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WO1998004535A1 - Synthese pratique de benzoxazinones utiles comme inhibiteurs de la transcriptase inverse du vih - Google Patents

Synthese pratique de benzoxazinones utiles comme inhibiteurs de la transcriptase inverse du vih Download PDF

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Publication number
WO1998004535A1
WO1998004535A1 PCT/US1997/012808 US9712808W WO9804535A1 WO 1998004535 A1 WO1998004535 A1 WO 1998004535A1 US 9712808 W US9712808 W US 9712808W WO 9804535 A1 WO9804535 A1 WO 9804535A1
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compound
formula
butyllithium
group
iii
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PCT/US1997/012808
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English (en)
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Michael Ernest Pierce
Lilian Alicia Radesca
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Du Pont Pharmaceuticals Company
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Priority to CA002260922A priority Critical patent/CA2260922A1/fr
Priority to AU37361/97A priority patent/AU3736197A/en
Publication of WO1998004535A1 publication Critical patent/WO1998004535A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates generally to novel methods for the synthesis of benzoxazinone compounds which are useful as human immunodeficiency virus (HIV) reverse transcriptase inhibitors.
  • HIV human immunodeficiency virus
  • Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral secjuences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication
  • HIV human immunodeficiency virus
  • nucleoside based inhibitors such as azidothymidine
  • non-nucleoside based inhibitors such as azidothymidine
  • Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase.
  • the benzoxazinone of the formula (Vl-a) is the formula (Vl-a) :
  • VI-a is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of benzoxazinones as reverse transcriptase inhibitors, synthetic processes for their production need to be developed.
  • European Patent Application 582,455 Al describes the synthesis of benzoxazinones via a three step process. 1. 2 eq. n-BuLi THF/0°C R-MgBr
  • This general method teaches (1) metallation of the pivalamide of parachloroaniline with n-butyllithium followed by nucleophilic substitution with an ester to form a ketone, (2) synthesis of a tertiary carbinol by Grignard addition to the ketone, and (3) cyclization of the unprotected amine with the carbinol by addition of a condensing agent to form a benzoxazinone.
  • the present invention provides an improved synthetic process for the preparation of benzoxazinones.
  • the process of the present invention eliminates use of highly toxic condensing agents such as phosgene and provides for a more efficient intramolecular cyclization using a stoichiometric equivalent of strong base.
  • the present invention eliminates the use of highly toxic eerie ammonium nitrate or replaces messy
  • the present invention provides novel processes for the addition of cyclopropylethynyl radical to N-Boc-aniline via the cyclopropylethynyl lithium or cyclopropylethynyl trifluoromethyl ketone to produce the carbinol necessary for the intramolecular cyclization reaction.
  • the present invention provides for intermediates as stable solids purifiable by recrystallization. None of the above-cited references describe the methods of the present invention for the synthesis of benzoxazinones useful as inhibitors of HIV reverse transcriptase.
  • the present invention concerns processes for the preparation of benzoxazinone compounds which are useful as HIV reverse transcriptase inhibitors.
  • the processes of the present invention provide high yields, can be conducted on a kilogram scale, and yield stable intermediates.
  • the invention further provides for a facile intramolecular cyclization under mild condition to form benzoxazinone compounds .
  • This invention a process for the preparation of compounds of formula (VI) and derivatives thereof :
  • R 1 is an amine protecting group, which forms a carbamate with the amine
  • R ⁇ is a chiral amine protecting group
  • the present invention provides a novel process for the preparation of compounds of formula (IV) and derivatives thereof:
  • X is halogen
  • R 2 is trihalomethyl or pentahaloethyl
  • R 3 is cyclopropylethynyl; said process comprising one or more of the following:
  • step (1) (nucleophilic substitution)
  • R--- is an amine protecting group, which forms a carbamate with the amine
  • step (3) (cyclization) contacting a compound of formula (III) with a suitable strong base in a suitable aprotic solvent and heating to a temperature sufficient to form a compound of formula (IV) .
