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CAS No. : | 10310-21-1 | MDL No. : | MFCD00075252 |
Formula : | C5H4ClN5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RYYIULNRIVUMTQ-UHFFFAOYSA-N |
M.W : | 169.57 | Pubchem ID : | 5360349 |
Synonyms : |
6-Chloropurines;6-Chloroguanine;6-Chloro-1H-purin-2-amine;NSC 29570
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.1 |
TPSA : | 80.48 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.82 cm/s |
Log Po/w (iLOGP) : | 0.48 |
Log Po/w (XLOGP3) : | 0.72 |
Log Po/w (WLOGP) : | 0.6 |
Log Po/w (MLOGP) : | -0.18 |
Log Po/w (SILICOS-IT) : | 1.09 |
Consensus Log Po/w : | 0.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.95 |
Solubility : | 1.9 mg/ml ; 0.0112 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.99 |
Solubility : | 1.74 mg/ml ; 0.0103 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.42 |
Solubility : | 0.649 mg/ml ; 0.00383 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.78 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.1% | With sodium nitrite In HBF4; dichloromethane; water | 6-Chloro-2-fluoro-9H-purine: A 0.3M aqueous solution of NaNO2 (200 mL, 60 mmol) was added dropwise to a cooled (-15° C.), vigorously stirred suspension of 2-amino-6-chloro-9H-purine (6.0 g, 35.4 mmol) in 120 mL HBF4 (48 wpercent in H20, 0.92 mol) over 75 min. The pale yellow reaction was stirred at r. t. for 20 min and then recooled to -15° C. and neutralized to PH=6.0 with aqueous NaOH (50 wpercent in H2O). The water was removed in vacuo and the resulting orange solid chromatographed on silica gel (90:10 CH2Cl2: MeOH, Rf 0.50). The final productproduct was obtained as white solid (3.0 g, 49.1percent). |
48% | Stage #1: With fluoroboric acid; sodium nitrite In water at -15 - 20℃; for 1.75 h; Stage #2: With sodium hydroxide In water at -15℃; |
6-CHLORO-2-FLUORO-9H-PURINE] This compound was prepared by a modification of a literature procedures (Gray, N. S.; Kwon, [S. ;] Schultz, P. G. Tetrahedron Lett. 1997,38 (7), 1161-1164.) [6-CHLORO-9H-PURIN-2-YLAMINE] (75.0 g, 0.44 mol) was suspended in aq HBF4 (1.5 L of 48 percent w/w solution in H2O). This mixture was cooled to-15 [°C] and was stirred vigorously. NaNO2 (2.5 L of an 0.3 M aq solution) was then added slowly over 75 min with stirring and careful temperature control (< 10 [°C).] After complete addition, the pale yellow solution was further stirred at room temperature for 30 min. It was then re- cooled to-15 [°C] and was neutralised carefully to pH = 6.2 with [NAOH] (50 percent w/v aq solution). This solution was rotary evaporated to semi-dryness. The resulting cake was divided with a spatula and dried under high vacuum overnight. The resulting yellow powder was dry-loaded onto a flash chromatography column (24 x 15 cm [SI02] bed), which was eluted with [CH2CL2/MEOH,] 9: 1. Appropriate fractions were collected, pooled, and evaporated. After drying in vacuo, the title compound (34.8 g, 48 percent) was obtained as a colourless powder. TLC: [RF=] 0.25 [(CH2CL2/MEOH,] 9: 1), starting material Rf= 0.16. m/z 173 (MH+, 100), 175 [(MH+2,] 33) |
48% | With tetrafluoroboric acid; sodium nitrite In water at -15 - 20℃; for 1.75 h; | This compound was prepared by a modification of a literature procedures (Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett. 1997,38 (7), 1161-1164.) [CHLORO-9H-PURIN-2-YLAMINE] (75.0 g, 0.44 mol) was suspended in aq HBF4 (1.5 L of 48 percent w/w solution in H2O). This mixture was cooled to-15 C and was stirred vigorously. NaN02 (2.5 L of an 0.3 M aq solution) was then added slowly over 75 min with stirring and careful temperature control (< 10 C). After complete addition, the pale yellow solution was further stirred at room temperature for 30 min. It was then re-cooled to- 15 [C] and was neutralised carefully to pH = 6.2 with [NAOH] (50 percent w/v aq solution). This solution was rotary evaporated to semi-dryness. The resulting cake was divided with a spatula and dried under high vacuum overnight. The resulting yellow powder was dry-loaded onto a flash chromatography column (24 x 15 cm Si02 bed), which was eluted with CH2Cl2/MeOH, 9: 1. Appropriate fractions were collected, pooled, and evaporated. After drying in vacuo, the title compound (34.8 g, 48 percent) was obtained as a colourless powder. TLC: Rf = 0.25 (CH2Cl2/MeOH, 9: 1), starting material Rf = [0.] [16.] m/z 173 (MH+, 100), 175 [(MH+2,] 33). