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Structure of 25850-22-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 25850-22-0 |
Formula : | C7H15NO |
M.W : | 129.20 |
SMILES Code : | CC1(C)CC(N)CCO1 |
MDL No. : | MFCD00778609 |
InChI Key : | VXCNRARJXVLHLI-UHFFFAOYSA-N |
Pubchem ID : | 3809203 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H302-H318 |
Precautionary Statements: | P280-P305+P351+P338 |
Class: | 3(8) |
UN#: | 2924 |
Packing Group: | Ⅱ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 37.48 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.25 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.81 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.31 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.9 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.14 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.94 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.84 |
Solubility | 18.8 mg/ml ; 0.146 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.61 |
Solubility | 31.5 mg/ml ; 0.244 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.14 |
Solubility | 9.27 mg/ml ; 0.0718 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 |
-6.87 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 |
1.0 |
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) |
2.14 |
* 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 |
---|---|---|
87.7% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 13h; | A mixture of 5-([(3,4-dimethoxyphenyl)amino]carbonyl}amino)-2-{phenyl[4-(trifluoromethyl)phenyl]methoxy}benzoic acid (300 mg, 0.530 mmol), 1-hydroxy-1H-benzotriazole (122 mg, 0.798 mmol), <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-yl amine</strong> (137 mg, 1.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 mg, 0.660 mmol) and DMF (3 ML) was stirred under ice-cooling for 1 hour and at room temperature for 12 hours, was poured into water, and was extracted with ethyl acetate.. The extracted solution was washed with water, was dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.. The residue was purified by silicagel column chromatography (hexane:ethyl acetate = 1:2), to obtain the titled compound as a solid.. This was recrystallized from hexane and ethyl acetate. 315 mg (87.7%) 1H-NMR (CDCl3) delta; 0.66 to 1.07 (8H, m), 1.27 to 1.86 (2H, m), 3.32 to 3.60 (2H, m), 3.84 (6H, s), 4.02 to 4.19 (1H, m), 6.32 (1H, s), 6.66 to 7.98 (18H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.8%; 22.1% | (4) (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide(2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (861 mg, 2.32 mmol) in THF (8 ml) were added DMF (0.10ml) and oxalylchloride (0.243 ml, 2.79 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (600 mg, 4.64 mmol), triethylamine (1.08 ml, 7.71 mmol) and THF (6 ml), the mixture was stirred under ice-cooling for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 2 : 1 to 1 : 1) to separate two kinds of diastereomers. Firstly eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide yield 247 mg, yield (rate) 22.1%1H-NMR (CDCl3) delta: 1.24-1.40 (8H, m), 1.80-2.30 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.23 (2H, m), 3.65-3.80 (2H, m), 4.19-4.24 (1H, m), 5.51 (1H, d, J = 8.0 Hz), 6.49 (1H, d, J = 7.5 Hz), 6.68-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1622, 1588, 1553, 1507, 1427, 1331, 1262, 1198, 735, 748. Later eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide Yield (amount) 222 mg, yield (rate) 19.8%1H-NMR (CDCl3) delta: 1.20-1.36 (8H, m), 1.76-2.29 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.16 (2H, m), 3.65-3.80 (2H, m), 4.19-4.23 (1H, m), 5.48 (1H, d, J = 7.8 Hz), 6.50 (1H, d, J = 8.1 Hz), 6.71-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1620, 1588, 1549, 1507, 1449, 1427, 1368, 1331, 1262, 1198, 750, 733. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.9%; 17.4% | (4) (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide(2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (861 mg, 2.32 mmol) in THF (8 ml) were added DMF (0.10 ml) and oxalylchloride (0.243 ml, 2.79 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (600 mg, 4.64 mmol), triethylamine (1.08 ml, 7.71 mmol) and THF (6 ml), the mixture was stirred under ice-cooling for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 2 : 1 to 1 : 1) to separate two kinds of diastereomers. Firstly eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide Yield (amount) 195 mg, yield (rate) 17.4%1H-NMR (CDCl3) delta: 1.24-1.40 (8H, m), 1.80-2.30 