  • X is chloro
  • R is selected from the group consisting of: ethoxycarbonyl , diisopropylmethoxycarbonyl , tert-butyloxycarbonyl , menthoxycarbonyl bornyloxycarbonyl benzyloxycarbonyl , cyclopentyloxycarbonyl , and adamantyloxycarbonyl ;
  • R 2 is trihalomethyl;
  • R3 is cyclopropylethynyl
  • R 5 is ethyl
  • the suitable lithiating agent is selected from the group consisting of n-butyllithium, sec-butyllithium, and t-butyllithium;
  • the suitable metallating agent is selected from the group consisting of n-butyllithium, sec-butyllithium, and t-butyllithium;
  • the suitable strong base is selected from the group consisting of potassium hexamethyldisilazide, sodium hydride, potassium hydride, lithium hydride, n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, triphenylmethyllithium, and potassium t-butoxide.
  • the compound of formula (IV) is a compound of formula (IV-a) :
  • said process comprises: step (1) (substitution)
  • step (3) (cyclization) contacting the compound of formula (Ill-a) with about one or more equivalents of n-butyllithium in a suitable aprotic solvent at a temperature of between -70 and 0°C and heating to a temperature sufficient to effect intramolecular cyclization to form a compound of formula (IV-a) .
  • the intermediates of formula (II) and (III) may optionally be carried through to the next step without isolation of the intermediate, for example, by crystallization or chromatography, between steps in the process.
  • the present invention provides a novel process for the preparation of compounds of formula (IV) :
  • X is halogen
  • R 2 is trihalomethyl or pentahaloethyl
  • R 3 is cyclopropylethynyl
  • R-*- is an amine protecting group, which forms a carbamate with the amine, in a suitable solvent at a suitable temperature
  • the present invention provides a process for the preparation of compounds of formula
  • X is halogen
  • R! is an amine protecting group, which forms a carbamate with the amine
  • R 2 is trihalomethyl or pentahaloethyl, and R 3 is cyclopropylethynyl; said process comprising:
  • the present invention provides a process for the preparation of compounds of formula (IV) :
  • X is halogen
  • R 2 is trihalomethyl or pentahaloethyl
  • R3 is cyclopropylethynyl
  • R-*- is an amine protecting group, which forms a carbamate with the amine
  • the present invention provides a process for resolving the racemate of a compound of formula (IV) to produce a stereoisomer of formula (VI) :
  • X is halogen
  • R 2 is trihalomethyl or pentahaloethyl
  • R 3 is cyclopropylethynyl; said process comprising: step (1) contacting a compound of formula (IV)
  • R ⁇ is the chiral amine protecting group camphanyl
  • step (2) separating the compound of formula (V) from the resulting stereoisomers; and step (3) removing the chiral amine protecting group by heating the compound of step (2) in a solution of DMSO and water at a sufficient temperature to effect formation of a compound of formula (VI) .
  • the present invention provides a novel compound of the formula (II-a) :
  • the present invention provides a novel compound of the formula (Ill-a) .*
  • the present invention provides a novel compound of the formula (XV) :
  • the present invention provides a novel compound of the formula (XVI) :
  • the processes of the present invention are useful for the preparation of benzoxazinones, and compounds which are useful intermediates in the synthesis of benzoxazinones, which are useful as human immunodeficiency virus (HIV) reverse transcriptase inhibitors.
  • HIV reverse transcriptase inhibitors are useful for the inhibition of HIV and the treatment of HIV infection.
  • HIV reverse transcriptase inhibitors are useful for the inhibition on HIV in an ex vivo sample containing HIV or expected to be exposed to HIV.
  • HIV reverse transcriptase inhibitors may be used to inhibit HIV present in a body fluid sample (for example, a body fluid or semen sample) which contains or is suspected to contain or be exposed to HIV.
  • HIV reverse transcriptase inhibitors are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program.
  • HIV reverse transcriptase inhibitors may be used as a control or reference compound in such assays and as a quality control standard.
