(1S,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol hydrochloride

Off-White to Tan Solid

N-[2-Amino-4-chloro-6-[[(1R, 4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinyl]formamide (0.1762 mol) was added to trietylorthoformate (7V). Cooled the mass to 0-5° C., hydrochloride acid (0.7V) was added at 0-10° C. After addition maintained the mass for 60 min at 0-5° C. Allowed the mass to room temperature and maintained for 16-18 hrs at. Filtered the mass and purified in methanol. (Yield: 76percent, HPLC purity: 98.69percent).Compound I (53.2 g, 0.36 mol) was added to absolute ethanol (700 mL) under nitrogen and then added Sodium bicarbonate (100 g, 0.94 mol) was stirred at room temperature for 0.5 hour; Compound II (74.5 g, 0.36 mol) was added to the above reaction system, and the temperature was raised to 75-80 ° C, and the reaction was allowed to cool for 3 hours and then cooled to room temperature. Perform suction filtration. To the filtrate was added triethyl orthoformate (251.5 g, 1.69 mol), and the mixture was stirred at 0 to 10 °C.An ethanolic hydrochloric acid solution (6.0 mol/L, 150 mL) was added dropwise to the reaction system during the stirring.After the addition is completed, Insulation reaction for 10 hours, Then suction filtration, drying, 100 g of brownish yellow abacavir intermediate was obtained.Wherein the molar yield of the obtained abacavir intermediate is 92.0percent;HPLC purityThe ratio was 93.90percent, the absorbance (λ = 420 nm) = 0.36, and the absorbance (λ = 450 nm) = 0.31.Example A [00029] Preparation of (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt. [00030] A suspension of (1R, 4S)-cis-[4-(hydroxymethyl)-2-cyclopentene-1-yl]carbamic acid, 1, 1-dimethylethyl ester (100 g) in industrial methylated spirit (IMS) (600 ml) was treated with concentrated hydrochloric acid (48 ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5 h. Heating under reflux was maintained for about 2.5 h. The solution was cooled to 20 to 25° C. and diluted with IMS (600 ml). Triethylamine (170 ml) was added followed by N-(2-amino-4, 6-dichloro-5-pyrimidinyl)formamide (WO95/21161) (97 g). The suspension was heated under reflux for about 17 h to give a clear solution, which was cooled to 25 to 30° C. and finely divided potassium carbonate (169 g) was added. The suspension was stirred in this temperature range for about 0.5 h then cooled to 0 to 5° C. and the solids filtered off. The solids were washed with IMS (3.x.180 ml and 1.x.140 ml) and the combined filtrates and washings were concentrated under reduced pressure to a red gum. This was redissolved in IMS (1000 ml) and the solution was concentrated under reduced pressure to a gum. The dilution and re-concentration were repeated twice more, and the final gum was redissolved in IMS (350 ml). [00031] Meanwhile, a mixture of triethylorthoformate (900 ml) and tetrahydrofuran (THF) (400 ml) was prepared and cooled to 0 to 5° C. Concentrated hydrochloric acid (80 ml) was added, maintaininglthe temperature between 0 and 10° C., and more THF (100 ml, ) was then added. To this mixture was added the IMS concentrate prepared above, which was rinsed in with IMS (100 ml). The mixture was warmed to 20 to 25° C. and seeded with authentic (1S, 4R)-c-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt and stirring continued for about 20 h. The slurry was filtered, the solid was washed with a mixture of tert-butyl methyl ether and IMS (9/1, 3.x.300 ml) and dried in vacuo at 40 to 45° C. to give the title compound (117 g, 82percent) as a fawn coloured solid Example B Preparation of (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-l-methanol hydrochloride salt. [00033] A suspension of (1R, 4S)-cis-[4-(hydroxymethyl)-2-cyclopentene-1-yl]carbamic acid, 1, 1-dimethylethyl ester (100 g) in industrial methylated spirit (IMS) (600 ml) was treated with concentrated hydrochloric acid (48 ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5 h. Heating under reflux was maintained for about 3 h. The solution was cooled to 20 to 25° C. and sodium bicarbonate (103.4 g) was added followed by N-(2-amino-4, 6-dichloro-5-pyrimidinyl)formamide (WO95/21161) (97g) and IMS (600 ml). The suspension was heated under reflux for about 4 h and then cooled to about -5° C. After stirring at this temperature for about 1h, the solids were filtered off and washed with IMS (2.x.100 ml). The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 400 ml. This was redissolved in IMS (1000 ml) and the solution was concentrated under reduced pressure to a gum. The dilution and re-concentration were repeated twice more, and the final gum was redissolved in IMS (350 ml). [00034] Meanwhile, triethylorthoformate (900 ml) was cooled to 0 to 5° C. and concentrated hydrochloric acid (80 ml) was added, maintaining the temperature between 0 and 10° C. To this mixture was added the IMS concentrate prepared above, which was rinsed in with IMS (600 ml). The mixture was warmed to 20 to 25° C. and seeded with authentic (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt and stirring was continued for about 7 h. The slurry was filtered, and the solid was washed with IMS (2.x.150 ml) and dried in vacuo at 40 to 45° C. to give the title compound (114 g, 81percent) as a fawn coloured solid, spectroscopically identical to the product of Example A.; Example C [00035] Preparation of (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt.A suspension of (1R, 4S)-cis-[4-(hydroxymethyl)-2-cyclopentene-1-yl]carbamic acid, 1, 1-dimethylethyl ester (100 g) in industrial methylated spirit (IMS) (600 ml) was treated with concentrated hydrochloric acid (48 ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5 h. Heating under reflux was maintained for about 3 h. The solution was cooled to 20 to 25° C. and sodium bicarbonate (103.4 g) was added followed by N-(2-amino-4, 6-dichloro-5-pyrimidinyl)formamide (WO95/21161) (97g) and IMS (600 ml). The suspension was heated under reflux for about 4 h and then cooled to about -5° C. After stirring at this temperature for about 1h, the solids were filtered off and washed with IMS (2.x.100 ml). The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 400 ml. This was redissolved in IMS (1000 ml) and the solution was concentrated under reduced pressure to a gum. The dilution and re-concentration were repeated twice more, and the final gum was redissolved in IMS (350 ml). [00034] Meanwhile, triethylorthoformate (900 ml) was cooled to 0 to 5° C. and concentrated hydrochloric acid (80 ml) was added, maintaining the temperature between 0 and 10° C. To this mixture was added the IMS concentrate prepared above, which was rinsed in with IMS (600 ml). The mixture was warmed to 20 to 25° C. and seeded with authentic (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt and stirring was continued for about 7 h. The slurry was filtered, and the solid was washed with IMS (2.x.150 ml) and dried in vacuo at 40 to 45° C. to give the title compound (114 g, 81percent) as a fawn coloured solid, spectroscopically identical to the product of Example A.Example C [00035] Preparation of (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt. [00036] A suspension of (1R, i4S)-cis-[4-(hydroxymethyl)-2-cyclopentene-1-yl]carbamic acid, 1, 1-dimethylethyl ester (72.5 kg) in industrial methylated spirit (IMS) (435 L) and water (about 200 L) was treated with concentrated hydrochloric acid (36.5 L, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 1.5 h. Heating under reflux was maintained for about 2 h. The solution was cooled to 20 to 25° C. and sodium bicarbonate (75 kg) was added followed by N-(2-amino-4, 6-dichloro-5-pyrimidinyl)formamide (WO95/21161) (70 kg) and IMS (435 L). The suspension was heated under reflux for about 4 h and then cooled to about -5° C. After stirring at this temperature for about 1 h, the solids were filtered off and washed with IMS (2.x.144 L). The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 290 L. This was diluted with IMS (about 300 L) and the solution was concentrated under reduced pressure to a residual volume of about 290 L. The dilution and re-concentration were repeated twice more, and the final concentrate was diluted with IMS (610 L) and heated to about 35-40° C. The resultant mixture was filtered and the solids were washed with IMS (2.x.144 L) The combined filtrate's and washings were concentrated under reduced pressure to a residual volume of about 290 L and then diluted with IMS (217 L). [00037] Meanwhile, a mixture of triethylorthoformate (660 L), concentrated hydrochloric acid (58 L) and IMS (72 L) was prepared at 0 to 8° C., To this mixture was added the IMS concentrate prepared above, which was rinsed in with IMS (2.x.72 L). The mixture was warmed to 20 to 25° C. and seeded with authentic (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt and stirring was continued for about 7 h. The slurry was cooled to 18-21° C., filtered, and the solid was washed with IMS (72 L and 217 L) and dried in vacuo at 40 to 45° C. to give the title compound (81.7 kg, 79.5percent) as a fawn coloured solid, spectroscopically identical to the product of Example A. Example D [00038] Preparation of (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt. [00039] A suspension of (1R, 14S)-cis-[4-(hydroxymethyl)-2-cyclopentene-1-yl]carbamic acid, 1, 1-dimethylethyl ester (10 g) in industrial methylated spirit (IMS) (60 ml) was treated with concentrated hydrochloric acid (5 ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5 h. Heating under reflux was maintained for about 3 h. The solution was cooled to 20 to 25° C. and weighed (45.7 g). A portion (14 g) was diluted with IMS (14 ml) and sodium bicarbonate (3.1 g) was added followed by 2, 5-diamino-4, 6-dichloropyrimidine (WO95/21161) (2.0 g). The suspension was heated under reflux for about 7 h and then cooled to about -5° C. The solids were filtered off and the combined filtrates and washings were concentrated under reduced pressure to a gum, which was redissolved in IMS (17 ml). [00040] Meanwhile, triethylorthoformate (21.4 ml) was cooled to 0 to 5° C. and concentrated hydrochloric acid (1.9 ml) was added, maintaining the temperature between 0 and 10° C. To this mixture was added the IMS solution prepared above, which was rinsed in with IMS (2.x.2.5 ml). The mixture was warmed to 20 to 25° C. and seeded with authentic (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol hydrochloride salt and stirring was continued for about 19 h. The slurry was filtered, and the solid was washed with IMS (2.x.4.5 ml) and dried in vacuo at 40 to 45° C. to give the title compound (2.06 g, 61percent) as a pale yellow solid, spectroscopically identical to the product of Example A.N-[2-Amino-4-chloro-6-[[(1R, 4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinyl]formamide (0.1762 mol) was added to trietylorthoformate (7V). Cooled the mass to 0-5° C., hydrochloride acid (0.7V) was added at 0-10° C. After addition maintained the mass for 60 min at 0-5° C. Allowed the mass to room temperature and maintained for 16-18 hrs at. Filtered the mass and purified in methanol. (Yield: 76percent, HPLC purity: 98.69percent).Compound I (53.2 g, 0.36 mol) was added to absolute ethanol (700 mL) under nitrogen and then added Sodium bicarbonate (100 g, 0.94 mol) was stirred at room temperature for 0.5 hour; Compound II (74.5 g, 0.36 mol) was added to the above reaction system, and the temperature was raised to 75-80 ° C, and the reaction was allowed to cool for 3 hours and then cooled to room temperature. Perform suction filtration. To the filtrate was added triethyl orthoformate (251.5 g, 1.69 mol), and the mixture was stirred at 0 to 10 °C.An ethanolic hydrochloric acid solution (6.0 mol/L, 150 mL) was added dropwise to the reaction system during the stirring.After the addition is completed, Insulation reaction for 10 hours, Then suction filtration, drying, 100 g of brownish yellow abacavir intermediate was obtained.Wherein the molar yield of the obtained abacavir intermediate is 92.0percent;HPLC purityThe ratio was 93.90percent, the absorbance (lambda = 420 nm) = 0.36, and the absorbance (lambda = 450 nm) = 0.31.To water (3V), triethyl amine (0.3458 mol) was added al S, 4R)-4-(2-amino-6-chloro-9H-purin-9-yl)cyclopent-2-enyl)methanol Hydrochloride (0.1158 mol). Stirred for 5-10 min and added cyclopropyl amine (0.1754 mol) at room temperature. Heated the mass to 70-75° C. and maintained for 2-3 hrs. Cooled to room temp. The reaction mass pH was adjusted to 9.5-10.0 with ammonium hydroxide solution. The mass was extracted in to MDC and methanol mixture and was given charcoal treatment for two times. The solvent was concentrated below 55° C. and the crude product was isolated in acetone to obtain pure compound. (Yield: 