WO1998009964A1 - PROCEDE DE PREPARATION AMELIORE DE L'AGENT ANTIVIRAL [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENE-CYCLOPENTYL]-6-H-PURINE-6-ONE - Google Patents

PROCEDE DE PREPARATION AMELIORE DE L'AGENT ANTIVIRAL [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENE-CYCLOPENTYL]-6-H-PURINE-6-ONE Download PDF

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Publication number
WO1998009964A1
WO1998009964A1 PCT/US1997/015007 US9715007W WO9809964A1 WO 1998009964 A1 WO1998009964 A1 WO 1998009964A1 US 9715007 W US9715007 W US 9715007W WO 9809964 A1 WO9809964 A1 WO 9809964A1
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formula
equivalents
reaction
compound
reagent
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PCT/US1997/015007
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English (en)
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Gregory S. Bisacchi
Joseph E. Sundeen
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Bristol-Myers Squibb Company
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Priority to AU40906/97A priority Critical patent/AU4090697A/en
Publication of WO1998009964A1 publication Critical patent/WO1998009964A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • This invention is directed to improvements in several steps of the process disclosed by Zahler et al . in U.S. Patent 5,206,244 for preparing the antiviral agent of the formula
  • One improvement involves the step where the protected guanine substituted cyclopentanol compound of the formula (VI )
  • Pi is a trityl or substituted trityl protecting group such as monomethoxytrityl or 4, 4 ' -dimethoxytrityl is oxidized to the keto compound of the formula
  • the oxidation is achieved by reacting the cyclopentanol of formula VI with Dess-Martin periodinane having the formula
  • the keto compound of formula VIII is obtained in higher yields than in the process of example 1(g) of U.S. Patent 5,206,244.
  • Another improvement involves the step where the keto compound of formula VIII is converted to the methylene compound of the formula
  • methylenation of the keto group is achieved by use of the Nysted reagent having the formula
  • Patent 5,206,244 the antiviral agent of formula I is prepared by treating the cyclopentenol of the formula
  • the epoxide of formula III can then be treated to introduce a benzyl protecting group onto the hydroxy.
  • the epoxide of formula III in tetrahydrofuran can be added to a suspension of sodium hydride in tetrahydrofuran followed by the addition of benzyl bromide and tetrabutyl-ammonium iodide to give the epoxide of the formula
  • the protected epoxide of formula IV can then be reacted with O-benzyl guanine to give the guanine substituted cyclopentanol of the formula
  • the amino group of the guanine substituted cyclopentanol of formula V can then be protected with trityl or substituted trityl to give the protected guanine substituted cyclopentanol of formula VI.
  • the compound of formula VI wherein Pi is monomethoxytrityl can be obtained by treating a solution of the compound of formula V in dichloromethane with triethylamine followed by p-anisylchlorodiphenylmethane and 4-dimethylamino-pyridine.
  • the compound of formula VI can then be oxidized to keto compound of formula VIII.
  • the yield of the keto compound of formula VIII is increased by employing the Dess-Martin periodinane of formula VII as the oxidizing agent.
  • the protected guanine substituted cyclopentanol of formula VI can be reacted with from about 1 to about 4 equivalents, preferably about 2 equivalents, of the Dess-Martin periodinane of formula VII at a temperature of from about -20°C to about 40°C, preferably at about room temperature, i.e. about 22 °C.
  • the reaction is performed in a suitable solvent such as dichloromethane, chloroform, 1, 2-dichloroethane, other chlorinated hydrocarbons, or acetonitrile.
  • Preferred solvents include dichloromethane, chloroform, and 1, 2-dichloroethane with dichloromethane being most preferred.
  • water or t-butanol can be included in the reaction mixture at up to about 1 equivalent of the Dess-Martin periodinane, preferably about 1 equivalent of t-butanol is included in the reaction mixture.
  • the reaction can be run for about 30 minutes to about 24 hours but will usually be completed in about 2 hours .
  • the keto compound of formula VIII can then be methylenated to the methylene compound of formula XI .
  • the yield of the methylene compound of formula XI is increased by the use of the Nysted reagent of formula IX, the Tebbe reagent of formula X, or the zinc reagent described by Takai et al . (J. Org. Chem., 1994, 5_9_, p. 2668 - 2670 and supplementary material) as the methylenation reagent.
  • the Nysted reagent of formula IX is the preferred methylenation reagent.
  • the methylenation is performed with the Nysted reagent of formula IX
  • from about 1 to about 4 equivalents of the Nysted reagent are employed per equivalent of the keto compound of formula VIII, preferably about 1.3 equivalents of Nysted reagent.