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With trichlorophosphate In ammonium hydroxide; water; N,N-dimethyl-formamide | EXAMPLE 1 46.0 g (0.3 mol) of phosphorus oxychloride was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 100 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 100 ml of 25percent aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 9.3 g (0.055 mol) of a white crystal of 2-amino-6-chloropurine (yield 55percent). |
42% | With tetraethylammonium chloride; trichlorophosphate In water; acetonitrile | EXAMPLE 1 2-Amino-6-chloropurine (Method A) A mixture of guanine (4.5g, 30 mmol), tetraethylammonium chloride (7.46 g, 45 mmol monohydrate, pre-dried), phosphorus oxychloride (16.5 ml) and acetonitrile (60 ml) was heated under reflux for 70 minutes and allowed to cool. The solid material was filtered off and suspended in water. The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide and back to pH 7 with dilute hydrochloric acid. Continuous extraction (24 hours) with ethyl acetate afforded 2-amino-6-chloropurine as a white solid (2.12 g, 42percent). |
42% | With tetraethylammonium chloride; trichlorophosphate In water; acetonitrile | Example 1 2-Amino-6-chloropurine (Method A) A mixture of guanine (4.5g, 30mmol), tetraethylammonium chloride (7.46g, 45mmol monohydrate, pre-dried), phosphorus oxychloride (16.5ml) and acetonitrile (60ml) was heated under reflux for 70 minutes and allowed to cool. The solid material was filtered off and suspended in water. The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide and back to pH 7 with dilute hydrochloric acid. Continuous extraction (24 hours) with ethyl acetate afforded 2-amino-6-chloropurine as a white solid (2.12g, 42percent). |
30% | With tetraethylammonium chloride; trichlorophosphate In water; acetonitrile | EXAMPLE 2 2-Amino-6-chloropurine (Method B) A mixture of guanine (4.5 g, 30 mmol), tetraethylammonium chloride (30 mmol), phosphorus oxychloride (16.5 ml and acetonitrile (60 ml) was placed in a flask in an ultrasonic bath at 60° C. for 2 hours. The mixture was then heated under reflux for 90 minutes and allowed to cool. The solid material was filtered off and suspended in water. The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide and back to pH 7 with dilute hydrochloric acid. Continuous extraction with ethyl acetate afforded 2-amino-6-chloropurine as a white solid (1.55 g, 30percent). |
30% | With tetraethylammonium chloride; trichlorophosphate In water; acetonitrile | Example 2 2-Amino-6-chloropurine (Method B) A mixture of guanine (4.5g, 30mmol), tetraethylammonium chloride (30mmol), phosphorus oxychloride (16.5ml and acetonitrile (60ml) was placed in a flask in an ultrasonic bath at 60oC for 2 hours. The mixture was then heated under reflux for 90 minutes and allowed to cool. The solid material was filtered off and suspended in water. The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide and back to pH 7 with dilute hydrochloric acid. Continuous extraction with ethyl acetate afforded 2-amino-6-chloropurine as a white solid (1.55g, 30percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 20 - 80℃; for 3 h; | The compound 3 (6.5 g, 33 mmol) was dissolved in 10percent (w/w)aqueous NaOH solution and allowed to stir at room temperature for3 h. Then, the reaction mixture was neutralized with conc. HCl(36percent) and the precipitatewas filtered and dried in a vacuum oven at60 °C to offer a pale yellow solid as product. Yield: 4.46 g, (80percent). |
