WO1997016450A1 - Oxydation electrochimique dans la production d'un intermediaire epoxyde utilise pour synthetiser un inhibiteur de la protease du vih - Google Patents

Oxydation electrochimique dans la production d'un intermediaire epoxyde utilise pour synthetiser un inhibiteur de la protease du vih Download PDF

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WO1997016450A1
WO1997016450A1 PCT/US1996/017143 US9617143W WO9716450A1 WO 1997016450 A1 WO1997016450 A1 WO 1997016450A1 US 9617143 W US9617143 W US 9617143W WO 9716450 A1 WO9716450 A1 WO 9716450A1
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Prior art keywords
mixture
epoxide
equivalents
synthesizing
current density
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PCT/US1996/017143
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English (en)
Inventor
Kai Rossen
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Merck & Co., Inc.
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Priority claimed from GBGB9603756.9A external-priority patent/GB9603756D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU74758/96A priority Critical patent/AU7475896A/en
Publication of WO1997016450A1 publication Critical patent/WO1997016450A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention is concerned with a novel intermediate and process for synthesizing compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular, the compound disclosed and referred to as "Compound J" in U.S. Patent 5,413,999.
  • HAV human immunodeficiency virus
  • the instant process involves the preparation of the epoxide intermediate for the production of Compound J, the HIV protease inhibitor depicted above.
  • the process relates to electrochemical epoxidation of allyl acetonide 2 in an electrochemical cell with halide salt in an aqueous system with a water miscible organic cosolvent.
  • a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
  • This virus was previously known as LAV, HTLV-III, or ARV.
  • a common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. et al., Proc. Nat'l Acad.
  • the epoxide is prepared by reacting allyl acetonide 2 with NCS and Nal to give iodohydrin, which is converted in a separate step to epoxide 3 with strong base.
  • iodohydrin which is converted in a separate step to epoxide 3 with strong base.
  • epoxide 3 is prepared by the electrochemical oxidation of allyl acetonide 2 with bromide or iodide salt in an aqueous system with a water miscible organic cosolvent.
  • the halohydrin intermediate 3a is prepared by reacting allyl acetonide 2 with NCS and Nal to give iodohydrin, which is converted in a separate step to epoxide 3 with strong base.
  • (X is halo); is prepared by substituting the water miscible solvent with a water immiscible solvent, i.e., electrochemical oxidation of allyl acetonide 2 with bromide or iodide salt with a water immiscible solvent.
  • a water immiscible solvent i.e., electrochemical oxidation of allyl acetonide 2 with bromide or iodide salt with a water immiscible solvent.
  • the present process is only one step and avoids expensive and environmentally hazardous reagents such as iodide.
  • Another embodiment of the present invention is a process for the synthesizing the halohydrin of formula,
  • halo is preferably either iodide or bromide.
  • the halide salt is preferably selected from the group consisting of Nal, NaBr, KI, KBr, Et4NI and Et4NBr.
  • the water miscible cosolvent when used, is preferably selected from the group consisting of THF, acetonitrile, DMF and NMP (N-methylpyrolli- dinone), and mixtures thereof.
  • the water immiscible solvent when used, is preferably selected from the group consisting of ethyl acetate, isopropyl acetate, related esters, toluene, methylene chloride and related halogenated solvents.
  • the electrochemical process of step (b) is preferably carried out at a current density of about 0.1 A/cm ⁇ , in an undivided flow cell, at a temperature range between about 0°C and about 35°C, for a time period to complete the reaction of between about 1 hour and about 10 hours.
  • Another embodiment of the present invention is a process for the synthesizing the epoxide of formula
  • Another embodiment of this invention is the process for synthesizing the halohydrin of formula,
  • the present invention may be divided into two processes, one involving the synthesis of epoxide, the other involving synthesis of halohydrin.
  • the two processes are substantially parallel, except for the solvent used during the electrochemical oxidation of step (b).
