Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• This invention relates to an efficient process for large-scale stereoselective production of (3i?) ⁇ 3-(2,3-dihydrobenzofuran-5-yl)-l, 2,3,4- tetrahydropyrrolo[3,4-b]quinolin-9-ones and key intermediates used for the preparation of benzofuranyl pyrroloquinolones as potent and selective PDE5 inhibitors for the treatment of erectile dysfunction, as well as pharmaceutical compositions and methods
• Patents and publications in the family of WO 01/87882 include United States
• Patent 6,818,646 and United States Patent 6,635,638 United States Patent Application 2005/0113402 (Al), published May 26, 2005; United States Patent Application 2004/0044021 (Al), published March 24, 2004 and United States Patent Application 2002/0010183 (Al), published January 24, 2002 which are incorporated herein by
• compound 65 (referred to as #65, mentioned in example 50A, on page 74 of the mentioned WO 01/87882) and compound 136 (referred to as #136, mentioned in example 92, on page 101 of the mentioned WO 01/87882).
• An important intermediate in the synthesis of these compounds is the (3R) ⁇ 3-(2,3-dihydro-benzofuran-5-yl)-l,2,3,4-tetrahydro- pyrrolo[3,4-b]quinolin-9-one compound with formula (A) as shown hereunder.
• the present inventive synthesis route is advantageous in a number of ways.
• the starting materials; tryptamine and 2,3-dihydrobenzo[b]furan-5-carboxaldehyde are commercially available and inexpensive; and the present route does not require chromatographic purifications to purify intermediates and the final product.
• the resolving reagent, N-acetyl-D-leucine, used to separate the (R)- enantiomer from the (S)-enantiomer is recovered with high chemical and enantiomeric purity.
• the (S)-enantiomer enriched mixture is epimerized to a near racemic mixture with high (>93%) yield, which is resolved with the recycled resolving reagent and produced an additional 33 ⁇ 3% yield of the desired (R)-enantiomer with high chemical and enantiomeric purity.
• AU processes are scalable and reproducible.
• the present invention is directed to a short practical commercial process for the efficient enantioselective synthesis and an efficient production process of a compound of general formula I:
• X is selected from the group consisting of -CH 2 - , NH, O and S;
• R is selected from H, C 1-1O aIlCyI, C 1-1O aIlCyI substituted with C 1-6 alkyloxy, or C 1-1O aIlCyI substituted with halo, aryl, heteroaryl, heterocycle, C(O)-C 1-1O aIlCyI, C(O)-aryl, C(0)0-Ci.ioalkyl or C(0)0-aryl.
• the present invention provides a process, which comprises as a first step, the condensation of the readily accessible tryptamine, with an aldehyde of formula II to form a Schiff base of formula XI.
• the formation of the Schiff base of formula XI can be carried out in a suitable solvent, such as xylene, toluene or other water-azeotropic solvents.
• the water that is formed during the reaction is removed using a trap such as a Dean-Stark apparatus.
• a trap such as a Dean-Stark apparatus.
• the solvent can be removed, for instance, by evaporation under reduced pressure.
• the Schiff base of formula XI can be dissolved in a suitable solvent, such as, for example, dichloromethane.
• a suitable solvent such as, for example, dichloromethane.
• An appropriate acid preferably a strong Br ⁇ nsted or Lewis acid, for example trifluoroacetic acid, is added as a catalyst.
• the reaction is performed at a temperature and time sufficient to cyclize to a tetrahydro- ⁇ -carboline derivative represented by formula DI. Suitable temperatures are dependent upon the solvent used. For example, temperatures of up to 60 °C, preferably below 50 0 C can be used.
• the resulting tetrahydro- ⁇ -carboline derivative of formula DI can be isolated and purified.
• the reaction can preferably be carried out under an inert atmosphere such as a nitrogen atmosphere.
• the resulting tetrahydro- ⁇ -carboline derivative of formula EI is a racemic mixture of (i?)-enantiomer of formula XII and (,S)-enantiomer of formula XDI.
• the next step is the reaction of the tetrahydro- ⁇ -carboline derivative represented by formula EI with a stoichiometric amount of N-acetyl-D-leucine in an organic solvent, preferably a polar solvent, such as for example an alcohol, e.g. methanol.
• an organic solvent preferably a polar solvent, such as for example an alcohol, e.g. methanol.
• the mixture is heated to a temperature and for a period of time that is sufficient to produce the (R)-enantiomer salt of the compound of formula IV with high chemical and enantiomeric purity.
• the (R)-enantiomer is produced as a crystalline solid, which is essentially free of the (S ⁇ -enantiomer.
• the mother liquor contains a mixture of (R)-enantiomer salt of formula IV and (,S)-enantiomer salt of formula VI, which is enriched towards the (S)-enantiomer.
• suitable temperature ranges for the heating are within a temperature range between 30 °C and 80 0 C.
