* 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.
Reference：
[1] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 6, p. 1365 - 1374
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[ 77287-34-4 ]
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[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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[ 77287-34-4 ]
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Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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[ 73-40-5 ]
[ 154-42-7 ]
Reference：
[1] Patent: US2697709, 1952, ,
[2] Journal of the American Chemical Society, 1955, vol. 77, p. 1676
[3] Patent: US2884667, 1955, ,
7
[ 73-40-5 ]
[ 39639-47-9 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 503 - 511
8
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[ 57-13-6 ]
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Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
10
[ 73-40-5 ]
[ 10310-21-1 ]
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).
Reference：
[1] Heterocycles, 2008, vol. 75, # 11, p. 2803 - 2808
[2] Patent: US5389637, 1995, A,
[3] Patent: US4736029, 1988, A,
[4] Patent: EP203685, 1991, B1,
[5] Patent: US4736029, 1988, A,
[6] Patent: EP203685, 1991, B1,
[7] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 503 - 511
[8] Bulletin of the Chemical Society of Ethiopia, 2010, vol. 24, # 3, p. 425 - 432
[9] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 675 - 686
[10] Patent: CN106336443, 2017, A, . Location in patent: Paragraph 0063; 0064
11
[ 73-40-5 ]
[ 7440-44-0 ]
[ 10310-21-1 ]
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).
Reference：
[1] Patent: US5910589, 1999, A,
12
[ 73-40-5 ]
[ 10310-21-1 ]
Reference：
[1] Patent: US5663338, 1997, A,
[2] Patent: US5663338, 1997, A,
13
[ 73-40-5 ]
[ 10310-21-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1140 - 1144
14
[ 73-40-5 ]
[ 5451-40-1 ]
Reference：
[1] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 503 - 511
[2] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 675 - 686
[3] European Journal of Organic Chemistry, 2018, vol. 2018, # 41, p. 5763 - 5772
15
[ 73-40-5 ]
[ 5451-40-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1140 - 1144
16
[ 73-40-5 ]
[ 19916-73-5 ]
Reference：
[1] Bulletin of the Chemical Society of Ethiopia, 2010, vol. 24, # 3, p. 425 - 432
17
[ 73-40-5 ]
[ 19962-37-9 ]
Yield
Reaction Conditions
Operation in experiment
72.7%
With acetic anhydride In ethanol; N,N-dimethyl acetamide
EXAMPLE 52 Preparation of N2 -Acetylguanine Guanine (10.1 g) was suspended in N,N-dimethylacetamide (100 ml), and acetic anhydride (20 ml) was added thereto. The mixture was stirred under reflux for 2 hours and filtered hot. After cooling the filtrate to room temperature, the solid precipitated was filtered, and the solid suspended in ethanol (66 ml). After stirring 1.5 hours, the suspension was filtered. The solid thus obtained was stirred under reflux in 50percent ethanol for 3 hours, and the solution cooled. The solid product thus obtained was filtered, washed with 50percent ethanol, and dried to provide the desired product (9.36 g, 72.7percent) as white solid. 1 H NMR (DMSO-d6) δ 13.14(bd,1H), 12.14(bs,1H), 11.67(bs,1H), 8.10 (bs,1H), 2.28(s,3H)
Reference：
[1] Patent: US6034087, 2000, A,
[2] Organic Letters, 2015, vol. 17, # 20, p. 4933 - 4935
18
[ 73-40-5 ]
[ 108-24-7 ]
[ 19962-37-9 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1987, vol. 41, # 8, p. 564 - 568
[2] Synthesis, 2004, # 12, p. 2026 - 2034
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1920 - 1923
[4] Angewandte Chemie - International Edition, 2010, vol. 49, # 11, p. 1963 - 1966
[5] Chemical Communications, 2010, vol. 46, # 8, p. 1218 - 1220
[6] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8915 - 8930
[7] Bioconjugate Chemistry, 2017, vol. 28, # 7, p. 1893 - 1905
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[ 66224-66-6 ]
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[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
