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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D317/34—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
  • C07D473/32—Nitrogen atom

Definitions

• the present invention relates to a process for, producing dioxolane nucleoside analogues and their precursors.
• Nucleoside analogues are an important class of therapeutic agents. More particularly, dioxolane nucleoside analogues in which a substituted 1,3-dioxolane is replacing the carbohydrate found in natural nucleoside have shown to have biological activity.
• DAPD and troxacitabine are currently in clinical development.
• the present invention relates to a process conducted in a single reaction vessel for producing a dioxolane nucleoside analogue of formula I or a pharmaceutically acceptable salt thereof; the process comprising the steps of adding:
• a process for producing a dioxolane compound of formula III comprising the step of reacting a dioxolane compound of formula IV in a suitable solvent; in the presence of DIB and I 2 , wherein said process is conducted using a suitable source of energy; wherein R 10 is an hydroxyl protecting group.
• the present invention relates to a process conducted in a single reaction vessel for producing a dioxolane nucleoside analogue of formula I or a pharmaceutically acceptable salt thereof; the process comprising the steps of adding:
• alkyl represents an unsubstituted or substituted (e.g. by a halogen, nitro, CONH 2 , COOH, O—C 1-6 alkyl, O—C 2-6 alkenyl, O—C 2-6 alkynyl, hydroxyl, amino, or COOQ, wherein Q is C 1-6 alkyl; C 2-6 alkenyl; C 2-6 alkynyl) straight chain, branched chain or cyclic hydrocarbon moiety (e.g. isopropyl, ethyl, fluorohexyl or cyclopropyl).
• alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably, the halogen is fluoro (e.g. CF 3 — or CF 3 CH 2 —).
• alkenyl and alkynyl represent an alkyl containing at least one unsaturated group (e.g. allyl).
• alkoxy represents an alkyl which is covalently bonded to the adjacent atom through an oxygen atom.
• aryl represents an unsaturated carbocyclic moiety, optionally mono- or di-substituted with OH, SH, amino, halogen or C 1-6 alkyl.
• arylalkyl represents an aryl group attached to the adjacent atom by a C 1-6 alkyl (e.g., benzyl).
• aryloxy represents an aryl which is covalently bonded to the adjacent atom through an oxygen atom.
• acyl is defined as a radical derived from a carboxylic acid, obtained by replacement of the —OH group. Like the acid to which it is related, an acyl radical may be straight chain, branched chain or cyclic aliphatic or aromatic, substituted (e.g.
• acyl includes acetyl, propionyl, pivaloyl, hexanoyl, trifluoroacetyl, cyclohexanoyl and benzoyl.
• acyloxy is defined as an acyl group attached to the adjacent group by an oxygen atom (e.g. acetoxy, benzoyloxy).
• cycloalkyl represents an “alkyl” as defined above which forms a ring (e.g. Cyclopropyl, cyclopentyl or cyclohexyl).
• cycloalkylamino represents a cycloalkyl which is covalently bonded to the adjacent atom through a nitrogen atom.
• hydroxyl protecting group is well known in the field of organic chemistry. Such protecting groups may be found in T. Greene, Protective Groups In Organic Synthesis , (John Wiley & Sons, 1981). Example of hydroxy protecting groups include but are not limited to benzyl, acetyl, benzoyl, pivaloyl and isopropyloxycarbonyl.
• a “dioxolane ring” is any substituted or unsubstituted five member monocyclic ring that has an oxygen in the 1 and 3 positions of the ring as illustrated below:
• Halogens are chosen from F. Cl, I, and Br.
• purine or pyrimidine or an analogue is meant to be a purine or pyrimidine base found in a nucleotide-or an analogue thereof which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the normal bases but may possess additional or lack certain of the functional properties of the normal bases.
• analogues include those derived by replacement of a CH moiety by a nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine) or vice versa (for example 7-deazapurines, such as 7-deazaadenosine or 7-deazaguanosine) or both (e.g. 7-deaza, 8-azapurines).
• Analogues of such bases also include those compounds wherein ring substituents are either incorporated, removed or modified by conventional substituents known in the art e.g. halogen, hydroxyl, amino, C 1-6 alkyl.
• ring substituents are either incorporated, removed or modified by conventional substituents known in the art e.g. halogen, hydroxyl, amino, C 1-6 alkyl.
• purine or pyrimidine bases, analogues and derivatives will be well known to those skilled in the art.
• TMSI means trimethylsilyl iodide
• HMDS hexamethyldisilazane
• DIB diacetoxy iodobenzene
• leaving group means a functional group that is cleaved from the parent molecule under the reaction conditions.
• single reaction vessel means the chemical reactions involved in the process are conducted in one vessel typically used for chemical synthesis.