• An example of the present invention is a reaction temperature in a range of from about 40 °C to about 70 0 C.
• the intermediate of formula HI can be added to the reaction mixture, preferably portion wise over a certain period. It was unexpectedly found that the intermediates of formula III could be resolved using N-acetyl-D-leucine. High enantiomeric excesses are obtained by this method.
• An example of the present invention is an enantiomeric excess of about 80 %. Another example is an enantiomeric excess of about 90 %. Another example is an enantiomeric excess of about 95 %. Another example is an enantiomeric excess of about 97 % or more.
• the resulting mother liquor can be saved for a recycle process.
• the mother liquor can be concentrated to dryness and the resulting solid material can be dissolved in an appropriate solvent, such as, for example, dichloromethane.
• An appropriate base can be added, such as, for example an alkali metal hydroxide, e.g. NaOH.
• the base can be added as a solution in water at a certain concentration (such as for example IN).
• the resulting reaction mixture can be agitated for an appropriate period. Appropriate periods are for example 5 to 30 minutes, preferably about 15 minutes.
• the organic phase can be condensed to dryness and can be set aside for epimerization.
• the aqueous phase can be cooled to a temperature ranging from about 0 °C to about 15 °C and then acidified with an appropriate acid, such as, for example a hydrohalic acid, e.g. a hydrochloric acid.
• the acid is preferably in a concentrated form so that a pH of about one can be reached.
• the acid aqueous phase can be then agitated.
• the addition of concentrated acid is normally an exothermic process and the addition of the concentrated acid can be done slowly.
• the resulting solid can be isolated and washed appropriately, such as, for example with water (preferably de-ionized water) at lower temperature.
• the solid can be dried by, for example, air-suction and is placed in an oven under vacuum in a range of from about 146 to about 210 hPa.
• the temperature in the drying oven ranges from about 30 0 C to about 90 °C, preferably around 60 °C for an appropriate period.
• An appropriate period of time ranges from about 4 hours to about 24 hours.
• An example of the present invention is a a period of 16 hours.
• the resulting solid is the resolving agent N-acetyl-D-leucine in a sufficiently pure form to be used again without further purification. This can be advantageous when applying the present inventive process at larger scales, such as industrial scales.
• One of the other inventive aspects of the present process is the epimerization of the intermediate of formula VI to the intermediate of formula V.
• This epimerization can be very advantageous when applying the process at larger scales, especially industrial scales.
• the undesired enantiomer can be converted into the desired enantiomer then that adds to the economic advantage of the process.
• the solid, recovered from the organic phase described in the process step to recover the N-acetyl-D-leucine, can be suspended in an appropriate solvent, such as, an apolar solvent, e.g. dichloromethane. .
• the suspension can be stirred under an inert atmosphere, such as, for example, nitrogen.
• the suspension can be preferably cooled to a temperature ranging from about 0°C about 15 0 C, preferably to a temperature of about 10 0 C.
• an acid such as, for example, trifluoroacetic acid can be added to the mixture.
• the acid can be preferably added over an appropriate period of time and not all at once.
• the reaction mixture can be heated.
• the temperature depends on the solvent used. For example when dichloromethane is used the reaction mixture can be heated to the boiling point of the mixture, i.e. about 40 °C, thus allowing the temperature to be maintained under reflux for an appropriate period of time.
• An appropriate period can be between about 4 hours to about 48 hours, preferably between about 10 to about 24 hours.
• An example of the present invention is a period of about 16 hours.
• the mixture can be cooled to about 20 0 C and preferably can be agitated while an alkaline solution, such as, for example NaOH solution; for instance, a 7 % aqueous solution of NaOH can be added over an appropriate period.
• an alkaline solution such as, for example NaOH solution
• a 7 % aqueous solution of NaOH can be added over an appropriate period.
• An appropriate period depends on the actual reactants and the amounts of reactants used. Appropriate periods range from about 5 minutes to 2 hours, preferably about 20 minutes.
• the organic phase can be washed with brine and subsequently concentrated to dryness.
• the resulting material can be placed in a vacuum oven under a vacuum, with a pressure in a range of between about 146 hPa to about 210 hPa.
• the material is a racemic intermediate of formula V and can, as such, be used to undergo resolution again.
• the next step in the process can be the protection of the nitrogen atom in the six-membered ring.
• Several protective groups for the nitrogen atom are available.
• a number of art-known protective methods are known from the literature, for instance T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999.
• the (R)-enantiomer salt of formula IV can be reacted with a stoichiometric excess of a substituted allyl halide, aryl halide or aryl-alkyl halide, or substituted alkyl/aryl carboxylic acid halide, or dialkyl/diaryl dicarbonate in the presence of an inorganic or organic base, such as potassium carbonate or triethylamine.
• an inorganic or organic base such as potassium carbonate or triethylamine.
