, m), 2.19-2.11 (1H, m), 1.93-1.92 (3H, m), 1.62 (1H, d, J=12.59 Hz), 1.57-1.52 (2H, m), 1.49 (6H, t, J=6.30 Hz), 1.38-1.16 (2H, m), 1.01-0.87 (1H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium carbonate; In ethanol;Reflux; | General procedure: 5.1.2. General procedure 1 (GP1). The amine (1.0equiv) in ethanol (1mL per mmol amine) was added to the alkyl halide (1.1equiv) and sodium carbonate (3equiv) in ethanol (2mL per mmol amine). The reaction was heated to reflux for 2-3h then water (5mL per mmol amine) and aqueous sodium carbonate (1M, 5mL per mmol amine) were added. The product was extracted with ethyl acetate (3 times, 20mL per mmol amine) and the organic layers combined. Dowex 50WX2 hydrogen form 100-200 mesh (4g per mmol amine) was washed with methanol (10mL per gram resin). The reaction mixture was loaded onto the ion exchange resin using gravity filtration and the resin was washed with methanol (10mL per gram resin). The product was eluted off the resin with ca. 1M NH3 in methanol (10mL per gram resin) and the solution was concentrate to give the product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45 mg | DIPEA (71 mg, 00.1 mL, 0.55 mmol) was added to a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (75 mg, 0.22 mmol) in DMF (1.5 mL) followed by addition of EDCl (63 mg, 0.33 mmol) and HOBt (32 mg, 0.24 mmol). After 10 minutes of stirring the reaction mixture, <strong>[4430-75-5]octahydro-1H-pyrido[1,2-a]pyrazine</strong> (46 mg, 0.33 mmol) was added and the resulting mixture was stirred for 16 h at 20-35 C. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine solution. The ethyl acetate portion was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude compound, which was refluxed in hexane, filtered, and the filtrate was concentrated under reduced pressure to afford 45 mg of the title compound as a yellow solid. MS (ESI): m/z 466.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In N,N-dimethyl-formamide; at 20℃; for 2h; | General procedure: A mixture ofdifferent fluoro substituted 2-nitrobenzoate (1.5 mmol) and various amines (7.5 mmol) in DMF (3 mL) was stirred atroom temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine. After dried by sodium sulfate and concentration, the residue was purified by chromatography on silica gel to give as yellowish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 75℃;Sealed tube; Inert atmosphere; | [00357] Step 1 : To a solution of 4-fluoronitrobenzene (0.55ml, 5.13 mmol) in AcN (6 mL), Octahydro-lH-pyrido[l,2-a]pyrazine (600 mg, 4.28 mmol) and DIEA (1.1 mL, 6.42 mmol) were added. The mixture was stirred at 75 C for overnight (in a sealed tube). The resulting mixture was cooled to room temperature and then concentrated. The crude product was purified by column chromatography (0-5% MeOH in DCM) to afford the desired product as yellow oil (1.03g, 92% yield). ESI-MS: calcd for (C14H19N302) 261, found 262 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere; | 1-fluoro-2-nitrobenzene (1.2 g, 8.56 mmol),Octahydro-1H-pyrido[1,2-a]pyrazine (1.0 g, 7.13 mmol), N,N-diisopropylethylamine (1.9 mL, 10.7 mmol) was added to N,N-dimethyl In formamide (20 mL),The reaction was heated to 90 C under nitrogen for 4 hours.After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was diluted with water (80 mL)The organic phases were combined and washed successively with water (50 mL) and brine (50 mL).Dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure.The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (V: V) = 5: 1) to give further title compound (yellow oil, 1.74g, 93.4%). |
93.4% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere; | 1-fluoro-2-nitrobenzene (1.2 g, 8.56 mmol), Octahydro-1H-pyrido [1, 2-a] pyrazine (1.0 g, 7.13mmol), N,N-Diisopropylethylamine (1.9 mL, 10.7 mmol) were added to N,N-dimethylformamide (20 mL), and the reaction was heated to 90 C for 4 hours under nitrogen. After the reaction was cooled to room temperature, the reaction solution was diluted with water (80 mL), extracted with dichloromethane (30 mL X 3), the organic phases were combined and washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the obtained crude product was passed through a silica gel chromatography column (petroleum ether: ethyl acetate (V:V) = 5:1) and further purified to give the title compound (yellow oil, 1.74 g, 93.4%). |
Tags: 4430-75-5 synthesis path| 4430-75-5 SDS| 4430-75-5 COA| 4430-75-5 purity| 4430-75-5 application| 4430-75-5 NMR| 4430-75-5 COA| 4430-75-5 structure
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