WO1999019327A1 - Process for the synthesis of chloropurine intermediates - Google Patents

Process for the synthesis of chloropurine intermediates Download PDF

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Publication number
WO1999019327A1
WO1999019327A1 PCT/GB1998/003080 GB9803080W WO9919327A1 WO 1999019327 A1 WO1999019327 A1 WO 1999019327A1 GB 9803080 W GB9803080 W GB 9803080W WO 9919327 A1 WO9919327 A1 WO 9919327A1
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Prior art keywords
formula
acid
compound
ims
carried out
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PCT/GB1998/003080
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French (fr)
Inventor
Martin Francis Jones
Christopher John Wallis
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Glaxo Group Limited
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Priority to IL13532398A priority Critical patent/IL135323A/en
Priority to AU95476/98A priority patent/AU738462B2/en
Priority to SK536-2000A priority patent/SK285331B6/en
Priority to PL98339904A priority patent/PL188477B1/en
Priority to JP2000515898A priority patent/JP4531250B2/en
Priority to APAP/P/2000/001790A priority patent/AP1182A/en
Priority to HU0003984A priority patent/HUP0003984A3/en
Priority to KR1020007003921A priority patent/KR100543845B1/en
Priority to SI9830556T priority patent/SI1023292T1/en
Priority to NZ503679A priority patent/NZ503679A/en
Priority to UA2000031789A priority patent/UA54550C2/en
Priority to AT98949093T priority patent/ATE249461T1/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to DE69818084T priority patent/DE69818084T2/en
Priority to US09/529,385 priority patent/US6646125B1/en
Priority to CA002306958A priority patent/CA2306958C/en
Priority to BRPI9813048-0A priority patent/BR9813048B1/en
Priority to EA200000318A priority patent/EA003183B1/en
Priority to EP98949093A priority patent/EP1023292B1/en
Priority to DK98949093T priority patent/DK1023292T3/en
Priority to EEP200000162A priority patent/EE04059B1/en
Publication of WO1999019327A1 publication Critical patent/WO1999019327A1/en
Priority to IS5423A priority patent/IS2195B/en
Priority to NO20001896A priority patent/NO325030B1/en
Priority to HR980147A priority patent/HRP20000216B1/en
Priority to HK00106983A priority patent/HK1027807A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for the preparation of a carbocyclic purine nucleoside analogue of formula (I) , its salts and pharmaceutically acceptable derivatives thereof.
  • EP 0434450 This is described in EP 0434450 as having potent activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) .
  • the protecting group P will desirably be an acyl or substituted oxycarbonyl group.
  • One aspect of the present invention comprises an in situ conversion of cyclopentenes of formula (IV) to 2- aminopurine derivatives of formula (I) easily and conveniently without the need to isolate any intermediates.
  • the deprotection of the starting material of formula (IV) in situ provides the desired amino alcohol without any wasteful workup, and because of the direct coupling and cyclisation, again without any work up or isolation of intermediates, the overall yield of the process is increased.
  • preferred protecting groups in the compound of formula (IV) are acyl or substituted oxycarbonyl groups .
  • Preferred acyl groups include for yl or lower alkanoyl (having e.g. 1 to 4 carbon atoms in the alkyl portion) , especially an acetyl group .
  • Preferred substituted oxycarbonyl groups will be of the formula R'OC(O)-, wherein R' may be an alkyl or aralkyl group.
  • a preferred alkyl group is tert butyl; a preferred aralkyl group is benzyl.
  • the hydrolysis step is preferably achieved by mild acid- catalysed hydrolysis in an organic solvent, such as an alkanol, a cyclic ether or a chlorinated hydrocarbon. It is preferred to use an organic or mineral acid such as trifluoroacetic acid or hydrochloric acid in an alkanol solvent such as industrial methylated spirit (IMS) , optionally in the presence of water.
  • organic solvent such as an alkanol, a cyclic ether or a chlorinated hydrocarbon.
  • an organic or mineral acid such as trifluoroacetic acid or hydrochloric acid
  • an alkanol solvent such as industrial methylated spirit (IMS)
  • the condensation step is then carried out without any isolation of the hydrolysis product of formula (V) .