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Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 32, p. 8126 - 8132
22
[ 73-40-5 ]
[ 74564-16-2 ]
[ 82410-32-0 ]
Reference：
[1] Patent: US4508898, 1985, A,
23
[ 73-40-5 ]
[ 82410-32-0 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, p. S221 - S221
[2] Synthetic Communications, 2004, vol. 34, # 5, p. 917 - 932
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 22, p. 3933 - 3938
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2003, vol. 42, # 3, p. 651 - 654
[5] Helvetica Chimica Acta, 1989, vol. 72, # 7, p. 1495 - 1500
[6] Canadian Journal of Chemistry, 1982, vol. 60, # 24, p. 3005 - 3010
In 1-methyl-pyrrolidin-2-one; at 20 - 150℃; for 27h;
[0100] A suspension of (5 g, 33 mmol) of guanine in 100 N-methy-2-pyrrolidinone NMP) and 20 ml acetic anhydride was heated to 150 C. for 3 hrs. The clear solution was stirred at room temperature for 24 hours. The precipitate was collected by filtration and washed with acetone. The N9,N2-diacetylated guanine (9) was dried and identified by 1H-NMR. [0101] M.P.=Decomp. 270 C. [0102] 1H-NMR (DMSO-d6): [0103] 12.1(bs, 1H-(N)), 8.53(s, 1H, H-(C8)); 2.91(s, 3H, Ac-(N9)); 2.31(s, 3H, -(N2-COCH3)). [0104] (5 g, 21.25 mmol) of (9) were suspended in 100 ml of dry pyridine and excess of diisopropyl ethylamine (DIEA). Then (5.91 g, 25.51 mmol) of diphenylcarbamoyl chloride ere added in portions. The reaction mixture turned orange immediately. Stirring continued for 2 hrs at r.t. then 20 nml if ice-cold water were added. The mixture was stirred for 10 minutes more and solvent was removed under reduced pressure. 100 ml of ethanol and 100 nml of water were added and the mixture was reflexed for 1.5 hr. After cooling to the room temperature, vigorous stirring continued for over night. The desired product (10) was collected by filtration and washed with 50 ml of ethanol, dried and characterized. [0105] M.P.=185 C. [0106] 1H-NMR (DMSO-d6): [0107] 10.7(s, 1H, H-(N2)); 8.55(s, 1H, H-(C8)); 7.61-7.38(m , 10H, aromatic); 2.28(s, 3H, -COCH3).
With triethylamine; In methanol; N,N-dimethyl-formamide; isopropyl alcohol;
Example 19 N2 -(Isobutanoyl)guanine Guanine (3.02 g) is suspended in dry DMF (40 ml), and triethylamine (1.45 ml) is added. Isobutyryl chloride (2.12 g) is then added dropwise using a syringe. The mixture is stirred for 3 hours at 100 C., the reaction solution is then treated with methanol, and the solvent is subsequently distilled off in vacuo. The residue is stirred with hot isopropanol, and the product which has precipitated is filtered off with suction and dried in vacuo. Yield: 2.67 g. Rf =0.45 (n-butanol/acetic acid/water 3:1:1).
Phosphoric acid (2R,3S,4R,5R)-4-amino-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-hydroxymethyl-tetrahydro-furan-3-yl ester (2R,3R,4R,5R)-2-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yl ester[ No CAS ]
With acetic anhydride; In ethanol; N,N-dimethyl acetamide;
EXAMPLE 52 Preparation of N2 -Acetylguanine Guanine (10.1 g) was suspended in N,N-dimethylacetamide (100 ml), and acetic anhydride (20 ml) was added thereto. The mixture was stirred under reflux for 2 hours and filtered hot. After cooling the filtrate to room temperature, the solid precipitated was filtered, and the solid suspended in ethanol (66 ml). After stirring 1.5 hours, the suspension was filtered. The solid thus obtained was stirred under reflux in 50% ethanol for 3 hours, and the solution cooled. The solid product thus obtained was filtered, washed with 50% ethanol, and dried to provide the desired product (9.36 g, 72.7%) as white solid. 1 H NMR (DMSO-d6) delta 13.14(bd,1H), 12.14(bs,1H), 11.67(bs,1H), 8.10 (bs,1H), 2.28(s,3H)
PREPARATION IV Preparation of N2,9-Diacetylguanine Guanine (20 g, 0.132 mol) was combined with 300 ml of acetic anhydride and the mixture heated at reflux for 16 hours. The mixture was cooled and the excess acetic anhydride removed by evaporation at reduced pressure. The residue was recrystallized from dimethyl sulfoxide to give 25.6 g of N2,9-diacetylguanine.