  • a water miscible solvent is employed, whereas for the halohydrin synthesis, a water immiscible solvent is employed.
  • Reaction conditions for the formation of the epoxide are the use of a divided or undivided electrochemical cell with anodes and cathodes that are stable to the reaction conditions.
  • the anode and cathode materials include, but are not limited to, graphite, palladium, platinum, iridium, nickel, stainless steel, titanium, titanium dioxide or other special makes such as coated titanium dioxide or coated stainless steel.
  • One preferred electrochemical cell is an undivided flow cell.
  • the current density is maintained between about 0.01 A/cm ⁇ and about 0.5A/cm2, preferably about 0.1 A/cm2.
  • the choice of current density depends on the type of electrode, its geometry, the geometry of the electrochemical cell and the distance between the anode and cathode.
  • the current density is kept constant during the reaction.
  • the voltage typically rises during the reaction, but usually stays within a safe range, e.g., about 0.1-10 volts.
  • Preferred halogenating reagents include halide salts in aqueous system, such as the bromides or iodides of Na, K, Li, Ca, or Mg.
  • Other preferred halide salts include quarternary ammonium salts, such as Et4NBr.
  • Most preferred halide salts are bromides or iodides of
  • halide salt can vary between about 0.2 to about 2.0 or more equivalents of allyl acetonide 2.
  • Reaction conditions include solutions, suspensions, or other biphasic systems containing the allyl acetonide reactant, the halogenating reagent and a water miscible solvent.
  • Suitable water miscible solvents include but are not limited to THF, acetonitrile, DMF, or NMP (N- methylpyrollidinone).
  • One preferred set of reaction conditions for the synthesis of the epoxide is a suspension in a mixture of acetonitrile and water.
  • Temperature range is between about -40°C and about 100°C, but preferably between about 0°C and about 35°C.
  • the typical time span to complete the reaction is between about 1 hour and about 10 hours.
  • the time needed to complete the reaction depends on the size of the electrodes as well as the geometry of the electrochemical cell.
  • Reaction conditions for the formation of the epoxide are the use of a divided or undivided electrochemical cell with anodes and cathodes that are stable to the reaction conditions.
  • the anode and cathode materials include, but are not limited to, graphite, palladium, platinum, iridium, nickel, stainless steel, titanium, titanium dioxide or other special makes such as coated titanium dioxide or coated stainless steel.
  • One preferred electrochemical cell is an undivided flow cell.
  • the current density is maintained between about 0.01 A/cm2 and about 0.5A/cm2, preferably about 0.1 A/cm2.
  • the choice of current density depends on the type of electrode, its geometry, the geometry of the electrochemical cell and the distance between the anode and cathode.
  • the current density is kept constant during the reaction.
  • the voltage typically rises during the reaction, but usually stays within a safe range, e.g., about 0.1 -10 volts.
  • Preferred halogenating reagents include halide salts in aqueous system, such as the bromides or iodides of Na, K, Li, Ca, or Mg.
  • Other preferred halide salts include quarternary ammonium salts, such as Et4NBr.
  • Most preferred halide salts are bromide or iodides of Na or K.
  • Quantities of halide salt can vary between about 0.2 to about 2.0 or more equivalents to allyl acetonide 2.
  • Reaction conditions for halohydrin synthesis include solutions, suspensions, or other biphasic systems containing the allyl acetonide reactant, the halogenating reagent and a water immiscible solvent.
  • Suitable water immiscible solvents include but are not limited to ethyl acetate, isopropyl acetate, butylacetate and related esters, as well as toluene, methylene chloride and related halogenated solvents.
  • One preferred set of reaction conditions for the synthesis of the halohydrin 3a is a biphasic system with ethyl acetate and Nal in water.
  • Temperature range for the synthesis of halohydrin 3a by electrochemical treatment is between about -40°C and about 100°C, but preferably between about 0°C and about 35°C.
