WO1995023797A1 - Process for making an epoxide - Google Patents
Process for making an epoxide Download PDFInfo
- Publication number
- WO1995023797A1 WO1995023797A1 PCT/US1995/002347 US9502347W WO9523797A1 WO 1995023797 A1 WO1995023797 A1 WO 1995023797A1 US 9502347 W US9502347 W US 9502347W WO 9523797 A1 WO9523797 A1 WO 9523797A1
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- WIPO (PCT)
- Prior art keywords
- formula
- epoxide
- acetonide
- allyl
- equivalent
- Prior art date
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- OOJWXEPSOUBJEM-NNWRFLSQSA-N CC1(C)O[C@H](Cc2c3cccc2)[C@H]3N1C([C@@H](CC=C)Cc1ccccc1)=O Chemical compound CC1(C)O[C@H](Cc2c3cccc2)[C@H]3N1C([C@@H](CC=C)Cc1ccccc1)=O OOJWXEPSOUBJEM-NNWRFLSQSA-N 0.000 description 1
- 0 CC1(C)O[C@](Cc2ccccc22)[C@]2N1C([C@@](C[C@@]1OC1)*c1ccccc1)=O Chemical compound CC1(C)O[C@](Cc2ccccc22)[C@]2N1C([C@@](C[C@@]1OC1)*c1ccccc1)=O 0.000 description 1
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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 EPO 541,168, which published on May 12, 1993, or pharmaceutically acceptable salts thereof.
- 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 iodohydrin formation of the allyl acetonide via the intermediate iodoiminolactone. Base-induced cyclization of the iodohydrin then forms the epoxide intermediate. The iodohydrin formation proceeds with high diastereoselectivity, and there is a substantial absence of hydrolysis of the amide bond linkage in this process.
- 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 nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et ah, Nature, 313, 277 (1985)].
- Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M.D. et al, Science, 231, 1567 (1986); Pearl, L.H. et al, Nature, 329, 351 (1987)].
- the end product compounds, including Compound J, that can be made from the novel intermediates and process of this invention are inhibitors of HIV protease, and are disclosed in EPO 541 ,168, which published on May 12, 1993.
- the acetonide is reacted with (S)- glycidyl tosylate in the presence of strong base LHMDS to form the epoxide (see Scheme BETA). Since both the starting material (S)- glycidyl tosylate and product are epoxides, the acetonide anion reacts also with the product epoxide; therefore, about 20% double addition byproducts after formed, in addition to the product epoxide in 71% yield. After crystallization from MeOH, an additional MTBE recrystallization was required to provide the epoxide free of dimer; consequently the overall isolated yield from the acetonide can range from 56-61%. The formation of double nucleophilic addition products is a problem inherent to the electrophile glycidyl tosylate. The (S)-glycidyl tosylate is also presently the most costly raw material in the synthesis of Compound J.
- a halohydrin from the allyl acetonide reactant comprising the first step of formation of a halohydrin from the allyl acetonide reactant, followed by the step of base-induced cyclization.
- An additional first step involves allylation of an acetonide reactant to form the allyl acetonide.
- the products are useful as intermediates for the synthesis of inhibitors of renin or HIV protease or other proteases.
- the preferred allylation reagents include allyl halides such as allyl chloride, allyl bromide or allyl iodide, as well as other allyl electrophiles such as allyl methane sulfonate or allyl esters in the presence of a transition metal catalyst.
- Most preferred allylation reagents include allyl halides such as allyl chloride, allyl bromide, and allyl iodide.
- preferred bases are strong bases and include amide bases such as the lithium, sodium, potassium or magnesium salts of amines, such as diethylamine, disopropylamine, dicyclohexylamine, piperidine, pyrrolidine, or bistrimethylsilylamine; metal alkyls such as the Ci-6 alkyllithium such as n-, iso-, sec-, and tert- butyllithium, methyl, ethyl, or aryl lithiums such as phenyllithium; Grignard reagents such as methyl ethyl, propyl, or butyl magnesium halide; alkoxides such as the methoxide, ethoxide, isopropoxide, tert- butoxide, tert-amyloxide alkoxides of lithium, sodium, potassium or magnesium.
- amide bases such as the lithium, sodium, potassium or magnesium salts of amines, such as diethylamine, disopropylamine
- the most preferred base is lithium hexamethyldisilazide (LHMDS).