90percent, HPLC purity: 99.57percent).Example 3 (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir base, 1) In a sealed reactor, isopropanol (200 ml) and cyclopropylamine (35 ml) were added to the compound obtained from (30 g). The reaction mixture was heated a 90-95°C for 12 hours. The mixture was allowed to cool at room temperature. A solution of sodium methylate 30percent (18 g) (or an aqueous solution of sodium hydroxide, 27 g) was then added, and the solvent was evaporated, Isopropanol (200 ml) was added, and the precipitated salts were fltered-off. The filtrate was concentrated, and the oily residue was taken-up with acetone (150 ml). The resulting slurry was filtered, washed with acetone on the filter, and the collected solid was dried, yielding 25 g of the tile product as free base.EXAMPLE-1 PREPARATION OF (1S, 4R) 4-[2-AMINO-6-(CYCLOPROPYLAMINO)-9H-PURIN-9-YL]-2-CYCLOPENTENE-1-METHANOL (ABACAVIR BASE) Cyclopropylamine (147.20 g, 2.582 mol) was added to a suspension of (1S, 4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanolhydrochloride (150 g, 0.497 mol) in ethanol (absolute alcohol, 1500 ml) at 25-30°C and reaction mass was heated to reflux at 74-78°C for -6 hrs to complete the reaction. Thereafter, the reaction mass was concentrated at 40-50°C under reduced pressure (700-50 mm of Hg) to remove the solvents completely. Obtained concentrated mass was diluted with DM water (450 ml) ethyl acetate (1500 ml) at 25-45°C and pH was adjusted to 40-45°C. Organic layer was separated and aqueous layer, saturated with sodium chloride (150g) was re-extracted with preheated ethyl acetate (1 x 900 ml, 1 x 450 ml, 40-45°C). Combined organic layer was treated with carbon enoanticromos and concentrated at 40-50°C under reduced pressure (200-50 mm of Hg) to yield a foamy solid i.e. (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (Abacavir base).The abacavir intermediate pure (30.2 g, 0.1 mol), cyclopropylamine (22.6 g, 0.4 mol) and sodium carbonate (11 g, 0.1 mol) was added to ethanol (700 mL), Heating to 70 ~ 80 ° C reaction, After the reaction is completed, a part of the solvent is distilled off, and the mixture is filtered while hot.The filtrate is concentrated and then cooled to 0 to 10 ° C.Crystallize for 3 to 6 hours, then filter and dry.This gave 25.0 g of white-like abacavir.among them, The molar yield of the obtained abacavir was 87.4percent; the HPLC purity was 99.63percentUnder nitrogen protection, (1S-cis) -4-Amino-2-cyclopentenyl-1-methanol hydrochloride II (15 g, 0.1 mol)And (1S-4R) -4- (2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol hydrochloride V (30 g, 0.1 mol)Was added to absolute ethanol (200 mL)Then sodium carbonate (21.2 g, 0.2 mol)Heating to 75 ~ 80 incubated for 6 hours.The reaction system was cooled to room temperature, FilteringThe filtrate was concentrated under reduced pressure to precipitate a solid, Cooling to 0 ~ 10 C crystallization 2 hours, Suction filtration, Isobutanol was added to the filter cake for recrystallization, To get it((1S, 4R) -4- (2-amino-6 - ((1R, 4S) -4- (hydroxymethyl) cyclopentyl-2-enylamino)-9H-purin-9-yl) cyclopent-2-enyl)Methanol compounds(29.8 g, molar yield 87.1%; HPLC purity 99.5%).EXAMPLE-3 PREPARATION OF (1S, 4R)-4-[2-AMINO-6-CHLORO-9H-PURIN-9-YL]-2-CYCLOPENTENE-1-METHANOL (CHLOROPURINE BASE) (1S, 4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol (6), hydrochloride (1S-cis)-4-amino-2cyclopentene-1-methanol, tartrate salt (55 g) was dissolved in ethanol (400 ml) in inert atmosphere, Sodium carbonate (48 g) was added. After 30 min 44 g of 4, 6-dichloro-2, 5-diformamidopyrimidinc (7) were added. The resulting mixture was then heated at gentle reflux. After 3 hours, the solvent was distilled off, and acetone (400 ml) was added. After 30 min reflux, the mixture is allowed to cool to 30°C, and the precipitate was filtered-off. The filtrate was evaporated to dryness, and the residue was taken-up with ethanol (200 ml). Triethylorthoformate (350 ml) and 35percent HCl (35 ml) were added to the suspension, maintaining the temperature below 25°C. After 16 hours the suspension was filtered, and the solid was washed twice (50 ml) on the filter with ethanol, collected and dried, to give 30 g of the title product.

Abacavir intermediate.