• This reaction can be performed in a solvent for a time and at a temperature sufficient to produce the TV-ally]-, or 7V-aryl-, or iV-alkyl/arylcarbonyl, or alkyl/aryl ester of N-carbonic acid of the (R)-enantiomer of the compound of formula VH.
• the (R)-enantiomer of the compound of formula VII is normally in the filtrate, and the potassium salt of the resolving reagent of the compound of formula Xa is found as a solid.
• a benzyl halide preferably benzyl bromide
• the reaction temperature range in that case is between 0 °C and 60 0 C.
• the reaction is preferably carried out under inert atmosphere, such as, for instance, a permanent nitrogen flow.
• the reaction work-up can be done according to art-known methods.
• the N-acetyl-D-Leucine can be recovered.
• the purity of the N- acetyl-D-Leucine can be high enough for the N-acetyl-D-Leucine to be reused as a resolving agent.
• the next step in the synthesis can be an oxidative rearrangement.
• the protected (7?)-enantiomer of formula VII is treated with a large stoichiometric excess of an oxidative agent in the presence of a phase transfer catalyst.
• the reaction is performed in a solvent, for a time and at a temperature sufficient to produce a N-allyl-, or iV-aryl-, or N-alkyl/arylcarbonyl, or alkyl/aryl ester of N- carbonic acid of (R)-enantiomer of the compound of formula VIH.
• the reaction can be performed by mixing an appropriate oxidant, such as, for example potassium superoxide with an appropriate solvent, such as, dimethylformamide under an inert atmosphere, such as for example, nitrogen, and adding to that mixture an appropriate phase transfer catalyst, such as, for example, Aliquat® 175 (methyltributylaramonium chloride).
• an appropriate oxidant such as, for example potassium superoxide
• an appropriate solvent such as, dimethylformamide
• an inert atmosphere such as for example, nitrogen
• an appropriate phase transfer catalyst such as, for example, Aliquat® 175 (methyltributylaramonium chloride).
• the reaction mixture can be heated and subsequently the intermediate of formula (VIE) dissolved in an appropriate solvent such as dimethylformamide can be added to the mixture. While agitating the resulting reaction mixture the reaction can be kept at a constant temperature between 20 0 C to 80 °C, preferably between 40 °C and 60 0 C for an appropriate period of time which may be a number of hours, for instance 4 hours.
• the reaction mixture When the reaction has reached its endpoint, the reaction mixture can be cooled and added to water, preferably de-ionized (D.I.) water with fast agitation under nitrogen atmosphere. After stirring for an appropriate time, the reaction mixture can be acidified with a hydrohalic acid, preferably with a hydrochloric acid solution.
• water preferably de-ionized (D.I.) water with fast agitation under nitrogen atmosphere.
• the reaction mixture can be acidified with a hydrohalic acid, preferably with a hydrochloric acid solution.
• the resulting solid can be isolated by filtration and then the filtrate can be washed with an appropriate solvent for instance water.
• the resultant cake can then be dried by air-suction and placed in a vacuum oven under a vacuum of 146 to 210 hPa at a temperature of about 60 °C for a number of hours, for instance 16 hours.
• Further purification can be performed by re-slurrying the resulting solid in an appropriate solvent, such as, for example, an alcohol, e.g. methanol at higher temperatures, such as for instance the boiling point of the alcohol and then cooling down and filtering the resulting mixture.
• an appropriate solvent such as, for example, an alcohol, e.g. methanol at higher temperatures, such as for instance the boiling point of the alcohol and then cooling down and filtering the resulting mixture.
• the deprotection method depends upon the protecting group that was used.
• the N-allyl-, or N-aryl-, or iV-alkyl/arylcarbonyl, or alkyl/aryl ester substituted iV-carbonic acid (/?)-enantiomer of formula VIII can be reacted under hydrogen pressure in the presence of a stoichiometric amount of an acid in an alcoholic solvent, for a time and temperature sufficient to produce a salt of the (R) enantiomer of formula IX.
• Suitable catalysts which can be used are platinum or another art-known catalysts, but preferred can be palladium on charcoal. After purging the reactor with nitrogen, the reactor can be purged with hydrogen and then an appropriate pressure of hydrogen can be kept in the reactor (appropriate pressure is in a range of about 3450 kPa).
• C 1-1O aIlCyI whether used alone or as part of a substituent group, means a straight or branched chain monovalent hydrocarbon alkyl radical or alkyldiyl linking group comprising from 1 to 10 carbon atoms, wherein the radical is derived by the removal of one hydrogen atom from a single carbon atom and the alkyldiyl linking group is derived by the removal of one hydrogen atom from each of two carbon atoms in the chain, such as, for example methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, tertiary butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 1-octyl, 2-octyl, 3-octyl, 1-nonyl, 2-nonyl
• Q ⁇ alkyloxy means a straight or branched chain alkyloxy group comprising from 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
• An alkoxy radical may be attached to a core molecule and further substituted where indicated
• halo means includes fluoro, chloro, bromo, and iodo.