  • THF tetrahydrofuran
  • DMSO di ethylsulfoxide
  • DMAC dimethylacetamide
  • fcBOC t-butyloxycarbonyl
  • BuLi butyllithium
  • NaH sodium hydride
  • KHMDS potassium hexamethyldisilazide
  • suitable solvents which may be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants) , the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent .
  • suitable solvents for a particular reaction step may be selected.
  • suitable halogenated solvents include chlorobenzene or fluorobenzene.
  • Suitable ether solvents include: tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
  • Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2, 2 , 2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol .
  • Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF) , dimethylformamide (DMF), dimethylacetamide (DMAC) , 1,3- dimethyl-3,4,5, 6-tetrahydro-2 (IH) -pyrimidinone (DMPU) , 1,3- dimethyl-2-imidazolidinone (DMI) , N-me hylpyrrolidinone (NMP) , formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N- dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexa-methylphosphora-mide
  • Suitable hydrocarbon solvents include: benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene , -, o-, or p- xylene, octane, indane, nonane, or naphthalene.
  • amine protecting group refers to any group known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected by formation of a carbamate .
  • amine protecting groups include those listed in Greene and uts, "Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991), the disclosure of which is hereby incorporated by reference.
  • amine protecting groups include, but are not limited to, the following: 1) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1- methylethoxycarbonyl, and 9-fluorenylmethyloxycarbony1 (Fmoc) ; 2) aliphatic carbamate types such as tert- butyloxycarbonyl (Boc) , ethoxycarbonyl , diisopropylmethoxycarbonyl, and allyloxycarbonyl; and 3) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl .
  • aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1- methylethoxycarbonyl, and 9-fluoreny
  • Additional amine protecting groups which form a carbamate with the amine, may include, but are not limited to, the following: 2 , 7-di-t-butyl- [9- (10 , 10-dioxo- 10,10,10, 10-tetrahydrothio-xanthyl ) ] methyloxycarbonyl ; 2- trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1, l-dimethyl-2 , 2-dibromoethyloxycarbonyl ; 1- ethyl-l- (4- biphenylyl ) ethyloxycarbonyl ; benzyloxycarbonyl; p-nitro- benzyloxycarbonyl ; 2- (p-toluenesulfonyl ) ethy1-oxycarbony1 ; m-chloro-p-acyloxybenzyloxycarbonyl ,* 5-benzyisoxazolyl-
  • chiral amine protecting group refers to any group known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with a chiral amine protecting group.
  • Such chiral amine protecting groups include those listed in Greene and Wuts , "Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991) , the disclosure of which is hereby incorporated by reference .
  • Examples of chiral amine protecting groups include, but are not limited to, the following: camphanyl, menthyl and borneol .
  • lithiumating agent means any organometallic reagent that can deprotonate the ortho position of compound (I) to yield by substitution with an R 2 - substituted ester a compound of formula (II) .
  • Preferred lithiating agents are, but without limitation, alkyllithium agents.
  • Exemplary lithiating agents include, by way of example but without limitation: n-hexyllithium, n-octyllithium, n-butyllithium, t-butyllithium, sec-butyllithium, and isobutyllithium.
  • metallating agent means any organometallic reagent that can effect the formation of a compound of the formula R- ⁇ -M, wherein M is lithium or magnesium halide and add a R3- substituent to the carbonyl of compound (II) to yield a compound of formula (III) .
  • Preferred metallating agents are, but without limitation, lithium hydride, alkyllithium agents and Grignard reagents such as alkylmagnesium halides and arylmagnesiu halides.
  • Exemplary metallating agents include, by way of example but without limitation: n-butyllithium, sec-butyllithium, t-butyllithium, ethylmagnesiu bromide, and phenylmagnesium bromide .
  • strong base means any organometallic reagent, metal hydride or metal alkoxide that can effect by intramolecular cyclization the formation of compound (IV) from a compound of formula (III) .