- preferred solvents include ethereal solvents such as THF, DME, MTBE, diethylether, diglyme, or dibutylether; hydrocarbon solvents such as pentane, hexane, heptane, benzene, toluene or ethyl benzene; or other solvents compatible with bases and organometallic reagents such as DMSO, DMPU, NMP, TMU, TMEDA, and crown ethers; and including mixtures of these solvents.
- ethereal solvents such as THF, DME, MTBE, diethylether, diglyme, or dibutylether
- hydrocarbon solvents such as pentane, hexane, heptane, benzene, toluene or ethyl benzene
- other solvents compatible with bases and organometallic reagents such as DMSO, DMPU, NMP, TMU, TMEDA, and crown
- Most preferred solvents for allylation are ethereal solvents for allylation such as THF, DME, and MTBE.
- the preferred temperature range for the allylation is -78 °C to +30°C.
- the incubation period lasts at least 15 minutes and typically up to 3 hours.
- preferred halogenating reagents include halogens, interhalogen compounds, halonium salts, or hypohalite salts or esters, oxyhalogen salts or acids, halo-amides, halo-ureas, halo- carbamates, halo-sulfonamides, halo-amines, or other halogenated nitrogen compounds, or combinations thereof with either halide salts or phase transfer catalysts or both.
- Preferred halogenating reagents are hypohalite salts or esters, halo amides, ureas, carbamates, sulfonamides, amines, or other halogenated nitrogen compounds such as N- iodosuccinimide, N-bromosuccinimide with an iodide salt, or N- chlorosuccinimide with an iodide salt.
- Most preferred halogenating reagents are N-iodosuccinimide, N-bromosuccinimide in combination with an iodide salt, or N-chlorosuccinimide in combination with an iodide salt.
- Reaction conditions for halohydrin formation are solutions, suspensions, or other biphasic systems containing weak bases such as sodium bicarbonate, calcium carbonate, magnesium hydroxide, basic alumina, neutral alumina, sodium acetate, dibasic sodium phosphate, dibasic potassium phosphate, potassium fluoride, other salts, or water in common organic solvents.
- Preferred reaction conditions are weak bases such as sodium bicarbonate, basic alumina, potassium fluoride, or water. Most preferred reaction conditions are basic alumina, or sodium bicarbonate.
- Solvents must be compatible with the reaction conditions and include ethers, aromatic chlorinated hydrocarbons, esters, alcohols, MeCN, DMF, DMPU, or ketones.
- chlorinated hydrocarbons Preferred are chlorinated hydrocarbons, ethers and esters. Most preferred are dichloromethane, IP AC, EtOAc, DME, and MTBE. Temperature range is between about -40°C and about 100°C, but preferably between about 0 and about 35°C. Incubation lasts at least about 10 minutes and is typically stopped before about 48 hours.
- Base-induced cyclization to form the epoxide is accomplished by treating the halohydrin with a base.
- bases for such cyclization include hydroxides and oxides of lithium, sodium, potassium, magnesium, calcium, or tetraalkylammonium; alkoxides such as lithium, sodium, potassium, magnesium, and tetraalkylammonium methoxide, ethoxide, n- and iso-propoxide, n-, iso-, sec-, and tert- butoxide.
- Suitable bases include tertiary and hindered amines such as triethylamine, DIEA, DBU, DBN, DABCO, methyl morpholine, diisiopropylamine, dicyclohexyl amine, bis trimethyl-silylamine or tetra- methylpiperidine as well as metal amide salts thereof.
- Most preferred bases are lithium, sodium, potassium, or tetraalkylammonium hydroxides; alkoxides such as lithium, sodium and potassium methoxide, ethoxide, iso-propoxide, or tert-butoxide; or tertiary amines such as DIEA.
- Alkali hydroxide means LiOH, KOH, or NaOH or mixtures thereof.
- preferred solvents are ethers, esters, hydrocarbons, aromatic solvents, chlorinated hydrocarbons, ketones, water, alcohols, DMSO, MECN, DMF, or DMPU, or other polar solvents, or mixtures thereof. Most preferred solvents are ethers, esters, alcohols, or polar aprotic solvents.
- Base-induced cyclization is carried out in a temperature range of between about -40°C and about 100°C. Incubation lasts at least about 10 minutes and is typically stopped before about 48 hours.