• aryl refers to an aromatic cyclic hydrocarbon ring radical derived by the removal of one hydrogen atom from a single carbon atom of the ring system.
• Typical aryl radicals - include phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, anthracenyl and the like.
• aromatic refers to a cycloalkylic hydrocarbon ring system having an unsaturated, conjugated ⁇ electron system.
• heteroaryl refers to an heteroaromatic cyclic hydrocarbon ring radical derived by the removal of one hydrogen atom from a single ring carbon atom of the ring system.
• Typical heteroaryl radicals include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, azaindolyl, isoindolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, azaindazolyl, benzimidazolyl, benzthiazolyl, benzox
• heterocycle refers to a saturated or partially unsaturated monocyclic ring radical derived by the removal of one hydrogen atom from a single carbon or nitrogen ring atom.
• Typical heterocyclyl radicals include 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3- dioxolanyl, 2-imidazolinyl (also referred to as 4,5-dihydro-lH-imidazolyl), imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, tetrazolyl, tetrazolidinyl, piperidinyl, 1,4- dioxanyl > morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, azetidinyl, azepanyl, hexahydro- 1 ,4
• high chemical purity means a chemical purity of more than 90 %, more specifically a chemical purity of more than 95 % and preferably a chemical purity of 98%, determined by HPLC analysis (area normalization %).
• enantiomeric purity refers to an enantiomeric excess (e.e.) of more than 90 %, more specifically an enantiomeric excess of more than 95 % and preferably an enantiomeric excess of more than 97% determined by chiral HPLC analysis (area normalization %).
• enantiomeric excess is as defined in standard chemical textbooks.
• the phrase "essentially free of the (S)-enantiomer" as used herein means that the compound contains less that about 4%, preferably less that about 2% of the (S)- enantiomer.
• a strong Br ⁇ nsted acid an organic or inorganic acid which is a proton donor including sulfuric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, substituted benzoic acid, acetic acid, trichloroacetic acid, tribromoacetic acid and trifluoroacetic acid.
• hydrochloric acid, /?-toluenesulfonic acid, or trifluoroacetic acid is preferred.
• the use of trifluoroacetic acid is more preferred.
• a Lewis acid any molecular species with a vacant orbital to accept a pair of electrons such as, for example, an aluminum halide (e.g. aluminum chloride, or bromide or iodide), boron halide (e.g. boron trichloride, or tribromide, or trifluoride), antimony halide (e.g. antimony (i ⁇ )/(V) chloride, or fluoride , or iodide), ferric halide (e.g. ferric (HI) chloride, or bromide), tin halide (e.g. tin (IV) chloride, or bromide, or fluoride), and zinc halide (e.g. zinc chloride, or bromide).
• aluminum chloride, boron trifluoride, tin (IV) chloride or ferric (Iff) chloride is preferred.
• the use of aluminum chloride or boron trifluoride is more preferred.
• an organic base is meant an organic tertiary alkyl/aryl/heterocyclic amine including trimethylamine, triethylamine, tripropylamine, iV-substituted piperidine, JV-substituted morpholine, substituted pyridine, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DabcoTM), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and l,l,3',3'-tetramethylguanidine (TMG).
• DBN diazabicyclo[4.3.0]non-5-ene
• DabcoTM 1,8- diazabicyclo[5.4.0]undec-7-ene
• TMG 1,8- diazabicyclo[5.4.0]undec-7-ene
• TMG l,l,3',3'
• substituted allyl or aryl halides is meant a straight or branched allyl halide and substituted benzyl halides including allyl chloride, allyl bromide, methylallyl chloride, methylallyl bromide, substituted benzyl chloride, benzyl bromide, benzyl iodide.
• substituted allyl bromide, benzyl chloride or benzyl bromide is preferred.
• the use of benzyl bromide is more preferred.
• substituted alkyl/arylcarboxylic acid halide is meant a straight or branched C 2 -C 6 alkylcarboxylic acid or acid halide and substituted arylcarboxylic acid or acid halide including acetyl chloride or bromide, propionyl chloride or bromide, 2-methylpropionyl chloride or bromide, butyryl chloride, 2-methylbutyryl chloride, 2- ethylbutyryl chloride, 2-methylpentanoyl chloride, 2-ethylpentanoyl chloride, cyclopentanylcarboxylic chloride, hexanoyl chloride, 2-methylhexanonyl chloride, 2- ethylhexanoyl chloride and cyclohexanylcarboxylic chloride.
• Substituted arylcarboxylic acid halide including substituted substituted furan-2-carboxylic acid or acid chloride, 2- thiophenecarbpnyl chloride, nicotinoyl chloride, substituted benzoyl chloride.
• substituted furan-2-carboxylic acid or acid chloride or 2-thiophenecarboxylic acid chloride is preferred.
• substituted furan-2-carboxylic acid or acid chloride is more preferred.
