WO2012115578A1 - Synthèse de flg - Google Patents

Synthèse de flg Download PDF

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Publication number
WO2012115578A1
WO2012115578A1 PCT/SE2012/050183 SE2012050183W WO2012115578A1 WO 2012115578 A1 WO2012115578 A1 WO 2012115578A1 SE 2012050183 W SE2012050183 W SE 2012050183W WO 2012115578 A1 WO2012115578 A1 WO 2012115578A1
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WO
WIPO (PCT)
Prior art keywords
dideoxy
fluoro
phenylbenzoyl
chloride
base
Prior art date
Application number
PCT/SE2012/050183
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English (en)
Inventor
Genadiy Kalayanov
Original Assignee
Medivir Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medivir Ab filed Critical Medivir Ab
Priority to KR1020137024651A priority Critical patent/KR20140007443A/ko
Priority to CN2012800078630A priority patent/CN103347871A/zh
Priority to JP2013555388A priority patent/JP2014506593A/ja
Publication of WO2012115578A1 publication Critical patent/WO2012115578A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • This invention relates to the field of nucleoside synthesis and in particular to the synthesis of 2',3'-dideoxy-3 '-fluororibosides useful in the preparation of the antiviral 2',3'-dideoxy-3 '- fluoroguanosine and its prodrugs.
  • WO88/00050 discloses the antiviral properties of a family of 2',3'-dideoxynucleosides, notably 2',3'-dideoxy-3 '-fluorothymidine FLT and 2',3'-dideoxy-3'-fluoroguanosine, FLG.
  • WO99/09031 and W099/41268 disclose prodrugs of FLG and their use in the treatment of hepatitis B and HIV infections.
  • a preferred prodrug is 2',3'-dideoxy-3 '-fluoro-5'-0-[S-2-(L- valyloxy)propionyl]guanosine, that is comprising an L-amino acid and an L-lactic acid prodrug moiety.
  • R H or OH
  • Herdiwijn et al describes in J. Med. Chem. 1988, 31, 2040-2048 the preparation of 2',3'- dideoxy-3'-fluoroguanosine according to method (a) by treatment of the corresponding arabinonucleoside (3 -OH) with (diethylamido)sulfur trifluoride (DAST) in dichloromethane.
  • DAST diethylamidosulfur trifluoride
  • EP 450 585 describes an extensive series of schemes to prepare 2-deoxy-threopentofuranosides and 3'-substituted-2-deoxyerythropentofuranosides. They disclose, inter alia the condensation of a base with an intermediate of the formul
  • R 7 is pivaloyl, triphenylmethyl, tert-butyldimethylsilyl, isobutyloxycarbonyl or tetrahydropyranyl
  • X is halogen, azido, cyano or thiocyanato and X is halo.
  • Pivaloyl is the favoured R 7 group.
  • EP625 158 discloses attempts to enhance stereospecificity at the -position during the synthesis of 2',3'-dideoxy-3 '-fluoroguanosine analogues, whereby the guanine base displaces the uracil base of 2'3'-dideoxy-3 '-fluorouridine under the action of purine nucleoside phosphorylase and thymidine phosphorylase.
  • This process with reaction times typically around 30 days, is not suitable for large scale production and the use of enzymes in a latter step is problematic from the point of view of product purification and pyrogenesis.
  • JP2002-293790 discloses a route to 2,3-dideoxy -3-fluoro-5-0-(4-phenylbenzoyl)-a-D- erythropentofuranosyl chloride using a two step procedure.
  • the synthesis starts by acetolys of methyl 2,3-dideoxy-3-fluoro-5-0-(4-phenylbenzoyl)-erythropentofuranoside yielding an ⁇ / ⁇ - mixture of the corresponding 1-0 Ac derivative, followed by transformation into the
  • the thus formed 1- chloro sugar can then be further transformed into another glycosyl donor and subsequently coupled to a desired base, or be used directly in the coupling with the base.
  • the method disclosed in JP2002-293790 is not leading to an anomerically pure glycosyl donor that can be used without separation of the two anomers in the synthesis of anomerically pure 3'- fluoronucleosides, such as FLG.
  • R alkyl e.g. Me, or Ac
  • X halide, e.g. CI, or OP0 3 H Nucleoside,
  • Desired nucleoside undesired anomer i) Transformation of sugar intermediate into a glycosyl donor,
  • a halide such as a chloride, or a phosphate
  • a key subject for achieving the desired anomeric configuration in the formed nucleoside is the requirement of using an anomerically pure glycosyl donor, such as the a-chloride of the sugar.
  • an anomerically pure glycosyl donor such as the a-chloride of the sugar.
  • this requirement is alleged to be dependent on the use of an anomerically pure sugar intermediate, such as the pure a-methyl glycoside, which in turn means that tedious and material consuming separation, typically by chromatography, of an ⁇ / ⁇ -mixture of a 2,3- dideoxy-3-fluoro sugar intermediate is necessary prior to formation of the glycosyl donor, in which separation compound having the undesired anomeric configuration is discarded.