  • the typical time span to complete the reaction is between about 1 hour and about 10 hours.
  • the time needed to complete the reaction depends on the size of the electrodes as well as the geometry of the electrochemical cell.
  • the processes and intermediates of this invention are useful for the preparation of end-product compounds that are useful in the inhibition of HIV protease, the prevention or treatment of infection by the human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS.
  • Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the end-product compounds that can be made from the processes and intermediates of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • the end-product HIV protease inhibitors are also useful in the preparation and execution of screening assays for antiviral compounds.
  • end-product compounds are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
  • such compounds are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition.
  • the end-product compounds that are made from the processes and intermediates of this invention are commercial products to be sold for these purposes.
  • HIV protease inhibitor compounds that can be made from the intermediates and processes of the instant invention are disclosed in EPO 541 ,164.
  • the HIV protease inhibitory compounds may be administered to patients in need of such treatment in pharmaceutical compositions comprising a pharmaceutical carrier and therapeutically- effective amounts of the compound or a pharmaceutically acceptable salt thereof.
  • EPO 541 ,164 discloses suitable pharmaceutical formulations, administration routes, salt forms and dosages for the compounds.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • Halo means fluoro, chloro, bromo and iodo.
  • the reagents and solvents are combined in a jacketed vessel equipped with a magnetic stirrer and electrodes made from graphite and carbon felt. A constant electrical current of 0.5 A is applied and the vessel is kept at 20°C. After completion of the reaction the product 3a is isolated.
  • the acetonide was dissolved in 200 mL THF in a 100 mL 3 neck flask equipped with an addition funnel and degassed by bubbling in nitrogen for 20 min.
  • the mixture was cooled to -25°C and the allyl bromide was added via a weighed syringe.
  • the LHMDS was transferred to the addition funnel under nitrogen pressure via cannula.
  • the LHMDS was allowed to slowly drop into the magnetically stirred reaction mixture over 20 min.
  • the internal temperature reached -14°C while the cooling bath was at -30°C.
  • the mixture was aged at -20 to - 15°C for 30 min. Water ( 100 mL) and IPAC ( 100 mL) were added and the temperature rose to 5°C.
  • the lower aqueous phase was discarded and the organic phase was washed with 100 mL of 0.2 M HCl in 3% aq. NaCl, 30 mL brine, and 30 mL 0.5 M sodium bicarbonate.
  • the organic phase was evaporated (55°C, 100 Torr) to an oil, another 40 mL of IPAC were added, and the mixture was again evaporated to an oil.
  • the crude allyl acetonide may be taken directly on to the next step or purified by crystallization from 30: 1 hexane-IPAC or 30: 1 methylcyclohexane-IPAC to give the allyl acetonide as a white crystalline solid in 87% yield.
  • the solution is subjected to three alternating vacuum/nitrogen purge cycles to thoroughly degas the solution of dissolved oxygen.
  • the reaction was quenched by the addition of a solution of citric acid (35.7 g, 0.186 mol) in 186 mL of THF.
  • the mixture was aged at 15°C for 30 min following the citric acid addition.
  • the mixture was concentrated at reduced pressure (about 28" Hg) to about 30 % of the initial volume while maintaining a pot temperature of 1 1 -15°C and collecting 900 mL of distillate in a dry ice-cooled trap.
  • the solvent was then switched using a total of 2.7 L of isopropyl acetate (IP Ac) while continuing the reduced pressure distillation.
  • IP Ac isopropyl acetate
  • the solvent switch was stopped when ⁇ 1 mole % THF remained by 1 H NMR (see analytical report for GC method).
  • the maximum temperature during the distillation should not exceed 35°C.
  • the crude mixture in IPAc was washed with 1.05 L of distilled water, 1.18 L of 0.3 M sulfuric acid, and 1.18 L of 6% a
  • the pH of the mixture after the three aqueous washes was 6.5, 1.3 and 8.5, respectively.