With trimethylsilyl trifluoromethanesulfonate; acetic acid; 1,1,1,3,3,3-hexamethyl-disilazane;
EXAMPLE 3 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 125 ml), and trimethylsilyl trifluoromethanesulfonate (1 ml) was heated to reflux (130-135 C.) for 24 hours. The resulting mixture was cooled to 70 C., 1,3-dioxolane (25 ml) added, and the resulting mixture refluxed for 16 hours. Excess HMDS and 1,3-dioxolane were removed by distillation under reduced pressure. The reaction mixture was cooled to 70 C., and poured into a mixture of 600 ml of 10% aqueous acetic acid. The mixture was heated to give a solution. The hot solution was treated with a small amount of activated carbon (1.25 g) to remove any color, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, to yield pure 9-(2-hydroxyethoxymethyl)guanine (29 g, 78%). 1 H NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
73%
With trifluorormethanesulfonic acid; 1,1,1,3,3,3-hexamethyl-disilazane; In water; acetic acid;
EXAMPLE 5 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 135 ml), and trifluoromethanesulfonic acid (0.75 ml) was heated to reflux (130-135 C.) for 24 hours. The resulting mixture was cooled to 70 C., and excess HMDS removed by distillation (0.1 to 1 mm Hg), slowly raising the bath temperature back to 110 C. The resulting mixture was cooled to 50 C., 1,3-dioxolane (36 ml) added, and the resulting mixture refluxed for 16 hours. The mixture was then cooled to 60 C., 300 ml of water and 2 ml of acetic acid added, and then low boiling solvent was removed by distillation at atmospheric pressure. The reaction mixture was cooled, and the yellow solid filtered off, which was then dissolved in a mixture of 450 ml water and 24 ml of acetic acid at 80 C. The hot solution was treated with a small amount of activated carbon (2 g) to remove any color, filtered, and the filtrate slowly cooled to 5 C., to yield pure 9-(2-hydroxyethoxymethyl)guanine (27.4 g, 73%). 1 NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
72%
With ammonium hydroxide; sodium hydroxide; trifluorormethanesulfonic acid; acetic acid; 1,1,1,3,3,3-hexamethyl-disilazane; In water; toluene;
EXAMPLE 8 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 125 ml), and trifluoromethanesulfonic acid (0.75 ml) was heated to reflux (130-135 C.) for 18 hours. The resulting mixture was cooled to 70 C., and excess HMDS removed by distillation (0.1 to 1 mm Hg). The resulting mixture was cooled, and toluene (250 ml) and 1,3-dioxolane (18 ml) added, and the resulting mixture refluxed for 10 hours at 105 C. The mixture was then cooled and 250 ml of water containing sodium hydroxide (7 g) added, and the aqueous layer separated. The toluene layer was washed with water (150 ml), and the combined aqueous layers were heated at atmospheric pressure to distill off low boiling organic material. The solution was cooled, and acetic acid (10.5 g) added to give a white precipitate. To this was added 29% ammonium hydroxide (6 g), the mixture heated to dissolve the solid, and the hot solution treated with a small amount of activated carbon (3 g) to remove any color. The slurry thus obtained was heated to redissolve the solid, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, to yield pure 9-(2-hydroxyethoxymethyl)guanine (26.8 g, 72%) 1 NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
66.6%
With trifluorormethanesulfonic acid; acetic acid; 1,1,1,3,3,3-hexamethyl-disilazane; In methanol; water;