- Hydrocarbon solvents include pentane, hexane, heptane, cyclohexane, methyl-cyclohexane, benzene, toluene and xylene.
- Aromatics as solvents include benzene, toluene, xylene, and ethyl-benzene.
- Chlorinated hydrocarbons as solvents include methylene chloride, chloroform, carbontetrachloride, dichloroethane, trichloroethane, tetrachloroethane, trichloroethylene, tetrachloroethylene, chlorobenzene and dichlorobenzene.
- Ethers as solvents include diethyl ether, dibutylether, tetrahydrof ⁇ ran, dimethoxyethane, diethoxyethane, and MTBE.
- Esters as solvents include ethyl acetate, IPAC, and ethoxyethyl acetate.
- Ketones as solvents include acetone, MEK, and MEBK.
- Alcohols as solvents include methanol, ethanol, propanol, isopropanol, butanol, and methoxyethanol.
- Polar aprotic solvents as solvents include DMF, DMA, DMSO, DMPU, TMU, NMP and acetonitrile.
- Tertiary amines as solvents include triethylamine, diisopropyl ethyl amine, pyridine, DABCO, DBU, DBN, penamethyl piperidine, and DMAP.
- said halogenating agent selected from the group consisting of N-iodosuccinimide, N-bromosuccinimide or N- chlorosuccinimide, the last two of which may be combined with an iodide salt, said solvent selected from the group consisting of dichloromethane, IPAC, EtOAc, DME, and MTBE, said weak base selected from basic alumina or sodium bicarbonate, and
- allylhalide selected from allyl chloride, allyl bromide and allyl iodide, to give the allyl acetonide of Formula ⁇ ,
- said halogenating agent selected from the group consisting of N-iodosuccinimide, N-bromosuccinimide or N- chlorosuccinimide, the last two of which may be combined with an iodide salt, said solvent selected from the group consisting of dichloromethane, IPAC, EtOAc, DME, and MTBE, said weak base selected from basic alumina or sodium bicarbonate, and
- a process of synthesizing the epoxide of Formula I comprises the steps of:
- 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 HTV 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.
- 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.
- any variable e.g., aryl, heterocycle, R, R , R , n, X, etc.
- its definition on each occurrence is independent of its definition at every other occurrence.
- combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl; t-Bu is tert-butyl); "Halo”, as used herein, means fluoro, chloro, bromo and iodo. As used herein, "aryl” is intended to mean phenyl (Ph) or naphthyl.
- 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 IP AC (100 mL) were added and the temperature rose to 5°C.
- IPAC Isopropyl acetate
- the crude allyl acetonide was dissolved in IPAC and stirred with the aqueous sodium bicarbonate and NIS for 17 h. Aqueous sodium bisulfite (38-40%) solution was added and the upper organic phase was separated. The organic phase was washed with 300 mL water and 2 x 100 mL brine. At this point the crude iodohydrin solution in IPAC can be directly taken on to the next step or the solution could be evaporated and crystallized from methylcyclohexane-IPAC to give the iodohydrin as a pale yellow crystalline solid, 13c NMR:, m.p. rotation.
- the iodohydrin in IPAC was stirred with the lithium hydroxide in water for 3 h at 25-30°C.
- the upper organic phase was washed with 200 mL water and 200 mL brine and was dried over ca 2 g of magnesium sulfate.
- the IPAC solution was filtered and evaporated (50-60°C, 100 Torr) down to ca 50 mL when the epoxide began to crystallize.
- the mixture was allowed to cool to 25°C over 30 min and 75 mL of methylcyclohexane were added in 10 mL portions with stirring over 30 min.
- the mixture was aged for 1 h and the crystals were filtered off and washed with 2 x 20 mL methylcyclohexane and dried to give 24.10 g (64%) of the epoxide as a white crystalline solid of 99.9 A% purity by HPLC.
- the mother liquor and washes were evaporated to an oil and dissolved in 40 mL IPAC.
- the solution was treated with 10 g of Darco G60 carbon for 2 h at 25°C and filtered through a pad of Solkafloc. The filtrate was evaporated down to ca 20 mL and 40 mL of methylcyclohexane were added.
- the crystalline epoxide was filtered off and washed with 2 x 10 mL methylcyclohexane to afford another 4.96 g (13%) of epoxide 96.2 A% by HPLC.