  • Preferred strong bases are, but without limitation, potassium hexamethyldisilazide, sodium hydride, potassium hydride, lithium hydride, potassium t-butoxide, phenyllithium, triphenylmethyllithium, and alkyllithium agents.
  • alkyllithium agents include, by way of example but without limitation: n-butyllithium, sec-butyllithium, and t-butyllithium.
  • leaving group refers to any group known in the art of organic synthesis which cleaves from a substrate ester upon addition of the ester carbonyl group to another nucleophile.
  • Such leaving groups wherein R- ⁇ is an alkyl or a carbocyclic group, can include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, phenoxy, and benzyloxy.
  • Halo or halogen as used herein refers to fluoro, chloro and bromo.
  • Alkyl as used herein is intended to include both branched and straight chain saturated aliphatic hyrdocarbon groups having one to twelve carbon atoms.
  • Carbocyclic or “carbocycle” as used herein is intended to include any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) .
  • the compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or iso er form is specifically indicated.
  • Multigram scale is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more.
  • Multikilogram scale is intended to mean the scale wherein more than one kilogram of at least one starting material is used.
  • Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
  • Scheme 1 details the general synthetic method for preparation of compounds of formula (IV) .
  • This step is conducted by reacting a compound of formula (I) in a suitable solvent at a suitable temperature with at least about two molar equivalents of a lithiating agent for a suitable length of time, followed by treatment of the activated lithiated intermediate with preferably at least about one molar equivalent, more preferably about two molar equivalents, of an ester of formula R COOR ⁇ , to form a compound of formula (II) .
  • compound (I) in an aprotic solvent at a temperature below -30°C may be contacted with 2-3 molar equivalents of a lithiating agent for 1-2 hours followed by treatment in situ of the resulting activated lithiated intermediate with 1-3 molar equivalents of an R 2 COOR 5 ester at a temperature below -30°C for 0.1-2 hours to form compound (II).
  • Compound (II) may be separated from the reaction as a stable solid by quenching with a suitable agent, preferably t-butyl methyl ether, followed by standard methods of work up. An example of standard work up is shown in Example 1.
  • compound (II) may be carried forward in synthesis of compounds of formula (III) and (IV) .
  • R! is an amine protecting group, which forms a carbamate with the amine, and is preferably tert- butyloxycarbonyl or ethoxycarbonyl .
  • Preferred lithiating agents for step (1) include n-butyllithium, sec-butyllithium, t-butyllithium, n-hexyllithium and iso-butyllithium.
  • a more preferred lithiating agent is sec-butyllithium.
  • Preferred solvents and mixtures thereof for step (1) are tetrahydrofuran and cyclohexane.
  • a preferred reaction time for step (1) following addition of the lithiating agent is about one hour and following addition of the ester is about 30 minutes.
  • a preferred temperature range for step (1) is about -35 to -45°C.
  • This step comprises the alkylation of the ketone carbonyl of a compound of formula (II) in a suitable solvent with preferably at least about one equivalent of a cyclopropylethynyl lithium, said cyclopropylethynyl lithium being generated in situ for the addition of an R- ⁇ substituent to compound (II) , for a suitable length of time at a temperature sufficient to form a compound of formula (III) .
  • Generation of about three equivalents of cyclopropylethynyl lithium in situ may be carried out by contacting about three equivalents of 5-halo-l-pentyne with about six equivalents of a suitable metallating agent in a suitable solvent at a temperature below 10°C for 1-3 hours.
  • compound (III) may be separated from the reaction as a stable solid by standard methods of work up. An example of standard work up is shown in Example 2.
  • compound (III) may be carried forward in synthesis of compounds of formula (IV) .
  • Preferred 5-halo-l-pentynes for step (2) include 5- bromo-1-pentyne and 5-chloro-1-pentyne.
  • Preferred metallating agents for step (2) include n- butyllithium, sec-butyllithium, t-butyllithium, iso- butyllithium, n-hexyllithium and octyllithium.
  • a more preferred metallating agent is n-butyllithium.
  • Preferred solvents and mixtures thereof for step (2) are tetrahydrofuran, hexane and methyl t-butylether .