  • This condensation reaction is preferably carried out under reflux in a polar solvent such as an alcohol, e.g. ethanol or butanol, or water or acetonitrile, or mixtures thereof, in the presence of at least sufficient base to neutralise both the acid used for the hydrolysis and that produced during the condensation.
  • a polar solvent such as an alcohol, e.g. ethanol or butanol, or water or acetonitrile, or mixtures thereof.
  • the base will desirably be a trialkylamine or an alkali metal carbonate or bicarbonate, e.g. potassium or sodium carbonate, and more preferably, sodium bicarbonate.
  • Preferred combinations are triethylamine or sodium bicarbonate in IMS.
  • the group R in the compound of formula (VI) preferably represents CHO.
  • the ring closure reaction is then carried out, again without any isolation of any preceding intermediate product of formula (VII) .
  • This is conveniently carried out using trialkylorthoformates in the presence of concentrated aqueous or anhydrous mineral acid, optionally in the presence of one or more non-aqueous solvents, e.g. tetrahydrofuran, ethyl acetate or IMS.
  • the unisolated product of formula (VII) is added to a mixture of acid and a trialkylorthoformate .
  • a preferred combination comprises use of from about 1.5 to 3, preferably around 2 molar equivalents of hydrochloric acid in triethylorthoformate, which results in precipitation of the hydrochloride salt of the 9- substituted-2-amino purine of formula (I) .
  • the free base may, if desired, be liberated by treatment with base .
  • the process of the invention has been found to provide yields of compounds of formula (I) starting from a compound of formula (IV) of in excess of 80%. This compares very favourably with yields of compounds of formula (I) which are obtained using earlier stepwise procedures in which the intermediates are isolated, which give, typically around 56% when the compound of formula (III) is used as starting material, or yields of around 75% when the procedure described in Publication No. W095/21161 is used, starting from a compound of formula (V) .
  • the compounds of formula (VI) can be synthesised by a method as described in W095/21161.
  • the compound can be synthesised from the readily available 2 , 5-diamino-4 , 6- dihydroxypyrimidine , by reacting this with a Vilsmeier reagent of formula (VIII)
  • R x and R 2 are as defined in W095/21161, viz: that R x and R 2 , which may be the same or different are selected from C ⁇ . _ 8 straight- chain alkyl, C ⁇ g branched alkyl, C 3 _ 8 cycloalkyl, and aryl groups (such as phenyl or naphthyl) , which may be optionally substituted, for example by C ⁇ _ 4 alkyl or halogen (e.g. Cl) .
  • R x and R 2 are both methyl) , followed by hydrolysis.
  • Compounds of formula (VIII) may be prepared from a variety of formamides of secondary amines by reaction with a variety of acid halides, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosgene, and oxalyl chloride, for example as detailed in a review by CM. Marson, Tetrahedon 1992, 48:3660- 3720 and references therein.
  • acid halides such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosgene, and oxalyl chloride, for example as detailed in a review by CM. Marson, Tetrahedon 1992, 48:3660- 3720 and references therein.
  • the compound of formula (VI) where R is H can be prepared from the compound of formula (IX) by hydrolysis in acidic solution, e.g. at pH 3 ⁇ 0.5, by adding a water miscible cosolvent, such as ethanol .
  • the compound of formula (VI) where R is CHO can also be prepared by the hydrolysis of the compound of formula (IX) in the minimum of water, with the pH controlled as described above. Under these conditions the compound of formula (VI) where R is CHO precipitates as formed and can be filtered off.
  • the compound of formula (IV) may be prepared by methods analogous to those described in Tetrahedron: Asymmetry Vol.4, p.1117 (1993) .
  • Triethylamine (170ml) was added followed by N- (2-amino- 4, 6-dichloro-5-pyrimidinyl) formamide (W095/21161) (97g) .
  • the suspension was heated under reflux -for about 17h to give a clear solution, which was cooled to 25 to 30°C and finely divided potassium carbonate (169g) was added.