• dialkyl/diaryl dicarbonate is meant a straight or branched dialkyl dicarbonate and substituted diaryl dicarbonate including diallyl dicarbonate, di-tert- dibutyl dicarbonate, and dibenzyl dicarbonate.
• diallyl dicarbonate di-tert- dibutyl dicarbonate
• dibenzyl dicarbonate dibenzyl dicarbonate is preferred.
• dibenzyl dicarbonate is more preferred.
• an oxidative agent or “oxidant” is meant an inorganic or organic oxygen-containing compound which can cleave a carbon-carbon double bond to two carbonyls
• agents include sodium perchlorate, sodium perborate, sodium periodate, potassium permanganate, sodium permanganate, potassium superoxide (KO 2 ), sodium persulfate, sodium hypochlorite, hydrogen peroxide, singlet oxygen, oxygen (O 2 ), ozone, 3-chloroperoxybenzoic acid (mCPBA) or potassium peroxy monosulfate (OXONE ® , E.I. Dupont DeMours brand of potassium peroxy monosulfate).
• mCPBA 3-chloroperoxybenzoic acid
• OXONE ® E.I. Dupont DeMours brand of potassium peroxy monosulfate
• An example of the present invention includes the use of reagents such as hydrogen peroxide, r ⁇ CPBA, OXONE ® , potassium superoxide, O 2 /NaH or f-BuOK.
• reagents such as hydrogen peroxide, r ⁇ CPBA, OXONE ® , potassium superoxide, O 2 /NaH or f-BuOK.
• the use of hydrogen peroxide or potassium superoxide are is preferred.
• phase transfer catalyst an organic alkyl/aryl quaternary ammonium halide salt including methyltributylammonium chloride (Aliquat ® 175), tricaprylylmethylammonium chloride (Aliquat ® 366), tetraethylammonium bromide (TEAB), tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride and 1,4,7, 10,13, 16-hexaoxacyclooctadencane (18- crown-6).
• TEAB tetraethylammonium bromide
• TBAB tetrabutylammonium bromide
• triethylbenzylammonium chloride 1,4,7, 10,13, 16-hexaoxacyclooctadencane (18- crown-6).
• Aliquat ® 175, Aliquat ® 366 or 18-crown-6 is preferred.
• Step 1 Formation of the formula 3 compound, involves a Pictet-Spengler condensation reaction of tryptamine, with the aldehyde of formula 2 in the presence of a solvent to produce a Schiff base in situ.
• the preferred solvent is toluene, but other aromatic hydrocarbons such as xylene; or an ether such as diglyme (2-methoxyethyl ether) may also be used.
• the condensation reaction is normally carried out by heating the reaction mixture of tryptamine and Compound 2 in toluene to reflux temperature under an inert atmosphere such as nitrogen or argon.
• the reaction is - driven to completion by removal of water from the reaction mixture. Removal of water is achieved by azeotropic distillation of toluene (or other solvent used) and water in the presence of a Dean-Stark trap.
• the reaction is refluxed for a sufficient time, preferably at least 6 hours, but as much as 10 hours, to complete the formation of Schiff base.
• the cyclization of the intermediate Schiff base to the Compound 3 is an acid-catalyzed process and the rate of reaction is dependant upon the concentration, temperature, solvent and acid involved in the reaction.
• the solubility of the Schiff base is low in aromatic hydrocarbon at room temperature.
• the complete formation (>95%) of the Schiff base compound is determined by HPLC and LC-MS analyses. About 80% volume of aromatic hydrocarbon solvent is removed by means of distillation under reduced pressure.
• reaction mixture After the reaction mixture is cooled to below 40 0 C, an equal volume (80%) of chlorinated hydrocarbon such as methylene chloride is added, in which the cyclization is performed in the presence of a stoichiometric excess of an acid.
• chlorinated hydrocarbon such as methylene chloride
• Trifluoroacetic acid TSA
• other strong Br ⁇ nsted acids such as methanesulfonic acid andp- toluenesulfonic acid, or Lewis acids such as aluminum chloride and boron trifluoride may also be used.
• the acidic reaction mixture is stirred at room temperature, for a sufficient time preferably at least 16 hours, but as much as 24 hours, to complete the cyclization.
• the excess TFA is removed by means of base-washing the reaction mixture with an aqueous alkaline solution to afford the free amine of formula 3.
• a saturated sodium hydrogen carbonate solution is preferred, but other general alkaline solutions such as sodium carbonate, sodium hydroxide and potassium hydroxide may also be used.
• the halogenated hydrocarbon solvent is removed (>90% of volume) by means of distillation, and then the crude Compound 3 is dissolved in a solvent mixture of ethyl acetate and hexane (3/5; volume/volume) at about 50 ⁇ 5 0 C and the mixture is heated to reflux preferably at least 10 minutes, but as much as 30 minutes, to form a homogenous solution.