EXAMPLE 4 Alternative Preparation of a Compound of Formula (I) A mixture of guanine (25 g), hexamethyldisilazane (HMDS, 125 ml), and trifluoromethanesulfonic acid (0.75 ml) was heated to reflux (130-135 C.) for 16 hours. The resulting mixture was cooled to 70 C., and excess HMDS removed by distillation (0.1 to 1 mm Hg), slowly raising the bath temperature back to 130 C. The resulting mixture was cooled to 60 C., 1,3-dioxolane (20 ml) added, and the resulting mixture refluxed for 16 hours. The mixture was then cooled to 45 C., 200 ml of methanol added, and then low boiling solvent was removed by distillation at atmospheric pressure. The reaction mixture was cooled, and poured into a mixture of 500 ml water and 10 ml of acetic acid. The mixture was heated to 80 C., removing low boiling material, to give a solution. The hot solution was treated with a small amount of activated carbon (2.5 g) to remove any color, and 100 ml of water added. The slurry thus obtained was heated to 75 C. to redissolve the solid, filtered, and the filtrate slowly cooled to 5 C. The white crystalline solid thus produced was filtered off, and recrystallized from 525 ml of 5% aqueous acetic acid, to yield pure 9-(2-hydroxyethoxymethyl)guanine (24.8 g, 66.6%). 1 NMR,: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
EXAMPLE 4 87.5 g (125 ml, apparent d-0.7) of strong basic resin (AMBERLITE IRA-400) were suspended in deionized water and loaded into a chromatographic column (diameter=4 cm, h=40 cm). After the usual regeneration treatments (subsequent elution with 2M NaOH, 2M HCl, 2M NaOH and deionized water till neutrality) a solution obtained by dissolving 50 g of acyclovir into 100 ml of a 10% NaOH solution, diluted up to 200 ml with water, was loaded. The solution was then eluted with a flow of 250 ml/hour (4.2 ml/min). After eluding the above solution, the column was eluted with the same flow rate with 900 ml of a 1:1 v/v MeOH/1M NaOH mixture. The so obtained elude was adjusted to pH 5-6 with aqueous HCl. The precipitated solid was filtered, washed with water and dried. 45 g of acyclovir (90% yield) free from guanine were obtained.
40 g of <strong>[35011-47-3]2,4,5-triamino-6-hydroxypyrimidine sulfate</strong> was charged into a clean and dry 500 mL three-necked flask andExample 1 Distilled formic acid (set 1),Less than 115g,Add new formic acid,Open the stir,2,4,5-triamino-6-hydroxypyrimidineThe sulphate salt was thoroughly mixed with formic acid and then slowly added 16 g of formamide and heated to reflux for 11 hours and refinedTo white guanine. Distilled formic acid continued to apply, the results shown in Table 1.
In a 500 ml three-necked flask, 240 g of pyridine, 20 g of guanine and 1 g of DMAP (4-dimethylaminopyridine) were successively added, stirred and dissolved in an ice bath to -5 C. 42g acetyl chloride was added to the separatory funnel, while stirring, while slowly dropping, control the drop process for 25 ~ 35min, the temperature is below 10 . After completion of the dropwise addition, the reaction solution was stirred at room temperature for 2.5 hours to obtain a X1 reaction solution. The reaction solution X1 was distilled under reduced pressure to control the pressure to -0.09 MPa. When the temperature rose to 51 C, the swallowed liquid acetyl chloride was passed into the water. When the temperature rises to 92 deg.] C, collecting the distillate pyridine, recycled and reused. Contains solid crystals containing X1. The obtained X1 solid was added to a flask equipped with 140 g of distilled water and stirred for 40 min to extract a solid containing X1 at room temperature. The solid containing X1 was added to 0.05ml / L 160ml acetic acid solution, stirred for 20min, and filtered at room temperature to obtain the filtrate containing X1. The resulting filtrate was placed in a 250 ml flask at a stirring speed of 300 r / min, cooled and cooled, and the time eluted from the crystal to -5 C was 0.5-1 h. The product was dried at 80 C and 18.34 g. Single yield of 91.7%, purity> 99.5%
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