  • the suspension was stirred in this temperature range for about 0.5h then cooled to 0 to 5°C and the solids filtered off.
  • the solids were washed with IMS (3 x 180ml and 1 x 140ml) and the combined filtrates and washings were concentrated under reduced pressure to a red gum. This was redissolved in IMS (1000ml) 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 (350ml) .
  • the suspension was heated under reflux for about 4h and then cooled to about -5°C. After stirring at this temperature for about lh, the solids were filtered off and washed with IMS (2 x 100ml) . The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 400ml. This was redissolved in IMS (1000ml) 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 (350ml) . Meanwhile, triethylorthoformate (900ml) was cooled to 0 to 5°C and concentrated hydrochloric acid (80ml) was added, maintaining the temperature between 0 and 10°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The present invention relates to a process for the preparation of a carbocyclic purine nucleoside analogue of formula (I), its salts and pharmaceutically acceptable derivatives thereof which comprises hydrolysing a compound of formula (IV) wherein P is a protecting group, in the presence of an acid, condensing the product of formula (V) formed in situ in the presence of a base with a compound of formula (VI) followed by in situ ring closure of the resulting intermediate.

Description

PROCESS FOR THE SYNTHESIS OF CHLOROPURINE INTERMEDIATES
The present invention relates to a process for the preparation of a carbocyclic purine nucleoside analogue of formula (I) , its salts and pharmaceutically acceptable derivatives thereof.
An enantiomerically pure compound of formula (I)
Figure imgf000003_0001
has been described in GB-A-2217320 and can be used as an intermediate in the manufacture of abacavir, a 2- aminopurine nucleoside analogue with the following structure (II)
Figure imgf000003_0002
This is described in EP 0434450 as having potent activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) .
There exists a need to synthesise large quantities of abacavir for clinical trials and once abacavir has been approved by the national medicine regulatory agencies, large quantities of abacavir will also be required for sale as a prescription medicine for the treatment of HIV infections.
Processes for the manufacture of abacavir using enantiomerically pure compounds of formula (III)
Figure imgf000004_0001
via the 2-aminopurine intermediate of formula (I) are described generally in PCT Publication Nos. O91/15490, in 095/21161, in EP 0434450 and in Tetrahedron: Asymmetry Vol . 4, p.1117, (1993). However, the procedures described provide an unsatisfactory route to the 2-aminopurine derivative of formula (I) , inasmuch as they require the isolation and purification of a number of intermediates resulting in a relatively high cost and a low yield for the synthesis.
We have developed a process for the production of the intermediate of formula (I) from N-protected-4-amino- cyclopentenes of formula (IV)
Figure imgf000005_0001
wherein P is a protecting group,
which provides a high yield and is more cost effective, The protecting group P will desirably be an acyl or substituted oxycarbonyl group.
One aspect of the present invention comprises an in situ conversion of cyclopentenes of formula (IV) to 2- aminopurine derivatives of formula (I) easily and conveniently without the need to isolate any intermediates. In our procedure, the deprotection of the starting material of formula (IV) in situ provides the desired amino alcohol without any wasteful workup, and because of the direct coupling and cyclisation, again without any work up or isolation of intermediates, the overall yield of the process is increased.
According to a further aspect of the invention, therefore, we provide a process for the preparation of a compound of formula (I) ,
Figure imgf000005_0002
optionally in the form of its salt or complex, which comprises hydrolysing a compound of formula (IV) as defined above in the presence of acid, condensing the product of formula (V) formed
Figure imgf000006_0001
in situ in the presence of a base with a compound of formula (VI)
Figure imgf000006_0002
in which R represents CHO or H, followed by ring closure in situ of the resulting intermediate of formula (VII)
Figure imgf000006_0003
CH20H (VII)
in which R represents CHO or H, to produce a compound of formula (I) , which can then be optionally reacted with an acid or complexing agent to form its salt or complex. As described above, preferred protecting groups in the compound of formula (IV) are acyl or substituted oxycarbonyl groups . Preferred acyl groups include for yl or lower alkanoyl (having e.g. 1 to 4 carbon atoms in the alkyl portion) , especially an acetyl group . Preferred substituted oxycarbonyl groups will be of the formula R'OC(O)-, wherein R' may be an alkyl or aralkyl group. A preferred alkyl group is tert butyl; a preferred aralkyl group is benzyl.