• the solution is gradually cooled to room temperature over a 1-2 hour period, seeded if necessary, and the resulting slurry is stirred at ice-water temperature for preferably at least 16 hours but as much as 24 hours.
• the crystalline racemic mixture of the compound of formula 3 is isolated by filtration and dried in a vacuum oven at 55 0 C to produce a > 84% yield (from tryptamine) of racemic Compound 3 which is 97.4% chemically pure.
• Step 2 uses N-acetyl-D-leucine of formula 10 as the resolving agent, to separate the racemic compound of formula 3 into ⁇ /-acetyl-D-leucine salt of formula 4 in good yield (70% over 3 cycles) and high chemical and optical purity (>97 % e.e.).
• iV-Acetyl-D-leucine is prepared by an improved method described in /. Am. Chem. Soc, 1951, 73, 3359-3360.
• the present invention is much improved over the prior art process published in Synthesis and Applications of lsotopically Labeled Compounds, Volume 7, 170-173, 2001 (Edited by U. Pleiss and R. Voges, John Wiley & Sons, Ltd.) which describes a two-step method for chemical resolution of another racemic /?-carboline, involving (R)-(-)- or (S)-(+)-camphorsulfonic acid in the first step, and then (R,R)-(+)- or (S,S)-(-)-tartaric acid in the second step to produce 29-33% yields of the desired (R)- or (S)-enantiomer of / ⁇ -carboline salt with high optical purity (>99% d.e.).
• the process of the present invention makes use of only one resolving agent, iV-acetyl-D-leucine, to produce iV-acetyl-D-leucine salt of formula 4 as a crystalline solid that is collected by filtration in 32-35% yield in a single step with high chemical (>97%) and optical purity (>97% e.e.).
• the mother liquor is mostly iV-acetyl-D-leucine (S)-enantiomer enriched salt mixture of the compound of formula 5, which is recycled to.(iS)-enantiomer enriched free base mixture (i?-/5-enantiomers, mixture ranging from 15%/85% to 35%/65%) in step 6.
• the (5)-enantiomer enriched free base is further converted to the near racemic mixture of formula 3 in step 7, and the sodium salt N-acetyl-D-leucine is recovered as resolving agent in step 6.
• the recycling process produces an additional 38% yield of N-acetyl-D-leucine salt of formula 4 after two more cycles with high chemical and optical purity (>97% e.e.).
• the process of recycle may be repeated at least three times without new impurities generated.
• the step 2 of the present invention is characterized by heating a solution of 4.5 ⁇ 0.5 mole of the resolving agent of the compound of formula 10 in about 5 to 9 liters, more preferably 6 to 7 liters of methanol to 50 0 C. Other solvents such as ethanol, 2-propanol and acetonitrile may be used, but methanol is preferred.
• One stoichiometric equivalent (4 to 6 moles, more preferable 4.5 to 5.5 moles) of racemic compound of formula 3 is added at a preferable temperature range 45 °C to 65 °C, more preferable about 50 to 55 °C.
• Ethyl acetate (1 to 3 liters, more preferable 1.5 to 2.0 liters) is added slowly, and the formed thick slurry in the mixed methanol/ethyl acetate (4.4/1.0) solvent system is heated to a temperature range 50 to 70 °C, more preferable about 62 to 55 °C for 10 to 40 minutes, more preferably 20 to 30 minutes.
• the reaction mixture is preferably agitated under an inert atmosphere such as nitrogen or argon during the heating and cooling process.
• the reaction mixture is cooled to 20 °C for about 1 to 10 hours, preferably 2 to 3 hours and agitated for about 16 to 24 hour, preferably 18 to 20 hours; then the optically pure N-acetyl-D-leucine salt of the compound of formula 4 is isolated by filtration and washed with ice-cold methanol and dried.
• the protecting reagent used for the N-alkylation of the salt of formula 4 are aryl halides or dialkyl/diaryl dicarbonate, for example, dibenzyl dicarbonate, benzyl chloride or bromide in the presence of potassium carbonate, use of benzyl bromide is more preferred.
• the presence of the resolving agent of formula 10 does not interfere with the N-benzylation, and no chromatography is required as the resolving agent of formula 10 is converted into the insoluble potassium salt of formula 10a in methylene chloride, which is isolated by filtration and converted to the resolving agent of formula 10 in step 8.
• the pure N-benzylated compound of formula 7 is obtained in quantitative yield and high optical purity (>97% e.e.) after removal of the solvent by means of concentration.
• the step 3 process of the present invention is characterized by 2.5 ⁇ 0.5 moles charge of the salt of formula 4 and 2.2 equivalents of potassium carbonate in methylene chloride at 20 °C and stirred for about 5 to 30 minutes, preferably 10 to 20 minutes.
• Other inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate may also be used, sodium carbonate and potassium carbonate are more preferred, and the fine powder of potassium carbonate (-325 mesh, Aldrich) is most preferred.