  • Preferred reaction times in step (2) are about two hours for generation of cyclopropylethynyl lithium and about 1.5-2 hours for addition of cyclopropylethynyl lithium to compound (II) .
  • Preferred temperature ranges for step (2) are about -5 to 5°C for generation of cyclopropylethynyl lithium and about -70 to -10°C for addition of cyclopropylethynyl lithium to compound (II) .
  • This step comprises reacting a carbinol compound of formula (III) in a suitable solvent with preferably at least about one equivalent of a suitable strong base at a sufficient temperature for a suitable length of time to form a compound of formula (IV) .
  • compound (III) in an aprotic solvent at a temperature below 20°C may be contacted with about one molar equivalent of a strong base and heated to a temperature for 2-6 hours sufficient to form compound (IV) .
  • Compound (IV) may be separated from the reaction as a stable solid by quenching with a suitable aqueous acid, followed by standard methods of work up. An example of standard work up is shown in Example 3.
  • Preferred strong bases for step (3) include n-butyllithium, sec-butyllithium, t-butyllithium, n-hexyllithium, and sodium hydride.
  • a more preferred strong base is n-butyllithium.
  • Preferred solvents and mixtures thereof for step (3) are toluene, hexane and tetrahydrofuran. Reaction times for step (3) depend on the solvent and temperature. A preferred reaction time for step (3) when the solvent is toluene following addition of the strong base is about four hours.
  • a preferred temperature range for the addition of strong base to compound (III) in step (3) is about 0-40°C.
  • This step comprises the reaction of a racemic benzoxazinone compound of formula (IV) in a suitable solvent with a chiral amine protecting group.
  • compound (IV) in an aprotic solvent may be contacted in alternating multiple additions with a total of about three equivalents of a suitable base, preferably sodium hydride or KHMDS, and a total of about 1.5 equivalents of a chiral amine protecting group at a sufficient temperature for a suitable length of time to form a compound of formula (V) .
  • Compound (V) may be separated from the reaction as a stable solid by quenching with a suitable aqueous acid, preferably acetic acid, followed by chromatography and standard methods of work up . An example of standard work up is shown in Example 4.
  • Preferred R ⁇ chiral amine protecting groups for step (4) include camphanyl, menthyl and borneol. Most preferably the chiral amine protecting group is camphanyl.
  • Preferred solvent for step (4) is tetrahydrofuran.
  • Preferred reaction time for step (4) is about eight hours .
  • a preferred temperature range for the addition of base and chiral amine protecting group to compound (IV) in step (4) is about 0-30°C.
  • This step comprises deprotection of the chiral amine protecting group, R ⁇ , on an isomericaly pure benzoxazinone compound of formula (V) in a suitable solvent by heating to sufficient temperature for a sufficient length of time to form a compound of formula (VI) .
  • Compound (VI) may be separated from the reaction as a stable solid by standard methods of work up. An example of standard work up is shown in Example 5.
  • Preferred solvents in step (4) are the mixtures of DMSO/H20 or DMAC/H2O in the ratio of 4/1. Most preferably the solvent mixture is DMSO/H2O.
  • Preferred reaction time for step (4) is about six hours .
  • Preferred temperature range in step (4) is about 100-110°C.
  • the present invention may be further exemplified by, without being limited to, reference to Scheme 2.
  • N-t-BOC-4-chloroaniline (Compound I-a) (495 g, 2.18 moles) was dissolved in 2.5 liters of anhydrous THF. The solution was cooled down to -50°C. sec-Butyllithium, 12 weight % in cyclohexane (2.91 Kg, 5.44 moles), was then added at a rate that the pot temperature was -40°C. The pot temperature was held between -39 and -42°C for 1 hour and then was cooled to -60°C. Ethyl trifluoroacetate (773 grams, 5.44 moles) was added at a rate that the temperature was below -40°C. The reaction mixture was then held at -39 to -42°C for 30 minutes. The reaction was -quenched with 3.75 liters of t-butyl methyl ether and 4.4 liters of 5% aqueous solution of acetic acid. Layers were separated.