The hydrolysis step is preferably achieved by mild acid- catalysed hydrolysis in an organic solvent, such as an alkanol, a cyclic ether or a chlorinated hydrocarbon. It is preferred to use an organic or mineral acid such as trifluoroacetic acid or hydrochloric acid in an alkanol solvent such as industrial methylated spirit (IMS) , optionally in the presence of water.
The condensation step is then carried out without any isolation of the hydrolysis product of formula (V) . This condensation reaction is preferably carried out under reflux in a polar solvent such as an alcohol, e.g. ethanol or butanol, or water or acetonitrile, or mixtures thereof, in the presence of at least sufficient base to neutralise both the acid used for the hydrolysis and that produced during the condensation. Generally, there will be at least 2 equivalents based on the amount of compound of formula (IV) . The base will desirably be a trialkylamine or an alkali metal carbonate or bicarbonate, e.g. potassium or sodium carbonate, and more preferably, sodium bicarbonate. Preferred combinations are triethylamine or sodium bicarbonate in IMS. The group R in the compound of formula (VI) preferably represents CHO.
The ring closure reaction is then carried out, again without any isolation of any preceding intermediate product of formula (VII) . This is conveniently carried out using trialkylorthoformates in the presence of concentrated aqueous or anhydrous mineral acid, optionally in the presence of one or more non-aqueous solvents, e.g. tetrahydrofuran, ethyl acetate or IMS. Suitably, the unisolated product of formula (VII) is added to a mixture of acid and a trialkylorthoformate . A preferred combination comprises use of from about 1.5 to 3, preferably around 2 molar equivalents of hydrochloric acid in triethylorthoformate, which results in precipitation of the hydrochloride salt of the 9- substituted-2-amino purine of formula (I) . The free base may, if desired, be liberated by treatment with base .
The process of the invention has been found to provide yields of compounds of formula (I) starting from a compound of formula (IV) of in excess of 80%. This compares very favourably with yields of compounds of formula (I) which are obtained using earlier stepwise procedures in which the intermediates are isolated, which give, typically around 56% when the compound of formula (III) is used as starting material, or yields of around 75% when the procedure described in Publication No. W095/21161 is used, starting from a compound of formula (V) .
The compounds of formula (VI) can be synthesised by a method as described in W095/21161. The compound can be synthesised from the readily available 2 , 5-diamino-4 , 6- dihydroxypyrimidine , by reacting this with a Vilsmeier reagent of formula (VIII)
Figure imgf000008_0001
o form a compound of formula (IX)
Figure imgf000009_0001
(wherein in both formulae (VIII) and (IX) , Rx and R2 are as defined in W095/21161, viz: that Rx and R2, which may be the same or different are selected from Cι._8 straight- chain alkyl, C^g branched alkyl, C3_8 cycloalkyl, and aryl groups (such as phenyl or naphthyl) , which may be optionally substituted, for example by Cχ_4 alkyl or halogen (e.g. Cl) . In a preferred embodiment of the invention Rx and R2 are both methyl) , followed by hydrolysis.
Compounds of formula (VIII) may be prepared from a variety of formamides of secondary amines by reaction with a variety of acid halides, such as phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosgene, and oxalyl chloride, for example as detailed in a review by CM. Marson, Tetrahedon 1992, 48:3660- 3720 and references therein.
The compound of formula (VI) where R is H can be prepared from the compound of formula (IX) by hydrolysis in acidic solution, e.g. at pH 3 ± 0.5, by adding a water miscible cosolvent, such as ethanol . The compound of formula (VI) where R is CHO can also be prepared by the hydrolysis of the compound of formula (IX) in the minimum of water, with the pH controlled as described above. Under these conditions the compound of formula (VI) where R is CHO precipitates as formed and can be filtered off. The compound of formula (IV) may be prepared by methods analogous to those described in Tetrahedron: Asymmetry Vol.4, p.1117 (1993) .