- the conversion of the iodohydrin to epoxide may also be accomplished by the addition of 1.7 M potassium- tert-butoxide in THF (0.70 mL, 1.2 mmol) or 5 M potassium hydroxide in methanol (0.24 mL, 1.2 mmol) or DIEA (155 mg, 1.2 mmol) to a solution of the iodohydrin (505 mg, 1.0 mmol) in IPAC (2-3 mL) followed by washing with 2 x 2 mL water and crystallization from methylcyclohexane-IPAC.
- N-chlorosuccinamide 22.7 g
- Aqueous sodium bicarbonate (0.5 M) 350 mL
- Isopropyl acetate (IPAC) 300 mL
- the NCS and Nal were stirred together in 200 mL of water for 20 min. The mixture turned dark brown then immediately a black solid separated out. The solid dissolved and the color faded to clear yellow with further aging.
- the crude allyl acetonide was dissolved in IPAC and stirred with the aqueous sodium bicarbonate and the clear yellow solution prepared above for 17 h. Aqueous sodium bisulfite (38-40%) solution was added and the upper organic phase was separated. The organic phase was washed with 300 mL water and 2 x 100 mL brine.
- the ethyl acetate extract was washed with 5% aqueous NaHC ⁇ 3 (10 L) and water (4 L).
- the ethyl acetate extract was dried by atmospheric distillation and solvent switched to cyclohexane (total volume of ⁇ 30L).
- the hot cyclohexane solution was allowed to slowly cool to 25°C to crystallize the product.
- the resulting slurry was further cooled to 10°C and aged for 1 h.
- the product was isolated by filtration and the wet cake was washed with cold (10°C) cyclohexane (2 X 800 mL).
- reaction mixture was stirred at -45 to -40°C for 1 h and then allowed to warm to -25°C over 1 h.
- the mixture is stirred between -25 to -22°C for 4 h (or until the starting acetonide is 3.0 area %).
- the residual ethyl acetate solvent was removed by charging 10 L of methanol and collecting 10 L of distillate. The resulting slurry was stirred at 22°C for 1 h, then cooled to 5°C and aged for 0.5 h. The product was isolated by filtration and the wet cake was washed with cold methanol (2 X 250 mL).
- the mixture was partitioned with ethyl acetate (40 L) and water (3 L). The mixture was agitated and the layers were separated.
- the HPLC assay yield of 6 in ethyl acetate was 86.5%.
- the penultimate compound 6 in DMF was directly used in the next step without further purification.
- 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 NaHC03 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 mixture was cooled to 4°C and filtered to collect the product. The product was washed with cold ethyl acetate (2 X 3 L), and dried at house vacuum at 25 °C to afford 2905 g (70.7%) of Compound J monohydrate as a white solid.
- 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. NaCI.
- 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.
- Acetonitrile 39 L Water 2.4 L
- the solution of amine 10 in 1 -propanol was charged to a 100 L flask with an attached batch concentrator.
- the solution was concentrated at 10 mbar and a temperature ⁇ 25°C to a volume of ca 12 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 ⁇ (11 mg) was added and the reaction mixture was allowed to age for 1 h. 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 Na2C ⁇ 3 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 internal 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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Abstract
Description
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Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SK1122-96A SK283067B6 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
NZ281866A NZ281866A (en) | 1994-03-04 | 1995-02-27 | Epoxide synthesis of condensed 1,3-oxazoles |
DK95911105T DK0748319T3 (en) | 1994-03-04 | 1995-02-27 | Process for preparing an epoxide |
EP95911105A EP0748319B1 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
HU9602412A HU222750B1 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
JP52294995A JP3871705B2 (en) | 1994-03-04 | 1995-02-27 | Epoxide synthesis method |
AT95911105T ATE210662T1 (en) | 1994-03-04 | 1995-02-27 | METHOD FOR PRODUCING EPOXIES |
CA002183976A CA2183976C (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
SI9530548T SI0748319T1 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