  • the organic layer was washed twice with 3.75 liters of 7.5% sodium chloride solution.
  • the organic solution was concentrated in vacuo to a volume of approximately 2 liters.
  • Solvent exchange to acetonitrile was done by adding 1.5 liters of acetonitrile twice and concentrating the crude to a yellow paste. 500 mL of acetonitrile was then added and the mixture was warmed up to 45°C until dissolution was complete. Then it was slowly cooled down to -20°C and held for 15 minutes. The solids were filtered and the cake was washed with cold (-20°C) acetonitrile.
  • Heptane (3.5 liters) was added. The mixture was concentrated to a volume of 3 liters. Heptane (3.5 liters) was added. The mixture was concentrated to a volume of 2.2 liters. Heptane (1.75 liters) was added. The mixture was concentrated to a volume of 2.6 liters. The product precipitated and the slurry was cooled to 10°C and it was stirred overnight at 10°C. The solids were filtered and the cake was washed with heptane (1.75 liters) at 10°C. 440 grams of Compound Ill-a was obtained, 65% yield.
  • the reaction was quenched with 1.8 liters of ethyl acetate and 3.6 liters of IN acetic acid at a rate that the temperature was below 20°C. It was stirred for 10 minutes. Layers were separated. Saturated sodium bicarbonate solution (1.8 liters) was added to the organic layer and stirred for 15 minutes. Layers were separated. The organic layer was concentrated in vacuo to a thick oil. Toluene (1.8 liters) was added and the solution was divided in two portions . Each portion was concentrated to a thick oil and chromatographed on silica gel using toluene as the eluent solvent to separate the desired diastereomer . All the desired fractions were combined and concentrated to a thick oil.
  • Heptane 750 mL was added and solvents were removed again in vacuo .
  • a heptane/toluene (85:15) mixture (2.45 liters) was added and heated until dissolution (about 65°C) . It was allowed to cool down slowly and it was seeded at 40°C. At 25°C it was thick slurry. Then it was cooled to -12°C and it was filtered. The cake was washed twice with heptane/toluene (85:15) mixture (200 mL) . The solid was recrystallized from heptane/toluene (88:12) mixture (2.25 liters) .
  • N-t-BOC-4-chloroanaline (Compound I-a) (5 g, 0.022 moles) was dissolved in THF (50 mL) and cooled down to -67°C.
  • sec-Butyllithium 1.3 M in cyclohexane (42 mL, 0.055 moles) was added at a rate that the temperature was below -45°C.
  • the mixture was held at -43 to -45°C for 1/2 h.
  • Cyclopropylacetinyl trifluoromethyl ketone (4 g, 0.024 moles) was added at -72°C and it was allowed to warm up to room temperature over a period of 3 1/2 hours. The mixture was heated to reflux (69°C) and held for 1 1/2 hours.
  • JV-Butyllithium (2.5M in hexanes, 2.85 mL, 0.0071 moles) was placed in a 100 mL round bottom flask and cooled to 0 °C. THF (5 mL) was slowly added, then cyclopropylacetylene (0.51 g, 0.00773 moles). The mixture was cooled to -70 °C and a solution of compound Il-a (1 g, 0.00309 moles) in THF (1 mL) was added. The mixture was allowed to warm up and it was heated to reflux (65 °C) .
  • N-ethoxycarbonyl-4-chloroaniline (0.44 g, 0.0022 moles) was dissolved in THF (5 mL) and the solution was cooled down to -50°C.
  • sec-Butyllithiu 1.3 M in cyclohexane (4.2 mL, 0.0055 moles) was added at a rate that the pot temperature was below -40°C.
  • the mixture was then cooled to -56°C cyclopropylacetinyl trifluoromethyl ketone (0.4 g, 0.0024 moles) was added. The mixture was allowed to warm up to room temperature and then it was heated to reflux (69°C) and held for one hour.