• Lewis acid is well known in the field of nucleoside and nucleotide chemistry. Such Lewis acid may be found in Chemistry of NUCLEOSIDES AND NUCLEOTIDES Vol 1 and Vol 2., (Edited by LEROY B. TOWNSEND, 1988). Examples of a Lewis acid includes but are not limited to trimethylsilyl triflate and TMSI.
• suitable solvent means an inert organic solvent that will allow the process to occur under the reaction conditions (e.g. dichloromethane).
• suitable temperature means a temperature that will allow the process to occur under the reaction conditions, and provide the desired product without adversely affecting the reaction.
• suitable period of time means the time necessary for obtaining a sufficient chemical transformation of the starting material, obtaining the desired purity or the desired yield of the reaction product or a combination of those.
• the reaction can typically be monitored, if desired, by thin layer chromatography or high performance liquid chromatography (HPLC).
• TMSI can be obtained from a commercial source or be prepared readily from a number of precursor reagents (e.g. trimethylsilyl chloride and sodium iodide).
• precursor reagents e.g. trimethylsilyl chloride and sodium iodide.
• suitable source of energy means a source of energy useful to carry out the desired chemical process without adversely affecting the reaction.
• energy include but are not limited to light (e.g. daylight or tungsten lamp light) or heat.
• compound I, compound Ia, compound II, compound III and compound IV contain at least two chiral centers (at C-2 and C-4 of the dioxolane ring).
• the compounds can thus exist in the form of different optical isomers (R and S) and geometric isomers (cis and trans). All such optical isomers, geometric isomers and mixtures thereof, including racemic mixtures are included within the scope of the invention.
• the process of the present invention comprises those wherein the following embodiments are present, either independently or in combination.
• the Lewis acid is chosen from SnCl 4 , AlCl 3 , trimethylsilyl triflate, trimethylsilyl nonaflate, trimethylsilyl perchlorate, TMSI, TMSCl, TMSBr or TiCl 4 .
• the Lewis acids have the formula V:
• the Lewis acid is TMSI.
• L is chosen from acetoxy, benzoyloxy or iodide.
• L is acyloxy
• L is acetoxy
• L is benzoyloxy
• L is a halogen
• L is iodide
• R 1 is chosen from C 1-6 alkyl, C 6-12 aryl, C 6-12 arylalkyl, CO—- 1-6 alkyl, CO—C 1-6 alkoxy, CO—C 6-12 aryloxy, or CO—C 6-12 arylalkyl.
• R 1 is chosen from acetyl, pivaloyl, benzoyl or benzyl.
• R 1 is benzoyl
• the suitable temperature is about ⁇ 78° C. or warmer.
• the suitable temperature is about ⁇ 15° C. or warmer.
• the suitable temperature is about room temperature.
• the Lewis acid is TMSI, and said Lewis acid is used in a molar ratio of about 1.0 equivalent to about 2.0 equivalents with respect to the dioxolane of formula II.
• TMSI is used in a molar ratio of about 1.0 equivalent to about 1.5 equivalents with respect to the dioxolane of formula II.
• TMSI is used in a molar ratio of about 1.0 equivalent to about 1.2 equivalents with respect to the dioxolane of formula II.
• the process for producing a dioxolane nucleoside of formula I comprises the steps of:
• the silylating agent is chosen from HMDS, bis(trimethylsilyl)acetamide, TMSI, trimethylsilyl chloride, tButyl-dimethylsilyl trifluoromethanesulfonate or trimethylsilyl trifluoromethanesulfonate.
• the silylating agent is HMDS.
• the silylating agent is used in a molar ratio of about 1.0 equivalent to about 5.0 equivalents with respect to the purine and pyrimidine base R 2 .
• the silylating agent is used in a molar ratio of about 1.0 equivalent to about 2.5 equivalents with respect to the purine and pyrimidine base R 2 .
• the silylating agent is used in a molar ratio of about 1.0 equivalent to about 1.5 equivalents with respect to the purine and pyrimidine base R 2 .
• R 2 is chosen from: wherein;
• R 2 is chosen from:
• R 2 is:
• R 2 is:
• the process for producing a dioxolane nucleoside of formula I further comprises the step of removing the protecting group R 1 to produce a compound of formula Ia or a pharmaceutically acceptable salt thereof;
• a process for producing a dioxolane compound of formula III comprising the step of reacting a dioxolane compound of formula IV in a suitable solvent; in the presence of DIB and I 2 , wherein said process is conducted using a suitable source of energy; and wherein R 10 is an hydroxyl protecting group.
• the dioxolane compound of formula IV is added to a mixture of DIB and I 2 over a suitable period of time.
• the dioxolane compound of formula IV is added to a mixture of DIB, I 2 and acetic acid over a suitable period of time.
