EP1404680A2 - Methode de preparation d'intermediaires d'inhibiteurs de protease vih - Google Patents

Methode de preparation d'intermediaires d'inhibiteurs de protease vih

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Publication number
EP1404680A2
EP1404680A2 EP01271082A EP01271082A EP1404680A2 EP 1404680 A2 EP1404680 A2 EP 1404680A2 EP 01271082 A EP01271082 A EP 01271082A EP 01271082 A EP01271082 A EP 01271082A EP 1404680 A2 EP1404680 A2 EP 1404680A2
Authority
EP
European Patent Office
Prior art keywords
furan
propynyloxy
group
ealkyl
hydrogen
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01271082A
Other languages
German (de)
English (en)
Inventor
Roman Glaxosmithkline Davis
Thomas Claiborne GlaxoSmithKline LOVELACE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
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Glaxo Group Ltd
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Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1404680A2 publication Critical patent/EP1404680A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • drugs currently used to treat HIV infections in humans are those that inhibit the HIV aspartyl protease enzyme.
  • Drugs that are used as protease inhibitors are, in general, chemically complex and are difficult to prepare in a cost-effective and efficient manner. As a 15 result of the inherent complexity of these molecules, new and more efficient methods for their preparation are of value.
  • a key step in the preparation of the hexahydrofuro[2,3-b]furan ring system is the cyclization of a 2-(2-propynyloxy)tetrahydrofuranyl derivative under radical cyclization conditions.
  • Ghosh et. al. reported that 3-iodo-2-(2- propynyloxy)tetrahydrofuran could be cyclized to the desired 3-methylene hexahydrofuro[2,3-6jfuran derivative using stoichiometric amounts of compounds capable of
  • radical initiators such as a mixture of sodium borohydride and cobaloxime.
  • the same cyclization reaction can be effected using a stoichiometric amount of a trialkyltin hydride, such as tributyltin hydride.
  • a trialkyltin hydride such as tributyltin hydride.
  • toxicity of trace amounts of metals such as cobalt or tin.
  • we developed a new process for the preparation of the hexahydrofuro[2,3-6]furan ring system that avoids the use of toxic metals in the key cyclization step.
  • radical cyclization of 0-allylic-2-halo sugar derivatives to afford alpha-C(2)-branched sugars has been described by Mesmaeker, et. al. (Synlett 1990, p. 201). This method utilizes radical initiating compounds, such as a combination of AIBN and tributyltin hydride, in addition to the use of light to effect the desired cyclizations.
  • the invention comprises a method for effecting intramolecular cyclization reactions using light, in the absence of radical initiators, to provide useful polycyclic compounds.
  • the present invention further provides a method of preparation of an intermediate useful in the synthesis of compounds that function as inhibitors of the aspartyl protease enzyme of human immunodeficiency virus (HIV).
  • the present method is characterized by the use of light to effect cyclization of a hexahydrofuro[2,3-6]furan ring system from a 2-(2- propynyloxy)tetrahydrofuranyl derivative without the use of a stoichiometric amount of a radical initiator.
  • hexahydrofuro[2,3-fa]furan derivative may be transformed through a series of further reactions to produce hexahydrofuro[2,3-b]furan-3-ol, an intermediate in the synthesis of compounds that are effective as inhibitors of HIV aspartyl protease.
  • the present method involves the use of light to effect the intramolecular cyclization of an appropriately substituted organic halo compound containing a pendant olefinic or alkynyl substituent
  • A which may be the same or different, is independently selected from the group consisting of -CH 2 - ( -CHR 10 -, -CR 10 R 11 -, -0-, -NH-, -NR 10 -, -S-; wherein R 10 and R 11 , which may be the same or different, are selected from the group consisting of hydrogen, Ce-uaryl, and G-ealkyl;
  • R 1 is selected from the group consisting of hydrogen, Ci-ealkyl, Ce- ⁇ aryl, Ci-ealkylheterocycle, and heterocycle;
  • R 2 is selected from the group consisting of hydrogen, Ce-uaryl, Ci- ⁇ alkyl, Ce-waryl, G-ealkylheterocycIe, and hetero
  • the present invention features a process for the preparation of a compound having the formula
  • A which may be the same or different, is independently selected from the group consisting of -CH2-, -CHR 10 -, -CR 10 R 11 -, -0-, -NH-, -NR 10 -, and -S-, wherein R 10 and R 11 , which may be the same or different, are selected from the group consisting of hydrogen, Ce-uaryl, and Ci-ealkyl; R 1 is selected from the group consisting of hydrogen, Ci-ealkyl, Ce-uaryl, Ci- ealkylheterocycle, and heterocycle;