• a slightly stoichiometric excess ( about 1.0 to 1.5 equivalents, or more preferable about 1.01 to 1.1 equivalents) of benzyl bromide is added over about 10 to 40 minutes, preferably 20 to 25 minutes.
• the reaction mixture is preferably agitated under an inert atmosphere such as nitrogen or argon for about 20 to 60 minutes, preferably 30 to 40 minutes at 20 0 C.
• the reaction mixture is gently heated between 30 0 C to 40 0 C, preferably between 38 0 C to 40 °C; for about 8 to 16 hours, preferably 10 to 12 hours.
• the reaction is cooled to 20 °C and the insoluble white solid is collected by filtration, and the filtration cake is washed with methylene chloride and dried to afford quantitative yield of potassium salt of formula 10a.
• a modified Winterfeldt oxidation makes use of low cost potassium superoxide (KO 2 ) in the presence of one equivalent of expensive 1,4,7,10,13,16- hexaoxacyclooctadencane (18-crown-6) as the phase transfer catalyst (PTC) in DMF ⁇ Organic Letters, 2003, 5, 43-46).
• KO 2 low cost potassium superoxide
• PTC phase transfer catalyst
• the process of the present invention is characterized by charge of 2 to 5 moles, preferably 3 to 4 moles of KO 2 in DMF (1 to 2 liters) in the presence of less expensive, water-soluble catalyst Aliquat ® 175 (methyl tributylammonium chloride) (20 mole % relative to the compound of formula VH).
• Aliquat ® 175 methyl tributylammonium chloride
• Other phase transfer catalysts such as Aliquat ® 366 (tricaprylylmethylammonium chloride), tetraethylammonium bromide or triethylbenzylammonium chloride may also be used ⁇ Organic Letters, 2003, 5, 43-46).
• Aliquat ® 175 is the preferred catalyst which catalyzes the reaction to completion within 4 hours, but as much as to 8 hours, and is easy to remove during work up.
• the solvents such as tetrahydrofuran (THF) or dimethyl sulfoxide (DMSO) may also be used, but DMF is preferred.
• THF tetrahydrofuran
• DMSO dimethyl sulfoxide
• the reaction mixture is warmed to 30 to 50 °C, more preferably 40 to 45 0 C for about 20 to 40 minutes, preferably 20 to 25 minutes.
• the reaction mixture is preferably agitated under an inert atmosphere such as nitrogen or argon during the heating, cooling or work-up processes.
• the solution of the compound of formula 7 (0.3 to 1.0 mole, more preferable 0.5 to 0.8 mole) in DMF (0.3 to 1.0 Liter, more preferable 0.4 to 0.6 Liter) is added over 30 to 60 minutes, preferably 30 to 40 minutes.
• the reaction temperature is maintained between 30 0 C to 60 °C, preferably 40 0 C to 60 0 C, more preferably 45 0 C to 50 °C which is controlled by careful adjustment of the addition rate of the Compound 7 in DMF.
• the reaction is initiated at above 45 °C and the latent exothermic reaction could last for 4 to 6 hours when the reaction temperature is maintained at between about 40 °C and 60 °C. However, the reaction temperature can reach 115 °C within 3 minutes if the reaction temperature is higher than 60 °C.
• a jacketed vessel connected to a cooling-heating circulator can be used for this reaction.
• the reaction mixture is agitated at about 40 °C to 60 °C, preferably 45 °C to 50 °C for about 4 to 8 hours, preferably 4 to 6 hours until the data of HPLC analysis determined about 5%, preferably less than 3% of the starting compound of formula 7 in the reaction mixture.
• the reaction is cooled to 20 0 C and the resulting slurry is slowly transferred into another reaction vessel , which is charged with water (4 to 6 liters) and ice (4 to 6 kg) with fast agitation for about 20 to 60 minutes, preferably 30 to 40 minutes.
• the aqueous pH is adjusted to about 7 to 10, preferably to a pH between 8 and 9, with 3N hydrochloride solution.
• the solid is isolated by filtration, washed with water and dried to afford the crude material of formula 8 in 61% yield.
• the reaction solution yields is at least 70%, but not more than 85%, (batch to batch variation as determined by 1 H-NMR). Recrystallization of the crude compound of formula 8 from methanol at about 40 to 65 0 C, preferably 55 to 65 0 C, afford the pure compound of formula 8 in 42% reaction yield with high chemical (>97%) and optical purity (>97% e.e.).
• Solvents ethanol, 2-propanol, or a mixture of methanol and water (1/1) may also be used to increase the recovery yield of the compound 8.
• Step 5 hydrogenolysis of chiral N-benzyl compound of formula 8 was carried out in ethanol in the presence of 0.20 equivalent of Pd (10% on activated carbon) as catalyst and one equivalent of hydrochloride, under 2413 hPa to 3102 hPa of hydrogen pressure at 25 °C for about 5 hours.