• R 10 is chosen from C 1-6 alkyl, C 6-12 aryl, C 6-12 arylalkyl, CO—C 1-16 alkyl, CO—C 1-6 alkoxy, C—C 6-12 aryloxy, or CO—C 6-12 arylalkyl.
• R 10 is chosen from acetyl, pivaloyl, benzoyl or benzyl.
• R 10 is benzoyl
• the suitable solvent for the process for producing a dioxolane compound of formula III is toluene or dichloromethane.
• the suitable solvent is dichloromethane.
• DIB is used in a molar ratio of about 1.0 equivalent to about 2.5 equivalents with respect to the dioxolane compound of formula III.
• DIB is used in a molar ratio of about 1.1 equivalent to about 1.5 equivalents with respect to the dioxolane compound of formula III.
• I 2 is used in a molar ratio of about 0.1 equivalent to about 1.0 equivalent with respect to the dioxolane compound of formula III.
• I 2 is used in a molar ratio of about 0.3 equivalent to about 0.5 equivalent with respect to the dioxolane compound of formula III.
• the suitable source of energy is light.
• the suitable source of energy is tungsten lamp light.
• the suitable source of energy is daylight.
• the suitable source of energy is heat.
• pharmaceutically acceptable salts of the compounds of formula I and formula Ia of the present invention are meant to include those compounds derived from pharmaceutically acceptable inorganic and organic acids and bases.
• suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.
• Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR 4 + (where R is C 1-4 alkyl) salts.
• alkali metal e.g. sodium
• alkaline earth metal e.g. magnesium
• ammonium e.g. sodium
• NR 4 + where R is C 1-4 alkyl
• Intermediate 1 can be prepared according to known procedures described in PCT publication number WO 00/39143 by NGUYEN-BA, Nghe et al. 6 Jul. 2000 and PCT publication number WO 00/47759 by CIMPOIA, Alex et al. 17 Aug. 2000.
• Cis 6-chloropurine dioxolane ⁇ (CDCl 3 ); 8.05 (s, 1H), 8.00 (d, 2H), 7.58 (m, 1H), 7.44 (m, 2H), 6.38 (d, 1H), 5.43 (t, 1H), 5.18 (bs, 2H), 4.68 (m, 3H), 4.31 (d of d, 1H): Cis 6-iodoropurine dioxolane ⁇ (DMSO); 8.13 (s, 1H), 7.82 (d, 2H), 7.68 (t, 1H), 7.52 (m, 2H), 6.92 (bs, 2H), 6.28 (d, 1H), 5.38 (t, 1H), 4.75 (d, 1H), 4.46 (m, 2H), 4.28 (m, 1H): Trans 6-chloropurine dioxolane ⁇ (CDCl 3 ); 8.08 (d, 2H), 7.95 (s, 1H), 7.60 (m, 1H), 7.47 (m, 2H), 6.43 (
• HMDS Hexamethyldisilazane
• HMDS 190 g, 1.18 moles
• 2-(R)-Benzoyloxymethyl-4-(R,S)-acetoxy-1,3-dioxolane 311 g, 1.17 moles
• dichloromethane 6.75 kg
• 2-amino-6-chloropurine 199 g, 1.17 moles
• TMSI trimethylsilyl iodide
• the reaction mixture is agitated at 19-25° C. for 19-24 hr.
• the reaction is checked by in-process TLC (2:1/hexane:ethyl acetate) for complete reaction.
• reaction mixture is heated at reflux for 1 hr.
• Aqueous 2% sodium thiosulfate solution (3.6 kg) is then added to the reaction mixture at 10-15° C. and agitated for 30-60 minutes.
• the reaction mixture is checked by in-process TLC (7:3 v/v ethyl acetate/hexane) for complete deprotection.
• Aqueous 10% sodium hydroxide solution (737 g) is added to the mixture to adjust the pH to 8-10.
• the organic layer is separated.
• the aqueous layer is extracted with dichlordmethane (750 g).
• the organic layers are combined, dried over magnesium sulfate (95 g) and filtered.
• the filter cake is washed with dichloromethane (750 g).
• the combined organic filtrate is distilled until distillation stops at 45-50° C.
• An in-process TDS is performed and the amount of dissolved solid (Q) calculated from the TDS value.
• Ethyl acetate (534 g) is added to the pot residue and distilled under partial vacuum at a maximum pot temperature of 50° C. The ethyl acetate distillation is repeated until a total of 1.3 ⁇ Q of ethyl acetate distillate is obtained.
• Toluene (700 g) is added to the pot residue. The mixture is agitated at 19-25° C. for 16-24 hours and at 0-5° C. for 2-3 hours. The precipitate is filtered and the filter cake washed with 10% ethyl acetate/hexane (300 g).