  • R 4 is selected from the group consisting of hydrogen, Ce-uaryl, Ci-ealkyl, Ci- ealkylheterocycle, and heterocycle
  • R 5 is selected from the group consisting of hydrogen, Ce-uaryl, Ci-ealkyl, G- ealkylheterocycle, heterocycle, -OR 12 , and -CH2OR 12 , wherein R 12 is selected from the group consisting of Ci-ealkyl and -C(0)R 10 ;
  • R 1 to R 6 are as hereinbefore defined to light with a wavelength of 200 to 400 nanometers in the presence of a compound of formula NR 7 R 8 R 9 , wherein R 7 , R 8 and R 9 , are independently selected from the group consisting of hydrogen, Ce-uaryl, G-ealkyl, Ci-ealkylheterocycle, and heterocycle.
  • the present invention further features a process for the preparation of 3- methyIenehexahydrofuro[2,3-b]furan in the absence of radical initiators comprising exposing a 3-halo-2-(2-propynyloxy)tetrahydrofuranyl derivative to light with a wavelength from 200 to 400 nanometers, in the presence of a solvent containing a compound of formula NR 7 R 8 R 9 , wherein R 7 , R 8 and R 9 , are independently selected from the group consisting of hydrogen, Ce- uaryl, Ci-ealkyl, Ci-ealkylheterocycle, and heterocycle, thereby cyclizing the 3-halo-2-(2- propynyloxy)tetrahydrofuranyl derivative to form 3-methylenehexahydrofuro[2,3-o]furan.
  • the present invention also features a process for the preparation of hexahydrofuro[2,3- 6]furan-3-ol consisting of: a) exposing a 3-halo-2-(2-propynyloxy)tetrahydrofuranyl derivative to light with a wavelength from 200-400 nanometers in the presence of a solvent containing a compound of formula NR 7 R 8 R 9 , wherein R 7 , R 8 and R 9 , are independently selected from the group consisting of hydrogen, Ce-uaryl, Ci-ealkyl, Ci-ealkylheterocycle, and heterocycle, thereby cyclizing the 3-ha!o-2-(2-propynyloxy)tetrahydrofuranyi derivative to form 3- methylenehexahydrofuro[2,3-b]furan; b) oxidizing said 3-methylenehexahydrofuro[2,3-rj]furan to produce tetrahydrofuro[2,3- ⁇ ]furan-3(2
  • the present invention includes a process as described above wherein the 3-halo-2-(2- propynyloxy)tetrahydrofuranyl derivative may be 3-iodo-2-(2-propynyloxy)tetrahydrofuran, 3-bromo-2-(2-propynyloxy)tetrahydrofuran, or 3-chloro-2-(2-propynyloxy)tetrahydrofuran, the light is at a wavelength of 254 nanometers, and the compound of formula NR 7 R 8 R 9 is triethylamine.
  • the processes of the present invention involve the initial preparation of a suitable substrate for the intramolecular photocyclization reaction. These substrates can be prepared by a number of methods known to one skilled in the art.
  • preparation of a 3- halo-2-(2-propynyloxy)tetrahydrofuranyl derivative is effected by reaction of 2,3- dihydrofuran with 2-propyn-1-ol in the presence of a suitable activating agent, to provide a 3-halo-2-(2-propynyloxy)tetrahydrofuran derivative.
  • 3-halo-2-(2- propynyloxy)tetrahydrofuran derivatives can be 3-iodo-2-(2-propynyloxy)tetrahydrofuran, 3- bromo-2-(2-propynyloxy)tetrahydrofuran or 3-chloro-2-(2-propynyloxy)tetrahydrofuran.
  • This reaction can be effected using an agent capable of activating the 2,3-dihydrofuran ring to nucleophilic addition by the alcoholic portion of a 2-propyn-1-ol derivative.
  • an agent capable of activating the 2,3-dihydrofuran ring to nucleophilic addition by the alcoholic portion of a 2-propyn-1-ol derivative can be performed using N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS), in a non-nucleophilic solvent, such as dichloromethane, and at temperatures from -10 °C to 25 °C, preferably 0 °C, followed by warming to 25 °C.
  • the 3-halo-2-(2-propynyloxy)tetrahydrofuran derivative such as 3-iodo-2-(2- propyny!oxy)tetrahydrofuran, 3-bromo-2-(2-propyny!oxy)tetrahydrofuran or 3-chloro-2-(2- propynyloxy)tetrahydrofuran, may be cyclized using light, in the presence of a trialkyl amine and in the presence of a suitable solvent. This reaction may be performed using a light source that is sufficient to cause homolytic cleavage of the carbon-halogen bond in the 3 ⁇ halo-2-(2- propynyloxy)tetrahydrofuran derivative.
  • the light source used can provide ultraviolet light of sufficient intensity to cause the desired homolytic cleavage of the carbon- halogen bond.
  • a light source is used that provides light with a wavelength of 254 nanometers, produced by low-pressure mercury lamps.
  • These reactions may be performed in a suitable solvent, one that is sufficiently stable under the photolytic conditions.
  • the reaction may be performed in a polar solvent such as acetonitrile.