  • an objective of the present invention is to provide an improved process for the preparation of 2',3'-dideoxy -3- fluoronucleosides, especially 2',3'-dideoxy -3 '-fluoroguanidine.
  • the present invention provides a method for the preparation of an anomerically pure glycosyl donor wherein a mixture of the ⁇ / ⁇ -anomers of the intermediate methyl glycoside is used in the formation of an anomerically pure glycosyl donor, without the requirement of separation of a mixture of ⁇ / ⁇ - anomers.
  • the thus afforded glycosyl donor can then be used in the formation of anomerically pure 2',3'-dideoxy -3 '-fluoronucleosides, such as 2',3'-dideoxy -3-fluoroguanidine.
  • a first aspect of the invention provides a method for the synthesis of substantially anomerically pure 2,3-dideoxy -3-fluoro-5-0-(4-phenylbenzoyl)-a-D-erythropentofuranosyl chloride (lb) using the corresponding methyl glycoside, i.e. methyl 2,3-dideoxy -3-fluoro-5-0- (4-phenylbenzoyl)-a-D-erythropentofuranoside (la) as starting compound, characterised in that a mixture of the a- and ⁇ -anomers of the methyl glycoside (la) is used.
  • the a-chloride is formed as shown in Scheme 2.
  • Substantially anomerically pure in this instance means >90% or preferably > 95% such as 99% anomeric purity, i.e. a ratio of the a- and ⁇ -anomer ⁇ : ⁇ of >90: 10 or preferably > 95:5 such as >99: 1.
  • the ratio of the a- and ⁇ -anomers of the methyl glycoside (la) ⁇ : ⁇ is between 30:70 and 70:30.
  • the conversion of methyl glycoside to the corresponding a-chloride is performed in an ether solvent, such as diethyl ether or diisopropyl ether or the like.
  • an ether solvent such as diethyl ether or diisopropyl ether or the like.
  • the conversion is performed in diisopropyl ether.
  • Suitable reagents for the chlorination include HC1, Cl 2 , boron chloride, magnesium chloride, aluminium chloride, trialkylsilyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, sulphuryl chloride, titanium tetrachloride, zinc chloride, acetyl chloride, and mixtures thereof.
  • the chlorination is performed by treatment of methyl glycoside (la) with HC1 (g).
  • HC1 g
  • the method of the invention allows formation of crystalline 2,3-dideoxy-3-fluoro-5-0-(4- phenylbenzoyl)- a-D-erythropentofuranosyl chloride (lb) without any need of column chromatography, which leads to improvements in yield, synthesis time and overall economy.
  • the method of the invention provides a route to 2',3'-dideoxy-3 '-fluoro nucleosides without the need of separation of anomers as required in the prior art methods, as generally illus rated in Scheme 3.
  • the invention provides a method for the preparation of FLG, starting from an anomeric mixture of the sugar intermediate methyl 2,3-dideoxy -3-fluoro-5-0-(4- phenylbenzoyl)-a-D-erythropentofuranoside (la), and further comprising the step of coupling of an optionally protected guanine base with 2,3-dideoxy -3-fluoro-5-0-(4-phenylbenzoyl)-a-D- erythropentofuranosyl chloride (lb) to provide 2-acetamino-6-chloro-9-(2', 3'-dideoxy-3'- fluoro-5'-0-(4-phenylbenzoyl)- -D-erythropentafuranosyl)-9H-purine (lc), followed by deprotection and oxidation, wherein the coupling step is effected by a non-enzymatic method.
  • the 2-amine function of the guanine base is protected with a conventional amine protecting group, most preferably acetyl.
  • the 6 position of the guanine derivative preferably comprises a chloro residue which is oxidised to the guanine keto function contemporaneously with deprotection.
  • the guanine base is 2-acetamido-6-chloro-9H-purine.
  • the sugar intermediate la can be prepared e.g. from the corresponding 3-hydroxy compound by fluonnation of the 3-position according to the method described in C. Bull. Soc. Chim. Fr., 1995, 132, 149.
  • the 3-fluoro compound la can be achieved from the corresponding 5-0- pivaloyl protected compound, which is disclosed in EP625158, by simply replacing the 5-0- pivaloyl group with the desired 4-phenylbenzoyl according to standard techniques.
  • the pivaloyl group can be removed by treatment with base such as sodium methoxide in methanol or equivalent, followed by acylation of the 5-hydroxy group with an activated derivative of 4-phenylbenzoyl, such as the chloride or the like.
  • the sparingly soluble purine base may be pretreated with trimethylsilyl derivatives prior to coupling (for example by reaction with hexamethyldisilazane/NH 4 S0 4 in dioxane under reflux under N 2 ) as is conventional in the nucleoside art.