  • Up to about 1 equivalent of titanium tetrachloride per equivalent of the keto compound of VIII can be also included in the reaction mixture, preferably 1 equivalent of titanium tetrachloride.
  • the keto compound of formula VIII and the Nysted reagent of formula IX can be reacted in a suitable solvent such as tetrahydrofuran or hexamethylphosphoramide, preferably tetrahydrofura .
  • the reaction can be kept at a temperature of from about -78°C to about 25°C during the initial mixing and then at from about 0°C to the reflux temperature of the solvent, e.g. 66°C for tetrahydrofuran, preferably at room temperature.
  • the reaction can be run from about one to about 72 hours but usually will be completed in about 3 hours .
  • Tebbe reagent of formula X from about 1 to about 4 equivalents of the Tebbe reagent are employed per equivalent of the keto compound of formula VIII, preferably about 2 equivalents of the Tebbe reagent.
  • the keto compound of formula VIII and the Tebbe reagent of formula X can be reacted in a suitable solvent such as tetrahydrofuran.
  • a suitable solvent such as tetrahydrofuran.
  • the reaction can be performed at from about -78°C to about the reflux temperature of the solvent, preferably at about 0°C during the initial mixing and at about room temperature for the remainder of the reaction.
  • the reaction can be run from about 15 minutes to about 24 hours but usually will be completed in about 30 minutes.
  • the reagent can be prepared by employing from about 2 to about 30 equivalents of zinc powder, from about 2 to about 20 equivalents of diiodomethane, from about 2 to about 4 equivalents of titanium tetrachloride, and from about 0.01 to 1 equivalent of lead powder or lead chloride per equivalent of the keto compound of formula VIII.
  • the preferred reagent contains about 18 equivalents of zinc powder, about 10 equivalents of diiodomethane, about 2 equivalents of titanium tetrachloride, and about 0.09 equivalents of lead chloride per equivalent of the keto compound of formula VIII .
  • This reaction can be performed in a suitable solvent such as tetrahydrofuran, ether or 1, 2-dimethoxyethane, preferably tetrahydrofuran at a temperature of from about -78°C to about the reflux temperature of the solvent, preferably at about room temperature.
  • the reaction can be run from about 1 hour to about 24 hours but usually will be completed in about 3 hours .
  • the methylene compound of formula XI is treated to remove the O-benzyl and Pi guanine protecting groups and give the compound of the formula
  • a mixture of the methylene compound of formula XI, methanol and tetrahydrofuran can be treated with aqueous hydrochloric acid at a temperature of about 50°C to about 60°C for about 3 to 5 hours, the pH is adjusted to about 7 , and the product is extracted with ethyl acetate to give the compound of formula XII .
  • the two benzyl protecting groups can be removed from the compound of formula XII to give the product of formula I in crude form.
  • a suspension of the compound of formula XII in dichloromethane at about -78°C can be treated with a solution of boron trichloride in dichloromethane to remove the benzyl protecting group.
  • the methylene compound of formula XI can be treated to remove only the Pi protecting group and give the compound of the formula
  • a mixture of the methylene compound of formula XI, methanol, and tetrahydrofuran can be treated with aqueous hydrochloric acid at room temperature for about 30 minutes to about 1 hour, the pH is adjusted to 7, and the product is extracted with ethyl acetate to give the compound of formula XIII.
  • the three benzyl protecting groups can then be removed from the compound of formula XIII to give the product of formula I in crude form.
  • a suspension of the compound of formula XIII in dichloromethane at about -78°C can be treated with a solution of boron trichloride in dichloromethane to remove the benzyl protecting groups.
  • the crude product of formula I can be purified by dissolving in methanol and concentrating in vacuo .
  • the pH of the aqueous phase can be basified to a pH of about 7 by adding IN sodium hydroxide.
  • the neutralized aqueous solution can then be concentrated, and the precipitated solid can be filtered, washed with water, dried, and optionally purified on a reverse phase resin column to give the final product of formula I as a crystalline monohydrate .
  • the product of formula I and pharmaceutically acceptable salts thereof are antiviral agents that can be used to treat viral infections in mammalian species such as domesticated animals (e.g. dogs, cats, horses and the like) and humans.
  • mammalian species such as domesticated animals (e.g. dogs, cats, horses and the like) and humans.
  • domesticated animals e.g. dogs, cats, horses and the like
  • the product of formula I is effective against various viruses but in particular is effective against hepatitis B virus.
  • the product of formula I may be administered parenterally (for example, by intravenous, intraperitoneal, or intramuscular injection) orally, or topically from conventional pharmaceutical formulations containing a sufficient amount of the product of formula I or a pharmaceutically acceptable salt thereof to treat the infection.