  • the cyclization reaction may be performed in the presence of a suitable trialkylamine of formula NR 7 R 8 R 9 , wherein R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, Ci-ealkyl, Ce-uaryl, heterocycle, and Ci-ealkylheterocycle, preferably Ci-ealkyl.
  • R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, Ci-ealkyl, Ce-uaryl, heterocycle, and Ci-ealkylheterocycle, preferably Ci-ealkyl.
  • the amine is triethylamine.
  • the reaction may be advantageously performed in the presence of water. The amount of water that may be used will vary depending on both the solvent and the trialkylamine chosen.
  • the reaction may be performed in any suitable reaction vessel that will allow the passage of a sufficient amount of light in the preferred wavelength.
  • the reaction may be advantageously performed in a vessel that is suitable as a flow-cell reactor.
  • the 3-bromo-2-(2-propynyloxy)tetrahydrofuran may be photolyzed using light at a wavelength of 254 nanometers, in a 3:7:5 ratio of acetonitrile, triethylamine and water at 20 °C for 15-20 hours, to afford 3-methylenehexahydrofuro[2,3-6]furan (Scheme IV).
  • the intermediate meth ⁇ lenehexahydrofuro[2,3-b]furan may then be oxidized to produce the desired tetrahydrofuro[2,3-b]furan-3(2f/)-one.
  • the oxidation may be performed using a variety of methods well known to those skilled in the art.
  • the olefin can be allowed to react with osmium (IV) oxide, followed by treatment with an agent capable of cleaving the resulting diol, sodium periodate for example.
  • the olefin can be treated with ozone in a suitable solvent, followed by the addition of an agent capable of cleaving the resulting ozonide.
  • the intermediate tetrahydrofuro[2,3-b]furan-3(2 /)-one may then be reduced to yield hexahydrofuro[2,3-b]furan-3-ol.
  • the reduction may be performed using an appropriate reducing agent, sodium borohyride or diisobutylaluminum hydride, or more preferably lithium aluminum hydride, in the presence of an aprotic, organic solvent, preferably dichloromethane, and at a temperature from 0 °C to 40 °C, preferably in the range from 20-30 °C.
  • an appropriate reducing agent will depend on factors known to those skilled in the art and include the properties of the particular compound being reduced and those of the solvent in which the reaction is being performed.
  • tetrahydrofuro[2,3-b]furan-3(2/V)-one may be allowed to react with lithium aluminum hydride in dichloromethane as solvent and at a temperature range of 20-30 °C to yield hexahydrofuro[2,3-b]furan-3-ol as a racemic mixture(Scheme VI).
  • Enantioenriched hexahydrofuro[2,3-b]furan-3-ol may also be obtained by the use of so- called “chiral reducing agents.” These agents are capable of reducing ketones and aldehydes in an enantioselective fashion to provide enantioenriched alcohols. The reactions may be performed with stoichiometric as well as catalytic chiral reducing agents using conditions known to those skilled in the art. For example, see Ernest L Eliel, "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., 1994, p. 941.
  • a racemic mixture of hexahydrofuro[2,3-b]furan-3-ol may be resolved to provide an enantioenriched mixture of each enantiomer.
  • a racemic mixture of hexahydrofuro[2,3-b]furan-3-ol may be resolved by converting the mixture of enantiomers into a mixture of diastereomers, followed by traditional methods of separation, such as silica chromatography.
  • the racemic alcohol may be allowed to react with a chiral nonracemic compound (the resolving agent) resulting in the formation of a diastereomeric mixture.
  • the chiral nonracemic compound is either an acid chloride or a chloroformate, resulting in the formation of a diastereomeric mixture of esters or ureas, respectively.
  • the choice of the chiral nonracemic resolving agent will depend on factors known to those skilled in the art. For example, see Eliel, et. al., p. 322.
  • the racemic alcohol may be allowed to react with a lipase enzyme capable of converting one enantiomer of the alcohol into an ester.
  • the ester and the remaining alcohol may then be separated by methods known to those skilled in the art. See Eliel, et. al., p. 413.
  • racemic alcohol may be separated into two enantioenriched mixtures by the use of an esterase.
  • These reactions typically consist of first converting the racemic alcohol to an appropriate ester, such as the corresponding acetate.
  • the conversion of the alcohol to the corresponding ester can be accomplished by reaction of the alcohol with an appropriate agent, an acid chloride or anhydride for example.
  • These reactions are typically performed in an aprotic solvent, tetrah ⁇ drofuran for example, and in the presence of a compound capable of acting as a base, sodium carbonate for example.