  • the purine base is reacted as the salt, for example the sodium salt or more preferably the potassium salt.
  • An alternative would be the phosphazonium salt as shown in WO 00/08025.
  • Suitable solvents for the coupling reaction include organic solvents such as acetonitrile, dioxane/CH 2 Cl 2 , DMSO, THF.
  • a preferred solvent is DMF.
  • the product 2-amino-6-chloro-9-(2',3'-dideoxy-3'-fluoro-5'-0-(4-phenylbenzoyl)- - D-erythropentafuranosyl)-9H-purine obtained according to the method of the invention is usable in a following step without intervening column chromatography.
  • the method of the invention may further comprise one or more crystallisations during work up following the coupling.
  • Convenient solvents for such crystallisation include acetic acid, ethyl acetate, methanol and acetone, optionally in conjunction with a conventional filter aid.
  • N-protected-2-amino -6-chloro-9-(2',3'-dideoxy-3'-fluoro-5'-0-(4-phenylbenzoyl)- -D- erythropentafuranosyl)-9H-purine prepared by the method of the invention is deprotected at the 2 and 5' positions by conventional techniques, such as reaction with sodium methylate, to release FLG.
  • the FLG may subsequently be esterified at the 5'-position to form an FLG prodrug using conventional techniques, for example a DCC/DMAP coupling agent in conjunction with a carboxylic acid.
  • esterification comprises reaction with an activated L-lactic acid derivative, for example S-2-0-(N-protected-L-valyloxy)propionic acid as shown in
  • Nucleoside lc (1 g, 1 eq) was charged under stirring in one portion into a reactor containing ethanol (7 ml), 2-mercaptoethanol (0.54 ml, 4.66 eq) and sodium methoxide (0.378 g, 3.57 eq). The reaction mixture was refluxed for 4 hours and then cooled to room temperature. The sodium salt of the title compound was filtered off and the filter cake was carefully washed with ethanol (6.1 ml). The filter cake was transferred back into the reactor and the reactor was charged with ethanol (7.9 ml), water (2.65 ml) and acetic acid (0.075 ml, 0.8 eq).
  • the reaction mixture was stirred for -30 minutes at room temperature and the pH-value was checked no to be below 7.
  • the solid was filtered off and washed with a mixture of ethanol/water 3/1 (2.83 ml). As soon as the aqueous ethanol washing solution was below the surface of the filter cake, washing was continued with pure ethanol (1.44 ml). The afforded product was dried under vacuum in an oven at 87 ° C overnight.
  • the title compound as obtained as a white solid (0.395 g, 75 %).
  • FLG was prepared by coupling of the "optimal" sugar intermediate of the above cited EP 450 585, namely methyl-5'-0-pivaloyl-2',3'-D-erythropentofuranoside to 2-acetamido-6- chloropurine.
  • 2-acetamido-6-chloropurine base (15.0 g, 70.9 mmol) was solubilised as the bis-trimethylsilane, analogously to the bis-trimethylsilylated pyrimidine base in Example 53 of EP 540 585.
  • the yield of the coupling reaction in Comparative Example 1 is 25-33%) which should be compared to the 48 %> yield of FLG when prepared according to the present invention, as illustrated in Example 1 above. Furthermore, it should be noted that column chromatography is needed in the conventional technique, in contrast to when FLG is prepared according to the method of the present invention and, even more important, in the method of the present invention the ⁇ / ⁇ -mixture of the methyl glycoside 1 is used, whereas in Comparative Example 1 the pure a -anomer is used, implying that a step of separation of the a- and ⁇ -anomers has to be performed prior to coupling to the base, a separation in which approximately 50% of the 2-F-sugar intermediate is discarded, namely the part having the undesired ⁇ -anomeric configuration.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention porte sur la synthèse de chlorure de 2,3-didésoxy-3-fluoro-5-O-(4-phénylbenzoyl)-α-D-érythropentofuranosyle pratiquement pur de point de vue des anomères à partir d'un mélange α/β du méthylglycoside correspondant. Le procédé de l'invention permet de produire le chlorure α pur sans avoir besoin de séparer les anomères. Le chlorure α ainsi obtenu est approprié pour être utilisé comme donneur de glycosyle dans la préparation de 2',3'-didésoxy-3'-fluoronucléosides. En particulier, l'invention porte sur la préparation de 2',3'-didésoxy-3'-fluoroguanosine, FLG, à l'aide d'un mélange α/β du méthylglycoside sans avoir besoin de séparer les anomères.
PCT/SE2012/050183 2011-02-21 2012-02-20 Synthèse de flg WO2012115578A1 (fr)