  • N-Ethoxycarbonyl-4-chloroaniline (0.44 g, 0.0022 moles) was dissolved in THF (5 mL) and the solution was cooled down to -50°C.
  • sec-Butyllithium 1.3 M in cyclohexane (4.2 mL, 0.0055 moles) was added at a rate that the pot temperature was below -40°C.
  • the mixture was then cooled to -56°C and ethyl trifluoroacetate (0.72 g, 0.0050 moles) was added. After lh 15 minutes, the reaction was quenched with t-butyl methyl ether (10 mL) and water (10 mL) .
  • the organic layer was washed twice with water (10 mL) , and the solvent was removed in vacuo to give 0.31 g of crude Compound VII .
  • N-Menthoxycarbonyl-4-chloroaniline (0.68 g, 0.0022 moles) was dissolved in THF (5 mL) and the solution was cooled down to -50°C.
  • sec-Butyllithium 1.3 M in cyclohexane (4.2 L, 0.0055 moles) was added at a rate that the pot temperature was below -40°C.
  • MgBr2*OEt 2 (1.42 g, 0.0055 moles) was added and the mixture was then cooled to -75°C.
  • Cyclopropylacetinyl trifluoromethyl ketone (0.4 g, 0.0024 moles) was added and after 3 hours isopropyl alcohol (0.08 mL) was used to quench the reaction.
  • N-Bornyloxycarbonyl-4-chloroaniline (0.71 g, 0.0022 moles) was dissolved in THF (5 mL) and the solution was cooled down to -50°C.
  • sec-Butyllithium 1.3 M in cyclohexane (5 mL, 0.0065 moles) was added at a rate that the pot temperature was below -42°C.
  • the mixture was then cooled to -48°C.
  • Cyclopropylacetinyl trifluoromethyl ketone (0.4 g, 0.0024 moles) was added.
  • the reaction was quenched with t-butyl methyl ether (10 mL) and 2.5% aqueous acetic acid (15 mL) .
  • the organic layer was washed with brine and the solvent was removed in vacuo to obtain 1.1 g of crude Compound IX as a mixture of diastereomers .
  • the reaction was considered complete when the level of starting material was below 0.5 A% .
  • the reaction was cooled to -50°C.
  • To the resulting thin slurry was added neat ethyl trifluoroacetate (260 ml) over 30 minutes. The internal temperature was allowed to rise to -40°C during the addition.
  • the batch was aged at -50°C for one hour and was quenched by the addition of 2N HCl (1500ml) .
  • the layers were separated and the light yellow organic layer was washed with DI water (2 x 750 ml) and dried (Na2S04) .
  • the batch was concentrated in vacuo (125 mm/25°C) to afford a red oil.
  • the batch was purified by fractional distillation through a 6" Vigreux column. The fration with a boiling range of 72-80°C/100mm was collected as the product. Yield: 136.4 grams (43%) of the ketone (XV) as a light yellow oil.
  • N-Butyllithium (2 M, 800 mL, 2.00 mol) was cooled to -28 °C.
  • THF 800 mL
  • 5-chloro- 1-pentyne 100 g, 0.98 mol
  • the mixture was cooled to -55 °C and ethyl trifluoroacetate (180 mL, 1.09 mol) was added over a period of 1 h.
  • the mixture was cooled to -45 °C and quenched with 2N HCl (750 mL) .
  • Pentafluoroethyl cyclopropylethynyl ketone, (XVI) can be synthesized in an analogous fashion using ethyl pentafluoropropionate in the above reaction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne de nouveaux procédés pour la synthèse de composés de benzoxazinones qui sont utiles comme inhibiteurs de la transcriptase inverse du virus de l'immunodéficience humaine. L'invention a pour objet le benzoxazinone selon la formule (VI-a), qui est particulièrement efficace pour le traitement du VIH.