  • the dosage will, of course, depend upon the severity of the infection, but will likely be in the range of about 1.0 to 50 mg/kg of body weight.
  • the desired dose may be administered from one to several times daily at appropriate intervals .
  • the pinene- borane complex was dried under vacuum yielding about 300 g (71%) of large colorless crystals (Brown et al . , J.0.C, vol. 49, p. 945 - 947, 1984) .
  • the reaction was stirred at -78°C for 1 hour and was then added to a suspension of the borane-pinene complex (300 g, 1.04 mole) in 900 ml of anhydrous tetrahydrofuran at - 78°C, which had been stirred for 3 hours under an argon atmosphere to break up the large crystals, keeping the temperature between -60°C and -78°C.
  • the reaction was stirred for 7 hours at -78°C and then overnight (14 hours) at -20°C.
  • the reaction was warmed to -10°C and with rapid stirring and 270 ml of 3 N sodium hydroxide was added keeping the internal temperature below 0°C.
  • the mixture was stirred at room temperature under argon for 17 hours after which time no starting material remained.
  • the mixture was placed in an ice-water bath and 120 mL of saturated aqueous sodium sulfite was added dropwise keeping the temperature below 20°C. After the addition was complete, the mixture was stirred at room temperature for 1.5 hours. Starch/iodine paper test showed no peroxide presence.
  • the mixture was transferred to a separatory funnel and the layers were separated.
  • the aqueous phase was back-extracted with ethyl acetate (2x) and combined organics (400 mL) were washed with brine, dried (magnesium sulfate) and concentrated to afford the title product (34.34 g) as a light-yellow oil.
  • the product still contains benzyl alcohol that was present in the starting material .
  • the aqueous phase was extracted with ethyl acetate (lx) followed by extraction with dichloromethane (lx) .
  • the combined organics were dried (magnesium sulfate) and concentrated to obtain the crude material (55 g) as a dark-brown oil.
  • the crude product was purified on silica gel (800 g cartridge) in a radially pressurized module (Biotage Corp.) eluting with hexane (3 L) , 10% ethyl acetate-hexane (3 L) and 25% ethyl acetate- hexane (4 L) .
  • the product eluted with 25% ethyl acetate- hexane .
  • Fractions containing product were combined and concentrated to afford pure title product (29.92 g, 83% over two steps) as a light yellow oil.
  • the combined organic phases were filtered through Celite, the Celite pad was washed with ethyl acetate and the combined filtrate (3 L) was washed with water (3x500 mL) , brine (lx) , dried (magnesium sulfate) and concentrated to obtain the crude material (69.1 g) .
  • the crude still contained some 0-benzyl guanine which was removed by filtering a suspension of crude in dichloromethane through a silica gel pad eluting with 5% methanol-dichloromethane.
  • the mixture was diluted with ethyl acetate (1 L) and washed with 5% aqueous sodium bicarbonate (2x100 mL) , water (2x100 L) , brine, dried (magnesium sulfate) and concentrated to afford the crude product.
  • the crude residue was flash chromatographed the first time on silica gel (800 g cartridge) in a radially pressurized module (Biotage Corp.) eluting with 0.5% triethylamine-chloroform (2L) , 1% triethylamine-chloroform (2L) , 1.5% ethanol-chloroform (3L) , 1.5% ethanol-chloroform (3L) , and 2% ethanol-chloroform (IL) . Most of the product eluted with 1% - 1.5% ethanol-chloroform but separation from excess monomethoxy trityl chloride was not achieved and about 5% of product was converted to the starting material from part (d) under the column conditions.
  • a radially pressurized module Biotage Corp.
  • the mixture was diluted with ethyl acetate (1 L) and stirred vigorously with 1.5:1:1 10% aqueous sodium sulfite-saturated aqueous sodium bicarbonate-brine (280 mL) for a period of 1 hour.
  • the phases were separated in a separatory funnel and aqueous phase back-extracted with ethyl acetate (1x100 mL) .
  • the combined organics were washed with brine, dried (magnesium sulfate) and concentrated to afford crude title product (9.8 g, 100% crude yield containing a small amount of impurity) as a light yellow solid.
  • the resulting black mixture was stirred under argon at room temperature over 3 hours and slowly poured into a suspension of dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (400 mL) .
  • the resulting suspension was stirred vigorously and additional saturated aqueous sodium bicarbonate was added (400 mL) as needed to keep the pH basic.
  • the suspension was filtered through Celite and the Celite pad washed with ethyl acetate (4x200 mL) .