Priority Applications (3)

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KR1020137024651A KR20140007443A (ko) 2011-02-21 2012-02-20 Ｆｌｇ의 합성
CN2012800078630A CN103347871A (zh) 2011-02-21 2012-02-20 Flg的合成
JP2013555388A JP2014506593A (ja) 2011-02-21 2012-02-20 Ｆｌｇの合成

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SE1150142-6 2011-02-21
SE1150142 2011-02-21

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KR (1) KR20140007443A (fr)
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009031A1 (fr) * 1997-08-15 1999-02-25 Medivir Ab Analogues de nucleosides tels que des antiviraux y compris des inhibiteurs de transcriptase inverse retrovirale et l'adn polymerase du virus de l'hepatite b(hbv)
WO1999041275A1 (fr) * 1998-02-13 1999-08-19 Medivir Ab Promedicaments
WO2004087140A1 (fr) * 2003-03-27 2004-10-14 Boehringer Ingelheim International Gmbh Combinaison antivirale d'une dipyridodiazepinone et compose antiretroviral
WO2004087169A1 (fr) * 2003-03-27 2004-10-14 Boehringer Ingelheim International Gmbh Combinaison antivirale de nevirapine et d'un autre compose antiretroviral
WO2007092326A2 (fr) * 2006-02-03 2007-08-16 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, Centers For Disease Control And Prevention Inhibition de l'infection par le vih par chimioprophylaxie

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002293790A (ja) * 2001-03-30 2002-10-09 Mitsui Chemicals Inc フッ化糖クロリド誘導体の製造法
CN101376667B (zh) * 2007-08-27 2011-01-12 上海迪赛诺医药发展有限公司 一种合成齐多夫定的中间体及其制备方法和该中间体在合成齐多夫定中的应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999009031A1 (fr) * 1997-08-15 1999-02-25 Medivir Ab Analogues de nucleosides tels que des antiviraux y compris des inhibiteurs de transcriptase inverse retrovirale et l'adn polymerase du virus de l'hepatite b(hbv)
WO1999041275A1 (fr) * 1998-02-13 1999-08-19 Medivir Ab Promedicaments
US7825238B2 (en) * 1998-02-13 2010-11-02 Medivir Ab Antiviral methods employing double esters of 2′, 3′-dideoxy-3′-fluoroguanosine
WO2004087140A1 (fr) * 2003-03-27 2004-10-14 Boehringer Ingelheim International Gmbh Combinaison antivirale d'une dipyridodiazepinone et compose antiretroviral
WO2004087169A1 (fr) * 2003-03-27 2004-10-14 Boehringer Ingelheim International Gmbh Combinaison antivirale de nevirapine et d'un autre compose antiretroviral
WO2007092326A2 (fr) * 2006-02-03 2007-08-16 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, Centers For Disease Control And Prevention Inhibition de l'infection par le vih par chimioprophylaxie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUGLIELMI, H. ET AL.: "Imidazole nucleosides, V. Synthesis of 3'-fluoro-3'-deoxy-ribofuranosides of 4(5)-amino-imidazole- 5(4)carboxamide. Zeitschrift fur Naturforschung - Section B", JOURNAL OF CHEMICAL SCIENCES, vol. 54, no. 8, 1999, pages 1055 - 1060 *
KOMATSU, H. ET AL.: "Chemo-enzymatic synthesis of 2','3- dideoxy-3'-fluoro-beta-D-guanosine via 2,3-dideoxy-3-fluoro- alfa-D-ribose 1-phosphate.", TETRAHEDRON LETTERS, vol. 44, 2003, pages 2899 - 2901 *
TORII, T. ET AL.: "Synthesis of 6-arylthio analogs of 2',3'- dideoxy-3'- fluoroguanosine and their effect against hepatitis B virus replication.", NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS, vol. 25, no. 4-6, 2006, pages 655 - 665 *

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JP2014506593A (ja) 2014-03-17
CN103347871A (zh) 2013-10-09
KR20140007443A (ko) 2014-01-17

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