The following Examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
Example A
Preparation of (1S . 4R) -cis -4 - I2 -amino- 6 -chloro- 9H-purin- 9 -yl] - 2 -cyclopentene-l- ethanol hydrochloride salt .
A suspension of (1R,4S) -c_ig- [4- (hydroxymethyl) -2- cyclopentene-1-yl] carbamic acid, 1, 1-dimethylethyl ester (lOOg) in industrial methylated spirit (IMS) (600ml) was treated with concentrated hydrochloric acid (48ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5h. Heating under reflux was maintained for about 2.5h. The solution was cooled to 20 to 25°C and diluted with IMS (600ml) . Triethylamine (170ml) was added followed by N- (2-amino- 4, 6-dichloro-5-pyrimidinyl) formamide (W095/21161) (97g) . The suspension was heated under reflux -for about 17h to give a clear solution, which was cooled to 25 to 30°C and finely divided potassium carbonate (169g) was added. The suspension was stirred in this temperature range for about 0.5h then cooled to 0 to 5°C and the solids filtered off. The solids were washed with IMS (3 x 180ml and 1 x 140ml) and the combined filtrates and washings were concentrated under reduced pressure to a red gum. This was redissolved in IMS (1000ml) 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 (350ml) .
Meanwhile, a mixture of triethylorthoformate (900ml) and tetrahydrofuran (THF) (400ml) was prepared and cooled to 0 to 5°C. Concentrated hydrochloric acid (80ml) was added, maintaining the temperature between 0 and 10 °C, and more THF (100ml) was then added. To this mixture was added the IMS concentrate prepared above, which was rinsed in with IMS (100ml) . The mixture was warmed to 20 to 25°C and seeded with authentic (IS, 4R) -cis-4- [2- amino-6 -chloro-9H-purin-9-yl] -2 -cyclopentene-1-methanol hydrochloride salt and stirring continued for about 2Oh. 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 (117g, 82%) as a fawn coloured solid XH-NMR
(DMSO-d6)δ: 8.38(s, 1, purine CH) , 7.50(br m, ca 5, NH3 +, OH, HOD), 6.20 (m, 1, =CH) 5.94 (m, 1, =CH) , 5.49 (m, 1, NCH) , 3.46(m, 2, OCH2) , 2.91(br m, 1, CH) , 2.70-2.60(m,
1, CH) , 1.75-1.66(m, 1, CH) .
Example B
Preparation of (IS, 4R) -cis.-4- [2-amino-6-chloro-9H-purin- 9-yl] -2-cyclopentene-l-methanol hydrochloride salt.
A suspension of (1R, 4S) -c_is.- [4- (hydroxymethyl) -2- cyclopentene-1-yl] carbamic acid, 1, 1-dimethylethyl ester (lOOg) in industrial methylated spirit (IMS) (600ml) was treated with concentrated hydrochloric acid (48ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5h. Heating under reflux was maintained for about 3h. The solution was cooled to 20 to 25°C and sodium bicarbonate (103.4g) was added followed by N- (2-amino-4 , 6-dichloro-5- pyrimidinyl) formamide (W095/21161) (97g) and IMS (600ml) . The suspension was heated under reflux for about 4h and then cooled to about -5°C. After stirring at this temperature for about lh, the solids were filtered off and washed with IMS (2 x 100ml) . The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 400ml. This was redissolved in IMS (1000ml) 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 (350ml) . Meanwhile, triethylorthoformate (900ml) was cooled to 0 to 5°C and concentrated hydrochloric acid (80ml) 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 (600ml) . The mixture was warmed to 20 to 25°C and seeded with authentic (1S,4R) -cis-4- [2-amino-6-chloro-9H-purin-9- ylj -2-cyclopentene-l-methanol hydrochloride salt and stirring was continued for about 7h. The slurry was filtered, and the solid was washed with IMS (2 x 150ml) and dried in vacuo at 40 to 45°C to give the title compound (114g, 81%) as a fawn coloured solid, spectroscopically identical to the product of Example A.