  • a compound capable of acting as a catalyst may be advantageously used, for example 4-N,N-dimethylaminopyridine.
  • the racemic mixture of esters may then be allowed to react with an appropriate esterase enzyme under conditions which allow for reaction of predominantly one racemate of the ester to provide a mixture of an alcohol of predominantly one enantiomer and the remaining ester, consisting of predominantly the other enantiomer.
  • the mixture of alcohol and ester may then be separated using methods known to those skilled in the art, silica gel chromatography for example.
  • the choice of an appropriate esterase enzyme, as well as appropriate reaction conditions will depend on a number of factors known to those skilled in the art. Eliel, et. al., p. 409.
  • racemic hexahydrofuro[2,3-b]furan-3-ol may be allowed to react with acetic anhydride in a mixture of tetrahydrofuran and water, and in the presence of sodium carbonate and 4-N,N-dimethylaminopyridine to yield hexahydrofuro[2,3- b]furan-3-y! acetate.
  • the resulting acetate may then be allowed to react with PS-800 in a buffered mixture of sodium hydrogen phosphate while the pH is kept between 6.2 and 7.2 with the addition of 15% aqueous sodium hydroxide as needed to yield a mixture of (3/?,3a5,6a/?)-hexahydrofuro[2,3-b]furan-3-yl acetate and (3S,3a/?,6aS)-hexahydrofuro[2,3- b]furan-3-ol (Scheme VII).
  • alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms.
  • alkyl radicals include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.
  • aryl refers to a carbocyclic aromatic radical (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably from 6-14 carbon atoms, and more preferably from 6-10 carbon atoms.
  • aryl radicals include, but are not limited to phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
  • aryl ring may be optionally substituted with one or more groups independently selected from the group consisting of halogen, Ci-ealkyl, -CF 3 , heterocycle, -OCH 3 , aryl, G-ealkylaryl, and G-ealkylheterocycle.
  • halogen refers to a radical of chlorine, bromine or iodine.
  • heterocycle refers to a 3-to 7- membered monocydic heterocyclic ring or 8-to 11- membered bicyclic heterocyclic ring which is either saturated, partially saturated or unsaturated, and which may be optionally benzofused if monocydic.
  • Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any carbon or heteroatom, which results in the creation of a stable structure.
  • Preferred heterocycles include 5-7 membered monocydic heterocycles and 8-10 membered bicyclic heterocycles. Examples of such groups include imidazolyl, imidazolinoyl, imidazolidinyl, quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl, pyridazyl, pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiamorpholinyl, furyl,
  • a vessel suitable for use as a flow-cell reactor for photolytic chemical reactions comprises a hollow container with a smooth, reflective interior, constructed of a suitable material, preferably stainless steel, an inlet and outlet suitable for the introduction and removal of a chemical reaction mixture, and a light source capable of providing light in the range of 200-400 nanometers, preferably 254 nanometers.
  • N-bromosuccinimide N-bromosuccinimide (NBS, 1.05 eq., 2.67 wt), followed by methylene chloride (10 vol).
  • NBS N-bromosuccinimide
  • methylene chloride 10 vol
  • the resulting slurry was cooled to 0 °C, and a mixture of 2,3- dihydrofuran (1 eq., 1.0 wt), and propargyl alcohol (1.5 eq., 1.2 wt) was added over 40 min.
  • the resulting clear solution was stirred at 0 °C for 1 h, heated to 25 °C over 30 min and held at that temperature overnight.
  • the solution was then washed with water (1 x 10 vol), 25% sodium meta-bisulfite (2 x 5 vol) and saturated sodium bicarbonate (2 5 vol).
  • Detector type and temperature FID, 300 °C;
  • Temperature ramp 20 degrees/min to 250 °C, followed by a 7.5 min hold.
  • a reactor was charged with 3-methylenehexahydrofuro[2,3-b]furan (1 eq., 1.0 wt), and methylene chloride (10 vol). The solution was stirred and cooled to - 30 °C. Ozone was introduced through a subsurface addition line while the temperature was kept at -30 +/- 5 °C. When the solution turned blue, it was purged with nitrogen and triethylamine (2.0 eq) was slowly added, keeping the temperature between -30 and -20 °C. After the addition was complete, the solution was allowed to warm to 20 °C and was allowed to stir overnight.
  • Carrier gas He @ 1 mL/min
  • Inject 1 uL sample prep The sample concentration may be adjusted as needed to give adequate sensitivity or to prevent column overloading.
  • Carrier gas He at 5 mL/min; Makeup gas: He at 25 mL/min;