• the light yellow suspension obtained was stirred at ⁇ 15° C. (2 hours) and at 23° C. (20 hours) at which time TLC indicated that the reaction was completed.
• the mixture was diluted with methylene chloride (150 mL) and poured into water (200 mL). The mixture was vigorously stirred (3 hours) and the phases were separated. The organic phase was washed with aqueous 10% K 2 SO 4 (20 mL) and water (50 mL). The organic phase was evaporated to a brown residue. The residue was dissolved in methanol (200 ml). After stirring at 23° C. for 2 hours TLC showed that complete desilylation had occurred.
• Cis iodopurine dioxolane ⁇ (DMSO); 8.13 (s, 1H), 7.82 (d, 2H), 7.68 (t, 1H), 7.52 (m, 2H), 6.92 (bs, 2H), 6.28 (d, 1H), 5.38 (t, 1H), 4.75 (d, 1H), 4.46 (m, 2H), 4.28 (m, 1H): Trans iodopurine dioxolane ⁇ (DMSO); 8.22 (s, 1H), 8.00 (d, 2H), 7.68 (t, 1H), 7.52 (m, 2H), 6.92 (bs, 2H), 6.37 (m, 1H), 5.84 (m, 1H), 4.50 (m, 4H).
• Benzoic acid 4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester (2.4 kg, 6.3 moles) and methanol (6.24 L) were combined under inert atmosphere.
• 25% MeONa/MeOH (33.6 g) was added at room temperature and the reaction mixture was stirred for 16-24 hours.
• the reaction was monitored by HPLC for complete deprotection of the benzoate ester.
• the reaction mixture was cooled to 2° C. for 2 hours.
• the solids were collected by filtration and dried in vacuo to give the desired compound (1.2 kg, 71% yield).
• Benzoic acid 4(R)-(2-amino-6-chloro-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester (1266 g, cis/trans:1.9/1), ethanol (20 L), and cyclopropylamine (643 g) were refluxed for 16 hours.
• the reaction mixture was cooled and concentrated to a residue.
• the residue was dissolved in dichloromethane (3.6 L) and agitated with an aqueous solution of sodium bicarbonate for 30 minutes. After settling the organic layer was separated and the aqueous was back-extracted with dichloromethane (2 ⁇ 750 mL).
• the combined organic layers were concentrated to give a yellow-brown foam (1304 g) of material (9) which is suitable for reaction in the subsequent deprotection step in NH 3 /MeOH.
• Benzoic acid 4(R)-(2-amino-6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2(R)-ylmethyl ester crude (1304 g) was stirred with NH 3 /MeOH (20 L, 2M) for 20 hours at room temperature. Excess ammonia was removed by sparging nitrogen gas through the reaction mixture. The volatiles were removed in vacuo to give a black syrup which was further purified by column chromatography (MeOH/DCM:25/1) to give crude final product (910 g).
• Intermediate 7 can be prepared according to known procedures described in U.S. Pat. No. 6,022,876 by CHUNG, K. Chu et al Feb. 8, 2000 and U.S. Pat. No. 5,817,667 by CHUNG, K. Chu et al Oct. 6, 1998.
• the reaction was quenched slowly (keep batch temperature ⁇ 25° C.) with a solution of sodium thiosulfate pentahydrate (568 g, 2.29 mole, 1.09 eq) in water (4.0 L) and was stirred for 15 minutes. The layers were allowed to separate and the bottom organic phase was collected. The aqueous phase was back-extracted with dichloromethane (2 ⁇ 630 mL) and the organic phases were combined and dried over sodium sulfate.
• a solution of cis-acid (2.39 kg) in dichloromethane (4.2 kg) was added in 5 portions (each portion was added over 2 hours keeping the batch temperature less than 30° C.) to a solution of DIB (4.03 kg), iodine (1.06 kg) and acetic acid (1.50 kg) in dichloromethane (12.6 kg) in the presence of a 100 watt tungsten lamp.
• the reaction mixture was stirred until TLC showed the absence of starting material.
• the reaction was cooled to 15° C. and a solution of sodium thiosulfate (1.89 kg) in water (10.5 kg) was slowly added keeping the batch temperature below 25° C. The contents were stirred for 30 minutes.
• the reaction mixture was concentrated in vacuo to 1 ⁇ 2 the original volume (to 300 mL). Toluene (400 mL) was charged to the reaction mixture. The reaction mixture was further concentrated in vacuo to a final volume of 500 mL. The resulting slurry was cooled in an ice bath for 1 hour. The solids were filtered and were washed with ethyl acetate (2 ⁇ 75 mL). The solids were dried at room temperature under high vacuum until constant weight to yield cytosine-dioxolane (82.2 g, >99% yield, purity 99.64%).

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• 2003
  • 2003-01-23 AU AU2003236757A patent/AU2003236757B2/en not_active Expired
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