Example C
Preparation of (1S.4R) -cis-4- r2-amino-6-chloro-9H-purin- 9-yl] -2-cyclopentene-l-methanol hydrochloride salt.
A suspension of (1R, 4S) -cis.- [4- (hydroxymethyl) -2- cyclopentene-1-yl] carbamic acid, 1, 1-dimethylethyl ester (72.5kg) in industrial methylated spirit (IMS) (435L) and water (about 200L) was treated with concentrated hydrochloric acid (36.5L, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 1.5h. Heating under reflux was maintained for about 2h. The solution was cooled to 20 to 25°C and sodium bicarbonate (75kg) was added followed by N- (2-amino-4, 6-dichloro-5-pyrimidinyl) formamide
(W095/21161) (70kg) and IMS (435L) . The suspension was heated under reflux for about 4h and then cooled to about -5°C. After stirring at this temperature for about lh, the solids were filtered off and washed with IMS (2 x 144L) . The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 290L. This was diluted with IMS (about 300L) and the solution was concentrated under reduced pressure to a residual volume of about 290L. The dilution and re-concentration were repeated twice more, and the final concentrate was diluted with IMS (610L) and heated to about 35-40°C. The resultant mixture was filtered and the solids were washed with IMS (2 x 144L) . The combined filtrates and washings were concentrated under reduced pressure to a residual volume of about 290L and then diluted with IMS (217L) .
Meanwhile, a mixture of triethylorthoformate (660L) , concentrated hydrochloric acid (58L) and IMS (72L) 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 72L) . The mixture was warmed to 20 to 25°C and seeded with authentic (IS, 4R) -c_is.-4- [2-amino-6-chloro- 9H-purin-9-yl] -2-cyclopentene-1-methanol hydrochloride salt and stirring was continued for about 7h. The slurry was cooled to 18 - 21°C, filtered, and the solid was washed with IMS (72L and 217L) and dried in vacuo at 40 to 45°C to give the title compound (81.7kg, 79.5%) as a fawn coloured solid, spectroscopically identical to the product of Example A.
Example D
Preparation of (1S,4R) -≤is.-4- [2-amino-6-chloro-9H-purin- 9-yl] -2 -cyclopentene-1-methanol hydrochloride salt.
A suspension of (1R, 4S) -c_is.- [4- (hydroxymethyl) -2- cyclopentene-1-yl] carbamic acid, 1, 1-dimethylethyl ester (lOg) in industrial methylated spirit (IMS) (60ml] was treated with concentrated hydrochloric acid (5ml, 1.2 molar equivalents) and the resultant solution was heated to the boil over about 0.5h. Heating under reflux was maintained for about 3h. The solution was cooled to 20 to 25°C and weighed (45.7g) . A portion (14g) was diluted with IMS (14ml) and sodium bicarbonate (3.1g) was added followed by 2, 5-diamino-4, 6- dichloropyrimidine (W095/21161) (2.0g). The suspension was heated under reflux for about 7h 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 (17ml) .
Meanwhile, triethylorthoformate (21.4ml) was cooled to 0 to 5°C and concentrated hydrochloric acid (1.9ml) 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 2.5ml) . 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-l-methanol hydrochloride salt and stirring was continued for about 19h. The slurry was filtered, and the solid was washed with IMS (2 x 4.5ml) and dried in vacuo at 40 to 45°C to give the title compound (2.06g, 61%) as a pale yellow solid, spectroscopically identical to the product of Example A.

Claims

Claims :
1. A process for the preparation of a compound of formula (I) ,
Figure imgf000016_0001
optionally in the form of its salt or complex, which comprises hydrolysing a compound of formula (IV)
Figure imgf000016_0002
wherein P is a protecting group, in the presence of an acid, condensing the product of formula (V) formed
Figure imgf000016_0003
in situ in the presence of a base with a compound of formula (VI)
Figure imgf000016_0004
in which R represents CHO or H, followed by ring closure in situ of the resulting intermediate of formula (VII)
Figure imgf000017_0001
H20H (VII) in which R represents CHO or H, to produce a compound of formula (I) , which can then be optionally reacted with an acid or complexing agent to form its salt or complex.