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

La présente invention concerne une méthode permettant d'effectuer des réactions de cyclisation intramoléculaire à l'aide de la lumière, en l'absence d'initiateurs de radicaux, de manière à obtenir des composés polycycliques utiles.
EP01271082A 2000-10-24 2001-10-22 Methode de preparation d'intermediaires d'inhibiteurs de protease vih Withdrawn EP1404680A2 (fr)

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US24282200P 2000-10-24 2000-10-24
US242822P 2000-10-24
PCT/US2001/051428 WO2002067239A2 (fr) 2000-10-24 2001-10-22 Methode de preparation d'intermediaires d'inhibiteurs de protease vih

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Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2268427T3 (es) * 2002-06-27 2007-03-16 Smithkline Beecham Corporation Preparacion de estereoisomeros de (3alfa, 3alfa/beta, 6alfa/beta) hexahidrofuro(2,3-b)furan-3-ol.
MX2008012398A (es) * 2006-03-29 2008-12-17 Gilead Sciences Inc Proceso para la preparacion de inhibidores de proteasa de vih.
AU2007316562B2 (en) 2006-11-09 2013-02-21 Janssen Sciences Ireland Unlimited Company Methods for the preparation of hexahydrofuro[2,3-b]furan-3-ol
CN103864813B (zh) * 2012-12-18 2017-02-22 上海迪赛诺化学制药有限公司 一种合成六氢呋喃并[2,3‑b]呋喃‑3‑醇及其对映体的方法
CN107607635B (zh) * 2017-08-15 2020-07-31 东北制药集团股份有限公司 一种采用顶空气相色谱检测左磷右胺盐中丙炔醇含量的方法
IL293592A (en) 2019-12-06 2022-08-01 Vertex Pharma Transduced tetrahydrofurans as sodium channel modulators
AU2022284886A1 (en) 2021-06-04 2023-11-30 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

Non-Patent Citations (1)

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Title
See references of WO02067239A3 *

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WO2002067239A2 (fr) 2002-08-29
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AU2002255473A1 (en) 2002-09-04

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