  • HPLC analysis of the mixture at this point indicated 93-94 % assay yield for aceotonide.
  • the ratio of allyl- acetonide/epi-allylacetonide was 96:4 by HPLC (same conditions as above).
  • GC analysis at this point indicated that the hexamethyldisilazane by-product had been completely removed in the workup.
  • the mixture was aged at 68 °C until the residual penultimate compound 6 was ⁇ 0.3 area % by HPLC analysis.
  • the mixture was stirred at 68°C for 4 h, then cooled to 25°C and partitioned with ethyl acetate (80 L) and a mixture of 24 L of saturated aqueous NaHC ⁇ 3 and distilled water (14 L). The mixture was agitated at 55°C and the layers were separated. The ethyl acetate layer was washed three times with water (20 L) at 55 °C. The washed ethyl acetate layer is concentrated at atmospheric pressure to a final pot volume of 30 L. At the end of the atmospheric concentration, water (560 mL) was added to the hot solution and the mixture was cooled to 55°C and seeded with Compound J monohydrate.
  • the carboxylic acid 8 was suspended in 27 L of EtOAc and 120 mL of DMF in a 72 L 3-neck flask with mechanical stirring under N2 and the suspension was cooled to 2°C. The oxalyl chloride was added, maintaining the temperature between 5 and 8°C.
  • the assay for completion of the acid chloride formation is important because incomplete reaction leads to formation of a bis-tert- butyl oxamide impurity.
  • the reaction mixture was aged at 5°C for 1 h.
  • the resulting slurry was cooled to 0°C and the tert-butylamine was added at such a rate as to keep the internal temperature below 20°C.
  • the mixture was aged at 18°C for an additional 30 min.
  • the precipitated ammonium salts were removed by filtration.
  • the filter cake was washed with 12 L of EtOAc.
  • the combined organic phases were washed with 6 L of a 3% NaHC ⁇ 3 and 2 X 2 L of saturated aq. NaCl.
  • the organic phase was treated with 200 g of Darco G60 carbon and filtered through Solka Flok and the cake was washed with 4 L of EtOAc.
  • the EtOAc solution of 9 was concentrated at 10 mbar to 25% of the original volume. 30 L of 1 -propanol were added, and the distillation was continued until a final volume of 20 L was reached.
  • the pyrazine-2-tert-butylcarboxamide 9/1 -propanol solution was placed into the 5 gal autoclave.
  • the catalyst was added and the mixture was hydrogenated at 65°C at 40 psi (3 atm) of H2.
  • the reaction could also be monitored by TLC with EtOAc/MeOH (50:50) as solvent and Ninhydrin as developing agent.
  • HPLC 25 cm Dupont Zorbax RXC8 column with 1.5 mL/min flow and detection at 210 nm, isocratic (98/2) CH3CN/0.1 % aqueous H3PO4.
  • CH 3 CN/1 -propanol ratio by ⁇ H NMR integration showed that the CH3CN/l -propanol/H2 ⁇ ratio was 26/8/1.6.
  • the concentration in the solution was 72.2 g/ L.
  • the (S)- lO-camphorsulfonic acid was charged over 30 min in 4 portions at 20°C. The temperature rose to 40°C after the CSA was added. After a few minutes a thick white precipitate formed. The white slurry was heated to 76°C to dissolve all the solids, the slightly brown solution was then allowed to cool to 21 °C over 8 h.
  • the ee of the material was 95% according to the following chiral HPLC assay: an aliquot of 11 (33 mg) was suspended in 4 mL of EtOH and 1 mL of Et3N. Boc2 ⁇ ( 1 1 mg) was added and the reaction mixture was allowed to age for lh. The solvent was completely removed in vacuo, and the residue was dissolved in ca. 1 mL of EtOAc and filtered through a Pasteur pipet with Si ⁇ 2, using EtOAc as eluent. The evaporated product fractions were redissolved in hexanes at ca. 1 mg/mL.