  • the two phases in the filtrate were separated and organic again stirred for 30 minutes with 250 mL of saturated aqueous sodium bicarbonate (as the pH had dropped below 7.0 at this point) .
  • the product was further purified on CHP-20 resin column eluting with water (600 mL) , 5% acetonitrile-water (800 mL) , 7.5% acetonitrile-water (300 mL) , 10% acetonitrile-water (600 mL) , 15% acetonitrile-water (300 mL) and 20% acetonitrile-water (300 mL) .
  • Product started eluting with 5% acetonitrile-water but trailed until the end of elution. Fractions were checked by analytical HPLC and all pure fractions were combined and concentrated to afford 1.9 g of the title compound as a white, crystalline solid; m.p. 234 - 236°C (dec.) for the bulk sample and 255°C (dec.) for an analytical sample recrystallized from water.
  • Example 1 The product of Example 1 was also prepared as described below.
  • the temperature of the mixture was not allowed to raise over -60°C during the addition. After the addition was complete, the mixture was stirred at -78°C for 15 minutes and then gradually warmed up to room temperature. After 3 hours stirring, the black solution was poured into a saturated sodium bicarbonte solution (1.0L), stirred for 30 minutes and filtered through a pad of Celite to remove the inorganic materials . The filtrate was diluted with dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x600ml) . The dichloromethane extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 21g of crude title product with consistent NMR spectra. This reaction was repeated twice using 70 g of cyclopentanone starting material each time and afforded a total of an additional 144 g of title product. This was used in the next step without purification.
  • Nitrogen gas was bubbled with stirring through freshly distilled tetrahydrofuran for a period of one hour.
  • To 2 ml of degassed tetrahydrofuran was added [2R- (2 ⁇ ,3 ⁇ , 5 ⁇ ) ]-5-[2- [[ (4-methoxyphenyl) diphenylmethyl] - amino] -6-phenylmethoxy-9-purin-9-yl] -3- (phenylmethoxy) -2- [ (phenylmethoxy) methyl ] -1-cyclopentanone (0.821 g, 1 mmol) [prepared as described in Example 1(a) through (f)] and the resulting solution was added 2 ml of 0.5 M solution of Tebbe reagent in toluene (Aldrich) via syringe.
  • the turbid light-yellow reaction mixture was stirred for 2 hours at -78°C, for 40 minutes at -20°C, and for 20 minutes at 0°C. TLC showed a single lower Rf product spot .
  • the reaction mixture was recooled to -78°C and methanol (3 ml) was added slowly affording a clear, colorless solution. This solution was warmed to room temperature, concentrated to dryness, and reconcentrated once from methanol to afford 58 mg of crude product as a light tan solid (greater than about 95% purity) .
  • This crude product was dissolved in water and extracted with ether.
  • the pH of the aqueous solution was . adjusted to 7 with aqueous sodium hydroxide.
  • the aqueous solution was applied to a column (2.5 x 5 cm) of HP-20 reverse phase resin and eluted with water (75 ml) , 5% acetonitrile (50 ml) , and 10% acetonitrile (75 ml) .
  • the product was eluted in the 5% - 10% acetonitrile fractions .
  • the product containing fractions were combined and concentrated to afford the title product as a white powdery solid; m.p. >225°C (dec).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des améliorations ont été apportées dans le rendement de l'agent antiviral de la formule (I) en utilisant periodinane Dess-Martin pour convertir le cyclopentol de la formule (VI) en cyclopentanone de la formule (VIII) et en effectuant la méthylènation de ce cyclopentanone pour obtenir le composé de la formule (XI) en utilisant un réactif de Nysted, un réactif de Tebbe ou un réactif préparé à partir de poudre de zinc, de diiodométhane, de poudre de plomb ou de chlorure de plomb, et du tétrachlorure de titane en un solvant approprié.