73.3% | at 25℃; for 3 h; | The above 2-formamido-6-chloro guanine was added to 500 mL of saturated sodium bicarbonate solution dissolved, hydrolysis reaction at room temperature (25 ° C) for 3 h, after the reaction was completed, the pH was adjusted to 7.5 with 35percent hydrochloric acid solution, Filtered, washed,The filter cake was dried to give white solid, 2-amino-6-chloroguanine 49.7 g,The yield of the product was 73.3percent, and the content of the product was 99.5percent by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With trichlorophosphate In water; acetone; acetonitrile | EXAMPLE 1 (2-Amino-6-chloropurine) A mixture of guanine (22.7 g, 0.15 mol), methyltriethylammonium chloride (TEMAC) (45.5 g, 0.3 mol), phosphorus oxychloride (82.6 ml, 0.9 mol) and acetonitrile (67 ml) was heated at 60° C. with stirring for 6 hours and then cooled to 10° C. The solid material was filtered off and suspended in water (300 mls). The aqueous mixture was brought to alkaline pH with aqueous sodium hydroxide to achieve dissolution and powdered carbon (6.8 g) added. The mixture was stirred for 1 hour and then filtered to remove the carbon. Acetone (72 mls) was added and then the pH reduced to 7 with dilute hydrochloric acid. The product was filtered off, washed with acetone/water (50:50 mixture, 50 mls), water (50 mls), acetone/water (50:50 mixture, 50 mls) and acetone (50 mls) and then dried to give 2-amino-6-chloropurine as a cream coloured solid (14.77 g, 54 percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: at 10℃; Stage #2: at -5 - 0℃; for 0.5 h; |
To a solution of ZnCl2 (7.0 g,110 mmol) in conc. hydrochloric acid(9.2 mL) at 10 °C was added finely powdered compound 4 (2.3 g,13.6 mmol) with stirring. The resulting stirred mixture was cooledto 5 °C and added NaNO2 (1.27 g, 18.4 mmol) over a period of30 min keeping the temperature below 5 °C. The mixture wasstirred for additional 30 min and was diluted with 12 mL of water.The product was extracted with ethyl acetate (4 x 15 mL). Theorganic phase was washed with water (2 x 7 mL), dried overNa2SO4, and evaporated to dryness to yield 2.37 g (47percent) of finalcompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | at 180℃; | Step 1: To acetic anhydride (25 mL) at 180 °C was added 6-chloro-9H-purin-2-amine (2 g) and the mixture was heated to reflux overnight. The reaction mixture was cooled to rt. and ethoxy ethane was added. The precipitate was collected by filtration and dried. Further purified by a reverse phase flash column chromatography (0-60percent MeOH in water) gave N- (6-chloro-9H-purin-2- yl)acetamide (450 mg, 17percent yield) as a white solid. LC-MS: m/z 212 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | at 80 - 90℃; for 5 h; | Benzyl alcohol (37.5 g, 0.347 mol) and sodium hydroxide (2.96 g, 0.074 mol) were mixed and heated, and sodium hydroxide was dissolved. After cooling, 2-amino-6-chloropurine (6.00 g, 0.035 mol) was added, and the reaction was completed by heating and stirring at 80-90 C for 5 hr. Methyl tert- butyl ether (120 ml) was added to the reaction mixture, and the mixture was extracted twice with queous sodium hydroxide solution (70 ml). The obtained aqueous alkali layers were combined, washed with toluene, and after removing toluene, neutralized with 35percent hydrochloric acid to pH 6-8. The precipitated crystals were collected by filtration. The obtained crystals were dried under reduced pressure to give 2- amino-6-benzyloxypurine (7.60 g, 0.032 mol, yield 92percent) as crude crystals. |