UA96103798A UA45968C2 (en) | 1994-03-04 | 1995-02-27 | METHOD OF OBTAINING EPOXY (OPTIONS) |
BR9506977A BR9506977A (en) | 1994-03-04 | 1995-02-27 | Process for synthesizing an epoxide and compound |
RU96120179A RU2137769C1 (en) | 1994-03-04 | 1995-02-27 | Method of preparing epoxide |
RO96-01750A RO117696B1 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide compound |
AU18828/95A AU690231B2 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
MX9603871A MX9603871A (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide. |
DE69524578T DE69524578T2 (en) | 1994-03-04 | 1995-02-27 | METHOD FOR PRODUCING EPOXIES |
FI963452A FI120259B (en) | 1994-03-04 | 1996-09-03 | A process for preparing the epoxide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US20607494A | 1994-03-04 | 1994-03-04 | |
US206,074 | 1994-03-04 |
Publications (1)
Publication Number | Publication Date |
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WO1995023797A1 true WO1995023797A1 (en) | 1995-09-08 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1995/002347 WO1995023797A1 (en) | 1994-03-04 | 1995-02-27 | Process for making an epoxide |
Country Status (25)
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EP (1) | EP0748319B1 (en) |
JP (1) | JP3871705B2 (en) |
KR (1) | KR100387741B1 (en) |
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997016450A1 (en) * | 1995-10-30 | 1997-05-09 | Merck & Co., Inc. | Electrochemical oxidation in the production of an epoxide intermediate for synthesizing an hiv protease inhibitor |
US5981759A (en) * | 1997-06-20 | 1999-11-09 | Merck & Co., Inc. | Process for indinavir intermediate |
HRP960369B1 (en) * | 1995-08-08 | 2009-05-31 | Merck & Co. Inc. | Process for the preparation of epoxide |
WO2011137222A1 (en) * | 2010-04-30 | 2011-11-03 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
US8853147B2 (en) | 2009-11-13 | 2014-10-07 | Onyx Therapeutics, Inc. | Use of peptide epoxyketones for metastasis suppression |
US8921324B2 (en) | 2007-10-04 | 2014-12-30 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US9051353B2 (en) | 2009-03-20 | 2015-06-09 | Onyx Therapeutics, Inc. | Crystalline tripeptide epoxy ketone protease inhibitors |
US9205125B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9309283B2 (en) | 2012-07-09 | 2016-04-12 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9359398B2 (en) | 2010-03-01 | 2016-06-07 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
US9511109B2 (en) | 2008-10-21 | 2016-12-06 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
US9657058B2 (en) | 2006-06-19 | 2017-05-23 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104692987B (en) * | 2015-01-22 | 2017-05-17 | 北京大学 | Cheap and efficient synthesis method of halogenated alcohols and derivatives thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0521686A1 (en) * | 1991-07-02 | 1993-01-07 | Merck & Co. Inc. | Stereoselective production of hydroxyamide compounds from chiral a-amino epoxides |
EP0541168A1 (en) * | 1991-11-08 | 1993-05-12 | Merck & Co. Inc. | HIV protease inhibitors useful for the treatment of aids |
-
1995
- 1995-02-24 TW TW084101733A patent/TW380137B/en not_active IP Right Cessation
- 1995-02-27 RU RU96120179A patent/RU2137769C1/en not_active IP Right Cessation
- 1995-02-27 WO PCT/US1995/002347 patent/WO1995023797A1/en active IP Right Grant
- 1995-02-27 CZ CZ19962543A patent/CZ291816B6/en not_active IP Right Cessation
- 1995-02-27 DE DE69524578T patent/DE69524578T2/en not_active Expired - Lifetime
- 1995-02-27 JP JP52294995A patent/JP3871705B2/en not_active Expired - Fee Related
- 1995-02-27 MX MX9603871A patent/MX9603871A/en unknown
- 1995-02-27 CA CA002183976A patent/CA2183976C/en not_active Expired - Fee Related
- 1995-02-27 SK SK1122-96A patent/SK283067B6/en not_active IP Right Cessation
- 1995-02-27 UA UA96103798A patent/UA45968C2/en unknown
- 1995-02-27 KR KR1019960704836A patent/KR100387741B1/en not_active IP Right Cessation
- 1995-02-27 BR BR9506977A patent/BR9506977A/en not_active IP Right Cessation
- 1995-02-27 RO RO96-01750A patent/RO117696B1/en unknown
- 1995-02-27 EP EP95911105A patent/EP0748319B1/en not_active Expired - Lifetime
- 1995-02-27 HU HU9602412A patent/HU222750B1/en not_active IP Right Cessation