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.23 (2H, m), 3.65-3.80 (2H, m), 4.19-4.24 (1H, m), 5.51 (1H, d, J = 8.0 Hz), 6.49 (1H, d, J = 7.5 Hz), 6.68-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1622, 1588, 1553, 1507, 1427, 1331, 1262, 1198, 735, 748. Later eluted diastereomer: (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]prop-2-enamide Yield (amount) 145 mg, yield (rate) 12.9%1H-NMR (CDCl3) delta: 1.20-1.36 (8H, m), 1.76-2.29 (6H, m), 2.59 (3H, s), 2.76 (3H, s), 2.90-3.16 (2H, m), 3.65-3.80 (2H, m), 4.19-4.23 (1H, m), 5.48 (1H, d, J = 7.8 Hz), 6.50 (1H, d, J = 8.1 Hz), 6.71-7.26 (7H, m). IR (KBr) cm-1; 3268, 2215, 1661, 1620, 1588, 1549, 1507, 1449, 1427, 1368, 1331, 1262, 1198, 750, 733. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | (4) (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)prop-2-enamide To a solution of (2E)-3-{3-cyano-1-[(4-fluorophenyl)(phenyl)methyl]-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (1.00 g, 2.35 mmol) in THF (10 ml) were added DMF (0.10 ml) and oxalylchloride (0.246 ml, 2.82 mmol), which was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (455 mg, 3.53 mmol), triethylamine (1.09 ml, 7.81 mmol) and THF (10 ml), the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to yield the objective product as a solid material. Yield (amount) 1.04 g, yield (rate) 82.5% 1H-NMR (CDCl3) delta: 1.17-1.42 (8H, m), 1.81-1.91 (2H, m), 2.56 (3H, s), 2.75 (3H, s), 3.62-3.74 (2H, m), 4.14-4.22 (1H, m), 5.48 (1H, d, J = 7.6 Hz), 6.73-7.46 (12H, m), 7.99 (1H, s). IR (KBr) cm-1; 3285, 2215, 1661, 1622, 1591, 1547, 1510, 1333, 1231, 1195, 735. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.1% | (4) (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)prop-2-enamide To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.677 mmol) in THF (3 ml) were added DMF (0.03ml) and oxalylchloride (0.071 ml, 0.813 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-ylamine</strong> (175 mg, 1.35 mmol), triethylamine (0.313 ml, 2.25 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the objective product as a solid material. Yield (amount) 177 mg, yield (rate) 47.1% 1H-NMR (CDCl3) delta: 1.18-1.40 (8H, m), 1.80-1.90 (2H, m), 2.56 (3H, s), 2.75 (3H, s), 3.69-3.77 (2H, m), 4.16-4.21 (1H, m), 5.49 (1H, d, J = 7.6 Hz), 6.78 (1H, d, J = 15.8 Hz), 6.92-7.26 (9H, m), 7.44 (1H, d, J = 15.8 Hz), 7.94 (1H, s). IR (KBr) cm-1; 3289, 2216, 1661, 1607, 1510, 1333, 1231, 1159, 733. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3 : 6-(3- [4-(2,2-Dimethyltetrahvdro-2h-pwan-4-yl)-3-oxopiperazm- 1 -yllcarbonvU -4-fluoro benzyl)-4,5-dimethylpyridazin-3(2H)-one trifluoroacetate (JJ3).To a 0.4 M solution containing the intermediate JJ2 (leq) and 2,2-dimethyltetrahydro-2H-pyran- 4-amine (1.5 eq) in MeOH, were added NaBH3(CN) (1.5 eq) and catalytic AcOH. The reaction was heated in a MW apparatus (100 0C , 7 min). After evaporation of the solvent the crude intermediate was dissolved in DMF, then HATU (2 eq) and DIPEA (2 eq) were added and the mixture heated in MW apparatus (120 0C, 10 min). The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents and the combined fractions were evaporated under reduced pressure to afford the title compound (JJ3). 1H-NMR (300 MHz, DMSO-d6, 300K) delta: 12.65 (IH, bs), 7.36-7.14 (3H, m), 4.79-4.54 (IH, m), 4.20-4.10 (lH,m), 3.95 (2H, s), 3.86-3.50 (4H, m), 3.46-3.14 (3H, m), 1.99 (6H, s), 1.69-1.35 (4H, m) 1.22-1.10 (6H, m). MS (ES). C25H3iFN4O4 required: 470, found 471 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | In tetrahydrofuran; at 0 - 20℃; | Example 13 A 0 C. suspension of <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-amine</strong> (0.806 g, 6.24 mmol) in THF (30 mL) was treated drop-wise with 2-chloroethyl isocyanate (0.585 mL, 6.86 mmol), allowed to warm to RT as the cooling bath expired and stirred overnight. The mixture was treated with additional 2-chloroethyl isocyanate (160 muL) and stirred at RT for an additional 24 hours, then concentrated to dryness, the residue dissolved in EtOAc and washed with saturated NH4Cl (1*), NaHCO3 (1*) and brine (1*), dried over MgSO4 and concentrated to dryness to afford 1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (700 mg, 48%) as a yellow oil. MS (ESI) m/z: 235.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.29 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; | Production Example 321 (0641) 5-Benzyloxymethylisoxazole-3-carboxylic acid (0.24 g, 1.0 mmol), <strong>[25850-22-0]4-amino-2,2-dimethyltetrahydropyran</strong> (0.18 ml, 1.2 mmol) and 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) were added to chloroform (amylene addition product) (2.5 mL). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1.2 mmol) was added to the mixture at room temperature, and the mixture was stirred overnight. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted twice with chloroform. The organic layer was passed through a short column to remove impurities, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 0.29 g of N-(2,2-dimethyltetrahydropyran-4-yl)-5-benzyloxymethylisoxa zole-3-carboxamidc: (hereinafter, referred to as Compound of Present Invention (335)) represented by the following formula. 1H-NMR(CDCl3, TMS, delta(ppm)):1.26(3H, s), 1.29(3H, s), 1.33-1.40(1H, m), 1.41-1.52(1H, m), 1.89-2.00(2H, m), 3.72-3.84(2H, m), 4.27-4.38(1H, m), 4.61(2H, s), 4.65(2H, s), 6.62(1H, br s), 6.72(1H, s), 7.30-7.40(5H, m) |
0.29 g | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; | 5-Benzyloxymethyl isoxazole-3-carboxylic acid (0.24 g, 1.0 mmol), <strong>[25850-22-0]4-amino-2,2-dimethyltetrahydropyran</strong> (0.18 ml, 1.2 mmol) And 1-hydroxybenzotriazole (0.01 g, 0.1 mmol) Was added to chloroform (amylene added product) (2.5 mL). To the mixture, 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.24 g, 1.2 mmol) was added at room temperature, After stirring overnight, Dilute hydrochloric acid was added, It was extracted twice with chloroform. The organic layer was passed through a short column of silica gel to remove impurities, And concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, Represented by the following equation N- (2,2-dimethyltetrahydropyran-4-yl) -5-benzyloxymethyl isoxazole-3-carboxamide (Hereinafter referred to as the present amide compound (335)) 0.29 g was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With palladium on activated charcoal; hydrogen; ammonium formate; In methanol; water; for 5h; | To a stirred solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (2 g, 20 mmol) in MeOH (40 mL) and H2O (5 mL) was added ammonium formate (10.33 g, 160 mmol) and pallidum on carbon (0.5 g). The reaction was stirred under atmospheric hydrogen atmosphere for 5 h. The reaction mixture was filtered through bed of celite and washed with methanol. The resulting filtrate was concentrated under reduced pressure to afford 2,2-dimethyltetrahydro-2H-pyran-4-amine (2.5 g, 85%) as a colourless gummy material. (1S,4S)-4-((2-((2,2-Dimethyltetrahydro-2H-pyran-4-ylamino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a stirred solution of 4-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.5 g, 2.2 mmol) in DMF (10 mL) was added <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-amine</strong> (0.24 g, 1.8 mmol) and sodium carbonate (0.53 g, 5.0 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. Completion of the reaction was confirmed by UPLC. The product was isolated and triturated with petroleum ether to afford (1S,4S)-4-((2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)-5-nitropyrimidin-4-yl)amino)cyclohexane-1-carboxamide (0.4 g, 61%) as an yellow solid. MS (ESI) m/z 393.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In benzene; for 4h;Heating; | General procedure: To a mixture of 40 mL of a solution of 0.02 mol of amine in anhydrous benzene and 2.6 g (0.026 mol) of triethylamine was gradually added the equimolar amount of chloride B. The mixture was boiled for 4 h. On the next day 10 mL of water was added. The benzene layer was separated and washed with water. Benzene was distilled off, and the residue was distilled in a vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h; | The 4-chloro-3-nitroquinoline-6-carbonitrile (4.74 g, 17.55 mmol) was suspended in MeCN (50 mL) then <strong>[25850-22-0]2,2-dimethyltetrahydro-2H-pyran-4-amine</strong> (2.49 g, 19.3 mmol) was added, after the DIEA (4.54 g, 35.1 mmol) was added the mixture was stirred at 20C for 2h, turning brown to tan. LCMS indicated complete conversion to the desired product. The mixture was concentrated under vacuum, the residue was purified by silica gel column chromatography (PE/EtOAc = 1/1) to give the desired product (4.88 g, 85% yield) as yellow solid. The purity and structure of the product were confirmed by LCMS and 1HNMR. LCMS: RT 0.73 mm, MS 327.0) 1H NMR (400 MHz, DMSO-d6) O 9.09 (5,1H), 9.02 (5, 1H), 8.42 (d, J= 8.4 Hz, 1H), 8.15(dd, J= 8.6, 1.6 Hz, 1H), 8.01 (d, J= 8.6Hz, 1H), 3.98 (m, 1H), 3.76-3.66 (m, 1H), 3.60 (td, J = 12.2, 2.3 Hz, 1H), 2.01 (ddd, J =12.6, 4.6, 2.6 Hz, 1H), 1.93-1.82 (m, 1H), 1.67 (m, 1H), 1.56 (t, J = 12.3 Hz, 1H), 1.19(d, J = 7.7 Hz, 6H). |