62% | With sodium hydride In mineral oil at 60℃; for 12 h; Inert atmosphere | 6OBenzylguanine (3). Sodium hydride (1.2 g, 35.4 mmol,55percent suspension in mineral oil) was added to benzyl alcohol(50 mL) with vigorous stirring under argon. Then, 2amino6chloropurin (2.0 g, 11.8 mmol) was added to the suspensionobtained. The reaction mixture was heated to 60 C and stirredfor 12 h. After cooling, glacial acetic acid (1.4 mL, 24.3 mmol)was added to the suspension. The resulting mixture was extracted with 2 M solution of sodium hydroxide (5×5 mL). The organic phase was diluted with diethyl ether (100 mL) and again extracted with 2 M solution of sodium hydroxide (10×10 mL). Theaqueous layers were combined, washed with diethyl ether(50 mL), glacial acetic acid was added to neutralize the solution(pH 7). Then, the solution was allowed to stand for 12 h at 4 C.A precipitate formed was filtered and washed with water. Afterrecrystallization (ethanol—water (1 : 1)), the crystals were driedin vacuo. The yield was 1.76 g (62percent), yellow crystals, m.p.201—202 C. 1H NMR (DMSOd6, 300 MHz), : 12.25 (br.s,1 H, N(9)HGua); 7.82 (s, 1 H, C(8)HGua); 7.56—7.21 (m, 5 H,Ph); 6.29 (s, 2 H, NH2Gua); 5.48 (s, 2 H, CH2Ph(Bn)). 13C NMR(DMSOd6, 75 MHz), : 159.7, 159.6, 156.1, 138.5, 136.8,128.1, 126.5, 112.8, 66.7. Found (percent): C, 56.0; H, 4.8; N, 27.5.C12H11N5O•H2O. Calculated (percent): C, 55.6; H, 5.1; N, 27.0. MS(ESI), found: m/z 243.1033 [M + H]+. C12H12N5O. Calculated:M = 242.1042. |
28% | for 4 h; Reflux | General procedure: Sodium or sodium hydride (7-10 mmol) was dissolved inthe appropriate alcohol (5-10 mL). Following the dissolutionand the hydrogen production, 2-amino-6-chloropurine (3) (1-3 mmol) was added and the mixture was refluxed for 4 hthen stirred at room temperature overnight. The reaction was acidified to pH 6 with glacial acetic acid and extracted withdiethylether (3 X 10 mL). The combined organic layers weredried over anhydrous MgSO4, and the solvent was removedunder vacuum. When necessary, the crude product was purifiedwith flash or circular chromatography with a mixture ofdichloromethane/methanol as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: With potassium carbonate In dimethyl sulfoxide at 48℃; for 0.5 h; Stage #2: at 22 - 48℃; for 12.5 h; |
Weigh respectively 2-amino-6-chloropurine 10mmol, anhydrous potassium carbonate 12mmol, the amount of 25mL DMSO was added to a 50mL round bottom flask, the oil bath was heated to 48 ° C, stirring reaction 30min;11 mmol of 2-chloromethyl-3,5-dimethylpyridine hydrochloride was weighed and added to the above reaction solution in 3 portions at intervals of 30 minutes.After reacting at 48 °C for 10 h, the temperature was set to 22 °C and stirred for 2 h. After the reaction was completed, the reaction solution was filtered and the filtrate was retained.The volume ratio of water: isopropyl alcohol = 1:1 mixed solution was added to the filtrate, until the solution became turbid to stop dropping, and the solution was placed in a refrigerator to stand still overnight. The filter residue was parent molecule BIIB021. 6-Chloro-9-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-9H-purin-2-amine (BIIB021):Light yellow solid; Yield: 77percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: With potassium carbonate In dimethyl sulfoxide at 48℃; for 0.5 h; Stage #2: at 22 - 48℃; for 13.5 h; |
Weigh the 2-amino-6-chloropurine 10mmol, anhydrous potassium carbonate 12mmol, measure 25mL DMSO into a 50mL round bottom flask, and raise the temperature in the oil bath to 48°C.The reaction was stirred for 30 min; 11 mmol of 2-chloromethyl-3,5-dimethylpyridine hydrochloride was weighed and added to the above reaction solution in 3 portions at intervals of 30 min. After reaction at 48 °C for 10 h, the temperature was set to 22 ° C and stirred for 2 h.After the reaction is completed, the reaction solution is suction-filtered, and the filtrate is retained; a mixed solution with a volume ratio of water:isopropanol = 1:1 is added to the filtrate, until the solution becomes turbid, and the solution is added dropwise. The solution is left in the refrigerator at rest overnight, and the filter is filtered. That is, the parent molecule BIIB021 |
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