- 1995-02-27 AT AT95911105T patent/ATE210662T1/en active
- 1995-02-27 PT PT95911105T patent/PT748319E/en unknown
- 1995-02-27 CN CN95192714A patent/CN1066728C/en not_active Expired - Lifetime
- 1995-02-27 AU AU18828/95A patent/AU690231B2/en not_active Ceased
- 1995-02-27 DK DK95911105T patent/DK0748319T3/en active
- 1995-02-27 NZ NZ281866A patent/NZ281866A/en not_active IP Right Cessation
- 1995-02-27 ES ES95911105T patent/ES2167419T3/en not_active Expired - Lifetime
- 1995-03-02 HR HR950096A patent/HRP950096B1/en not_active IP Right Cessation
- 1995-03-03 YU YU14595A patent/YU49010B/en unknown
-
1996
- 1996-09-03 FI FI963452A patent/FI120259B/en not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0521686A1 (en) * | 1991-07-02 | 1993-01-07 | Merck & Co. Inc. | Stereoselective production of hydroxyamide compounds from chiral a-amino epoxides |
EP0541168A1 (en) * | 1991-11-08 | 1993-05-12 | Merck & Co. Inc. | HIV protease inhibitors useful for the treatment of aids |
Non-Patent Citations (1)
Title |
---|
DAVID ASKIN ET AL: "Highly diastereoselective reaction of a chiral,non-racemic amide enolate with (s)-glycidyl tosylate.Synthesis of the orally active HIV-1 protease inhibitor L-735,524", TETRAHEDRON LETTERS, vol. 35, no. 5, 31 January 1994 (1994-01-31), OXFORD GB, pages 673 - 676 * |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
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HRP960369B1 (en) * | 1995-08-08 | 2009-05-31 | Merck & Co. Inc. | Process for the preparation of epoxide |
WO1997016450A1 (en) * | 1995-10-30 | 1997-05-09 | Merck & Co., Inc. | Electrochemical oxidation in the production of an epoxide intermediate for synthesizing an hiv protease inhibitor |
US5981759A (en) * | 1997-06-20 | 1999-11-09 | Merck & Co., Inc. | Process for indinavir intermediate |
US9205125B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US10150794B2 (en) | 2005-11-09 | 2018-12-11 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9205126B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9205124B2 (en) | 2005-11-09 | 2015-12-08 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US9657058B2 (en) | 2006-06-19 | 2017-05-23 | Onyx Therapeutics, Inc. | Compounds for enzyme inhibition |
US8921324B2 (en) | 2007-10-04 | 2014-12-30 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US8921583B2 (en) | 2007-10-04 | 2014-12-30 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US9511109B2 (en) | 2008-10-21 | 2016-12-06 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
USRE47954E1 (en) | 2008-10-21 | 2020-04-21 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
US10596222B2 (en) | 2008-10-21 | 2020-03-24 | Onyx Therapeutics, Inc. | Combination therapy with peptide epoxyketones |
US9403868B2 (en) | 2009-03-20 | 2016-08-02 | Onyx Therapeutics, Inc. | Crystalline tripeptide epoxy ketone protease inhibitors |
US9051353B2 (en) | 2009-03-20 | 2015-06-09 | Onyx Therapeutics, Inc. | Crystalline tripeptide epoxy ketone protease inhibitors |
US8853147B2 (en) | 2009-11-13 | 2014-10-07 | Onyx Therapeutics, Inc. | Use of peptide epoxyketones for metastasis suppression |
US9359398B2 (en) | 2010-03-01 | 2016-06-07 | Onyx Therapeutics, Inc. | Compounds for immunoproteasome inhibition |
US20130053557A1 (en) * | 2010-04-30 | 2013-02-28 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
CN103025730A (en) * | 2010-04-30 | 2013-04-03 | 印第安纳大学研究及科技有限公司 | Processes for preparing linezolid |
US9656973B2 (en) | 2010-04-30 | 2017-05-23 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
US9206141B2 (en) * | 2010-04-30 | 2015-12-08 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
WO2011137222A1 (en) * | 2010-04-30 | 2011-11-03 | Indiana University Research And Technology Corporation | Processes for preparing linezolid |
US9878047B2 (en) | 2012-07-09 | 2018-01-30 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9315542B2 (en) | 2012-07-09 | 2016-04-19 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US9309283B2 (en) | 2012-07-09 | 2016-04-12 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
US10682419B2 (en) | 2012-07-09 | 2020-06-16 | Onyx Therapeutics, Inc. | Prodrugs of peptide epoxy ketone protease inhibitors |
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