  • the chiral assay was carried out using the same system as in the previous step.
  • the solution was then concentrated to ca. 10 L at an intemal temperature of ⁇ 20°C in a batch-type concentrator under 10 mbar vacuum.
  • the solvent switch was completed by slowly bleeding in 20 L of EtOAc and reconcentrating to ca 10 L.
  • the reaction mixture was washed into an extractor with 60 L of EtOAc.
  • the organic phase was washed with 16 L of 5% aqueous Na2C03 solution, 2 X 10 L Di water and 2 X 6 L of saturated aqueous sodium chloride.
  • the combined aqueous washes were back extracted with 20 L of EtOAc and the organic phase was washed with 2 X 3 L water and 2 X 4 L of saturated aqueous sodium chloride.
  • the combined EtOAc extracts were concentrated under 10 mbar vacuum with an intemal temperature of ⁇ 20°C in a 100 L batch-type concentrator to ca. 8 L.
  • the solvent switch to cyclohexane was achieved by slowly bleeding in ca. 20 L of cyclohexane, and reconcentrating to ca. 8 L.
  • To the slurry was added 5 L of cyclohexane and 280 mL of EtOAc and the mixture was heated to reflux, when everything went into solution.
  • the solution was cooled and seed (10 g) was added at 58°C.
  • the slurry was cooled to 22°C in 4 h and the product was isolated by filtration after a 1 h age at 22°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Ce procédé destiné à synthétiser les composés de la formule (I) ou (II), dans laquelle X représente halo, consiste à effectuer au minimum une oxydation électrochimique du réactif à base d'acétonide d'allyle à l'aide d'un sel d'halogénure et dans un système aqueux. Ces composés sont utiles en tant qu'intermédiaires dans la synthèse d'inhibiteurs de la rénine ou de la protéase du VIH ou d'autres protéases.
PCT/US1996/017143 1995-10-30 1996-10-25 Oxydation electrochimique dans la production d'un intermediaire epoxyde utilise pour synthetiser un inhibiteur de la protease du vih WO1997016450A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74758/96A AU7475896A (en) 1995-10-30 1996-10-25 Electrochemical oxidation in the production of an epoxide intermediate for synthesizing an hiv protease inhibitor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US812595P 1995-10-30 1995-10-30
US60/008,125 1995-10-30
GB9603756.9 1996-02-22
GBGB9603756.9A GB9603756D0 (en) 1996-02-22 1996-02-22 Electrochemical oxidation

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WO1997016450A1 true WO1997016450A1 (fr) 1997-05-09

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AR (1) AR004071A1 (fr)
AU (1) AU7475896A (fr)
TW (1) TW415948B (fr)
WO (1) WO1997016450A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5550474A (en) * 1978-10-03 1980-04-12 Kuraray Co Ltd Production of halohydrin body and/or epoxy body
JPS6048982A (ja) * 1983-08-29 1985-03-16 Takasago Corp イソサフロ−ルハロヒドリンおよび／またはイソサフロ−ルエポキシドの製造方法
WO1995023797A1 (fr) * 1994-03-04 1995-09-08 Merck & Co., Inc. Procede de fabrication d'un epoxyde

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5550474A (en) * 1978-10-03 1980-04-12 Kuraray Co Ltd Production of halohydrin body and/or epoxy body
JPS6048982A (ja) * 1983-08-29 1985-03-16 Takasago Corp イソサフロ−ルハロヒドリンおよび／またはイソサフロ−ルエポキシドの製造方法
WO1995023797A1 (fr) * 1994-03-04 1995-09-08 Merck & Co., Inc. Procede de fabrication d'un epoxyde

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 8021, Derwent World Patents Index; AN 80-37406C, XP002020722 *
DATABASE WPI Week 8517, Derwent World Patents Index; AN 85-102773, XP002020721 *

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TW415948B (en) 2000-12-21
AU7475896A (en) 1997-05-22

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