2. A process as claimed in claim 1 wherein R is CHO.
3. A process as claimed in claim 1 or claim 2 wherein P is an acyl or substituted oxycarbonyl group.
4. A process as claimed in claim 3 wherein P is a formyl , C1_4-alkanoyl group or oxycarbonyl group of formula R'OC(O) wherein R' is alkyl or aralkyl.
5. A process as claimed in claim 4 wherein P is an acetyl group or R' is tert butyl or benzyl.
6. A process as claimed in any of the preceding claims wherein the hydrolysis step is carried out in an alkanol, a cyclic ether or a chlorinated hydrocarbon in the presence of an organic or mineral acid.
7. A process as claimed in claim 6 wherein the hydrolysis step is carried out in IMS and the acid is trifluoroacetic acid or hydrochloric acid.
8. A process as claimed in any one of the preceding claims wherein the condensation reaction is carried out under reflux in a polar solvent in the presence of base .
9. A process as claimed in claim 8 wherein the polar solvent is an alcohol, water or acetonitrile and the base is a trialkylamine or an alkali metal carbonate or bicarbonate .
10. A process as claimed in claim 9 wherein the base is potassium or sodium carbonate or sodium bicarbonate.
11. A process as claimed in any of the preceding claims wherein the ring closure reaction is carried out using a trialkylorthoformate in the presence of a mineral acid and optionally one or more non-aqueous solvents.
12. A process as claimed in claim 11 wherein the ring closure reaction is carried out using triethylorthoformate in the presence of hydrochloric acid.
13. A process as claimed in claim 11 wherein the non- aqueous solvent is tetrahydrofuran, ethyl acetate or IMS.
14. A process substantially as described in any of the preceding claims with reference to the Examples .
PCT/GB1998/003080 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates WO1999019327A1 (en)

Priority Applications (24)

Application Number Priority Date Filing Date Title
DE69818084T DE69818084T2 (en) 1997-10-14 1998-10-14 METHOD FOR PRODUCING CHLOROPURINE INTERMEDIATE PRODUCTS
AU95476/98A AU738462B2 (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
US09/529,385 US6646125B1 (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
JP2000515898A JP4531250B2 (en) 1997-10-14 1998-10-14 Synthetic method of chloropurine intermediate
APAP/P/2000/001790A AP1182A (en) 1997-10-14 1998-10-14 Proces for the synthesis of chloropurine intermediates.
HU0003984A HUP0003984A3 (en) 1997-10-14 1998-10-14 Process for synthesis of carbocyclyc chloropurine nucleoside analogues
KR1020007003921A KR100543845B1 (en) 1997-10-14 1998-10-14 Process for the Synthesis of Chloropurine Intermediates
SI9830556T SI1023292T1 (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
NZ503679A NZ503679A (en) 1997-10-14 1998-10-14 Preparation of (lB,4R)-cis-4- [2-amino-6-chloro-9R-purin- 9-yl] -2-cyclopentene-1-methanol hydrochloride salt.
UA2000031789A UA54550C2 (en) 1997-10-14 1998-10-14 a process FOR CHLORPURINE INTERMEDIATES SYNTHESIS
AT98949093T ATE249461T1 (en) 1997-10-14 1998-10-14 METHOD FOR PRODUCING CHLOROPURINE INTERMEDIATE PRODUCTS
IL13532398A IL135323A (en) 1997-10-14 1998-10-14 Process for the synthesis of 4-[2-amino-6-chloro-9h-purine-9-yl]-2-cyclopentene-1-methanol
SK536-2000A SK285331B6 (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
PL98339904A PL188477B1 (en) 1997-10-14 1998-10-14 Method of synthesising intermediate chloropurin compounds
CA002306958A CA2306958C (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
BRPI9813048-0A BR9813048B1 (en) 1997-10-14 1998-10-14 process for the preparation of a compound.