PCT/US1997/012808 1996-07-26 1997-07-24 Synthese pratique de benzoxazinones utiles comme inhibiteurs de la transcriptase inverse du vih WO1998004535A1 (fr)

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CA002260922A CA2260922A1 (fr) 1996-07-26 1997-07-24 Synthese pratique de benzoxazinones utiles comme inhibiteurs de la transcriptase inverse du vih
AU37361/97A AU3736197A (en) 1996-07-26 1997-07-24 A practical synthesis of benzoxazinones useful as hiv reverse transcripta se inhibitors

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US68679396A 1996-07-26 1996-07-26
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064405A1 (fr) * 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
US6114569A (en) * 1997-02-12 2000-09-05 Merck & Co., Inc. Efficient synthesis of A 1,4-dihydro-2H-3,1-benzoxazin-2-one
US6639071B2 (en) 1997-02-05 2003-10-28 Merck & Co., Inc. Crystal Forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one
US6673372B1 (en) 1998-06-11 2004-01-06 Bristol-Myers Squibb Pharma Company Crystalline Efavirenz
WO2012097511A1 (fr) * 2011-01-19 2012-07-26 Lonza Ltd Dmp-266 par cyclisation

Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
US8080655B2 (en) * 2009-07-20 2011-12-20 Apotex Pharmachem Inc. Methods of making efavirenz and intermediates thereof

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EP0582455A1 (fr) * 1992-08-07 1994-02-09 Merck & Co. Inc. Benzoxazinones utilisées comme inhibiteurs de transcriptase inverse de HIV
WO1995020389A1 (fr) * 1994-01-28 1995-08-03 Merck & Co., Inc. Benzoxazinones en tant qu'inhibiteurs de transcriptase inverse du vih
WO1996022955A1 (fr) * 1995-01-23 1996-08-01 Merck & Co., Inc. Synthese amelioree de cyclopropylacetylene
WO1996037457A1 (fr) * 1995-05-25 1996-11-28 Merck & Co., Inc. Synthese asymetrique de (-) 6-chloro-4-cyclopropyle-ethynyle-4-trifluoromethyle-1,4-dihydro-2h-3,1-benzoxazin-2-one

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EP0582455A1 (fr) * 1992-08-07 1994-02-09 Merck & Co. Inc. Benzoxazinones utilisées comme inhibiteurs de transcriptase inverse de HIV
WO1995020389A1 (fr) * 1994-01-28 1995-08-03 Merck & Co., Inc. Benzoxazinones en tant qu'inhibiteurs de transcriptase inverse du vih
WO1996022955A1 (fr) * 1995-01-23 1996-08-01 Merck & Co., Inc. Synthese amelioree de cyclopropylacetylene
WO1996037457A1 (fr) * 1995-05-25 1996-11-28 Merck & Co., Inc. Synthese asymetrique de (-) 6-chloro-4-cyclopropyle-ethynyle-4-trifluoromethyle-1,4-dihydro-2h-3,1-benzoxazin-2-one

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CHEMICAL ABSTRACTS, vol. 125, no. 2, 8 July 1996, Columbus, Ohio, US; abstract no. 25284, R.W. RODGER: "Entropically driven chiral separations in supercritical fluid chromatography. Confirmation of isoelution temperature and reversal of elution order" XP002045166 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6639071B2 (en) 1997-02-05 2003-10-28 Merck & Co., Inc. Crystal Forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one
US6939964B2 (en) 1997-02-05 2005-09-06 Merck & Co., Inc. Crystal forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one
US6114569A (en) * 1997-02-12 2000-09-05 Merck & Co., Inc. Efficient synthesis of A 1,4-dihydro-2H-3,1-benzoxazin-2-one
WO1999064405A1 (fr) * 1998-06-11 1999-12-16 Du Pont Pharmaceuticals Company Efavirenz sous forme cristalline
US6673372B1 (en) 1998-06-11 2004-01-06 Bristol-Myers Squibb Pharma Company Crystalline Efavirenz
WO2012097511A1 (fr) * 2011-01-19 2012-07-26 Lonza Ltd Dmp-266 par cyclisation

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CA2260922A1 (fr) 1998-02-05

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