PCT/US1997/015007 1996-09-03 1997-08-26 PROCEDE DE PREPARATION AMELIORE DE L'AGENT ANTIVIRAL [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENE-CYCLOPENTYL]-6-H-PURINE-6-ONE WO1998009964A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40906/97A AU4090697A (en) 1996-09-03 1997-08-26 Improved process for preparing the antiviral agent {1s-(1alpha, 3alpha, 4beta)}-2-amino-1,9-dihydro-9-{4-hydroxy-3-(hydroxymethyl)-2 -methylenecyclopentyl}-6h-purin-6-one

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US2537896P 1996-09-03 1996-09-03
US60/025,378 1996-09-03

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US6627224B2 (en) 2000-02-29 2003-09-30 Bristol-Myers Squibb Co. Low dose entecavir formulation and use
WO2004052310A2 (fr) * 2002-12-11 2004-06-24 Bristol-Myers Squibb Company Preparation de l'agent antiviral [1s-(1alpha, 3 alpha, 4 beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclo
US6831102B2 (en) 2001-12-07 2004-12-14 Bristol-Myers Squibb Company Phenyl naphthol ligands for thyroid hormone receptor
WO2005118585A1 (fr) * 2004-06-04 2005-12-15 Bristol-Myers Squibb Company Procede pour l'elaboration d'entecavir par oxydation de carbone-silicium, et intermediaires correspondants
WO2007030657A1 (fr) * 2005-09-09 2007-03-15 Bristol-Myers Squibb Company Formes cristallines de [1s-(1$g(a), 3$g(a), 4$g(b))]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6h-purin-6-one
CN100379736C (zh) * 2005-05-13 2008-04-09 上海仲夏化学有限公司 恩替卡韦的制备方法
WO2008098471A1 (fr) * 2007-02-14 2008-08-21 Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory Forme cristalline d''entecavir, son mode de préparation, compositions pharmaceutiques et utilisations
WO2009026790A1 (fr) * 2007-08-23 2009-03-05 Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory Formulation de la forme cristalline d'entécavir et son procédé de préparation
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CN1964972B (zh) * 2004-06-04 2011-04-20 布里斯托尔-迈尔斯斯奎布公司 经由碳-硅氧化制备恩替卡韦及其新中间体的方法
DE102009060194A1 (de) 2009-12-23 2011-06-30 ratiopharm GmbH, 89079 Orale Darreichungsform umfassend Entecavir
WO2011076412A1 (fr) 2009-12-23 2011-06-30 Ratiopharm Gmbh Forme d'administration orale contenant de l'entecavir
WO2011046303A3 (fr) * 2009-10-12 2011-10-06 Hanmi Holdings Co., Ltd. Nouveau procédé de préparation d'entécavir et intermédiaire utilisé dans ce procédé
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WO2012006964A1 (fr) 2010-07-15 2012-01-19 台州市奥翔医药科技有限公司 Procédé de synthèse de l'entécavir et composé intermédiaire associé
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EP2514750A1 (fr) 2007-06-18 2012-10-24 Sunshine Lake Pharma Co., Ltd Thiazolyl-dihydropyrimidines a substitution bromo-phenyle
US8338372B2 (en) 2007-09-20 2012-12-25 Zhejiang Medicine Co., Ltd. Dehydroxy vancomycin, the preparation, pharmaceutical composition and the use
CN101781301B (zh) * 2010-01-15 2013-04-10 复旦大学 一种制备恩替卡韦的方法
WO2013135165A1 (fr) * 2012-03-12 2013-09-19 浙江奥翔药业有限公司 Intermédiaire synthétique d'entécavir et son procédé de préparation
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8569490B2 (en) 2008-12-26 2013-10-29 Hanmi Science Co., Ltd Intermediate and process for preparing entecavir using same
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8722725B2 (en) 2007-03-23 2014-05-13 Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory Caffeoylquinic acid derivatives containing nitrogen, and preparation method, pharmaceutical composition and usage thereof
US8748495B2 (en) 2009-03-09 2014-06-10 Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory Method of preparing oil suspensions of carotenoid with low viscosity and high fluidity and use thereof
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EP2832351A1 (fr) 2013-07-29 2015-02-04 Sanovel Ilac Sanayi ve Ticaret A.S. Comprimé multicouche comprenant du tenofovir et de l'entecavir
CN106749252A (zh) * 2017-01-23 2017-05-31 山东鲁抗医药股份有限公司 一种恩替卡韦中间体n8的提纯方法
CN106749249A (zh) * 2017-01-13 2017-05-31 信泰制药（苏州）有限公司 恩替卡韦中间体的晶型
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TWI588146B (zh) * 2010-08-30 2017-06-21 浙江奧翔藥業股份有限公司 恩替卡韋的合成方法及其中間體化合物
CN108101908A (zh) * 2017-12-29 2018-06-01 郑州泰丰制药有限公司 一种氘代恩替卡韦的制备方法
CN108148061A (zh) * 2018-03-14 2018-06-12 湖北广济药业股份有限公司 恩替卡韦的工业化制备方法
CN110759912A (zh) * 2018-07-25 2020-02-07 连云港润众制药有限公司 恩替卡韦中间体的制备方法
CN110818714A (zh) * 2018-08-14 2020-02-21 连云港润众制药有限公司 一种恩替卡韦中间体的合成方法

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