EA200000318A EA003183B1 (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
EP98949093A EP1023292B1 (en) 1997-10-14 1998-10-14 Process for the synthesis of chloropurine intermediates
DK98949093T DK1023292T3 (en) 1997-10-14 1998-10-14 Process for the synthesis of chlorpurin intermediates
EEP200000162A EE04059B1 (en) 1997-10-14 1998-10-14 Method for the synthesis of chloropurine intermediates
IS5423A IS2195B (en) 1997-10-14 2000-03-28 Method of synthesis of chloropurine intermediates
NO20001896A NO325030B1 (en) 1997-10-14 2000-04-12 Process for the preparation of chlorpurine intermediates
HR980147A HRP20000216B1 (en) 1997-10-14 2000-04-14 Process for the synthesis of chloropurine intermediates
HK00106983A HK1027807A1 (en) 1997-10-14 2000-11-02 Process for the synthesis of chloropurine intermediates

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9721780.6 1997-10-14
GBGB9721780.6A GB9721780D0 (en) 1997-10-14 1997-10-14 Process for the synthesis of chloropurine intermediates

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FR2849030A1 (en) * 2002-12-20 2004-06-25 Isochem Sa Pure N-(2-amino-4,6-dihalo-pyrimidin-6-yl)-formamide production, for use as intermediate for nucleotide antiviral agents, from corresponding diamine, formic acid and acetic anhydride
US7557209B2 (en) 2003-09-04 2009-07-07 Glaxo Group Limited Process for the preparation of (1S,4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol

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CN100465174C (en) * 2006-06-13 2009-03-04 中国科学院上海有机化学研究所 Process for preparing optics pure abacavir
KR101109476B1 (en) * 2009-06-26 2012-01-31 현대제철 주식회사 Jig device for changing cylinder
MX356891B (en) 2010-01-27 2018-06-19 Viiv Healthcare Co Antiviral therapy.
CN104672239A (en) * 2013-11-26 2015-06-03 上海迪赛诺化学制药有限公司 Process for preparing abacavir intermediate in formula V by adopting one-pot method

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US6448402B2 (en) * 1997-11-27 2002-09-10 Lonza Ag Process for the preparation of aminoalcohol derivatives and their further conversion to (1R, 4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino)-2-cyclopentenyl-1-methanol
EP1418170A2 (en) * 1997-11-27 2004-05-12 Lonza AG Process for the preparation of optically active amino alcohols by optical resolution
EP1418170A3 (en) * 1997-11-27 2004-05-19 Lonza AG Process for the preparation of optically active amino alcohols by optical resolution
EP1508565A1 (en) * 1997-11-27 2005-02-23 Lonza AG Process for the preparation of optically active aminoalcohols
US7229981B2 (en) 1997-11-27 2007-06-12 Lonza Ag Process for the preparation of aminoalcohol derivatives and their further conversion to (1R,4S)-4-(2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino)-2-cyclopentenyl-1-methanol
US7338945B2 (en) 1997-11-27 2008-03-04 Lonza Ag Process for the preparation of aminoalcohol derivatives and their further conversion to (1R, 4S)-4(2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino-2-cyclopentenyl-1-methanol
US7358073B2 (en) 1997-11-27 2008-04-15 Lonza Ag Process for the preparation of aminoalcohol derivatives and their further conversion to (1R, 4S)-4(2-amino-6-chloro-5-formamido-4- pyrimidinyl)-amino-2-cyclopentenyl-1-methanol
FR2849030A1 (en) * 2002-12-20 2004-06-25 Isochem Sa Pure N-(2-amino-4,6-dihalo-pyrimidin-6-yl)-formamide production, for use as intermediate for nucleotide antiviral agents, from corresponding diamine, formic acid and acetic anhydride
US7557209B2 (en) 2003-09-04 2009-07-07 Glaxo Group Limited Process for the preparation of (1S,4R)-cis-4-[2-amino-6-chloro-9H-purin-9-yl]-2-cyclopentene-1-methanol

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