• the prior art process produced about 5% of over-reduced product and 72% yield of the desired compound of formula A with >94% e.e., which required chiral HPLC purification as described as Tetrahedron Letters 2002, 43, page 8943.
• the process of the present invention is characterized by charge of 0.6 to 1.2 mole, preferably 0.8 to 1.0 mole of iV-benzyl compound of formula 8 in methanol in a floor stand 6-L Parr pressure reactor under an inert atmosphere such as nitrogen or argon at 20 °C with moderate agitation (300 to 500 rpm, 400 rpm is preferred). Solvents ethanol or 2-propanol may be used but methanol is preferred.
• the reaction mixture is stirred for about 4 to 6 hours, more preferably 4 hours at 20 to 30 0 C, preferably between 23 to 28 0 C under 2758 hPa to 4136 hPa, more preferably 3102 hPa to 3792 hPa, most preferably 3309 hPa to 3947 hPa of hydrogen pressure.
• Step 6 Both the conversion of (S)-enantiomer enriched salt (R- ⁇ S-enantiomers, ranging from a 15 % / 85 % mixture to a 35 % / 65 % mixture of formula S to the (S)- enantiomer enriched free base mixture (R-AS-enantiomers, ranging from a 15 % / 85 % mixture to a 35 % / 65 % mixture) in step 6, make the process of the present invention more economical and efficient.
• the resulting material is dissolved in methylene chloride (6.0 L) and agitated vigorously with IN to 5 N, preferably IN to 3N of sodium hydroxide solution 2 to 6 liters, preferably 3 to 4 liters for about 10 to 30 minutes, preferably 15 to 20 minutes.
• the organic phase is condensed to dryness to afford (5)-enantiomer enriched free base mixture (R-/S- enantiomers, ranging from a 15 % / 85 % mixture to a 35 % / 65 % mixture).
• Step 7 (5)-Enantiomer enriched free base mixture (R-AS-enantiomers in a mixture ratio in a range of about 15 %/85 % to about 35 %/65 %) obtained from step 6 is epimerized into a near racemic mixture (R-AS-enantiomers in a mixture ratio in a range of about 44 %/56% to about 50%/50%) of formula 3 in step 7.
• the process of the present invention is characterized by a charge in a range of from about 2 to about 5 moles, preferably from about 3 to about 4 moles of the compound in a volume of from about 5 to about 8 liters, preferably from about 6 to about 7 liters of methylene chloride.
• the suspension is stirred under an inert atmosphere such as nitrogen or argon and is cooled to a temperature of from about 0 to about 10 °C, preferably of from about 6 to about 10 °C.
• An excess (4 to 8 mole, preferably 6 to 7 mole) of TFA is added over 30 to 60 minutes, preferably 30 to 40 minutes.
• the addition of TFA is an exothermic process, the suspension becomes a homogenous solution, and the solution temperature is about 25 to 30 °C with cooling after the addition.
• the reaction mixture is heated to gentle reflux at about 30 to 40 °C, preferably 36 to 38 °C for 12 to 24 hours, preferably 16 to 18 hours. More TFA (0.2 to 0.5 equivalents) can be added and the reaction can be refluxed for an extended time until the epimerization is completed (R- ⁇ S'-enantiomers, ranging from 44 % / 56 % to 50 % / 50 %, determined by chiral HPLC analysis).
• reaction is cooled to 20 °C and then agitated vigorously while a 5 to 20%, preferably 7 to 10% sodium hydroxide solution is added over 20 to 40 minutes.
• Other alkaline solutions such as potassium hydroxide, potassium carbonate or sodium carbonate may be used.
• the organic phase is separated, washed with brine and concentrated to afford 93% of the compound in formula 3 with high chemical purity (>97%, HPLC area%), which is further used in step 3 with the resolving agent of formula 10 to produce more than 36% yield of (i?)-enantiomer of formula 4 after two recycles and no new impurities detected.
• Step 8 The conversion of the potassium salt 10a generated from step 3 to resolving agent of formula 10 is a similar process as described in step 6 of the present invention.
• Step 8 is characterized by dissolving 2 to 5 moles, preferably 3 to 4 moles of potassium salt of formula 10a in 3 to 6 liters, preferably 4 to 5 liters of water and the solution is cooled to about 0 to 10 0 C, preferably 0 to 4 0 C.
• the white slurry is stirred at 0 0 C for about 20 to 60 minutes, preferably 30 to 40 minutes. Then the solid is isolated by filtration, washed with cold water and dried to afford the recovered resolving agent of formula 10 in 80% yield with high chemical purity (>98%, HPLC area%) and high optical purity (>97%, e.e.; chiral HPLC area%).
• the potassium salt and sodium salt of formula of N- acetyl-D-leucine may be combined to produce the resolving agent acid of formula lOas described hereinabove.
• HPLC Method A for chemical purity ZORBAX Ecilipse XDB-Phenyl column (4.6 mm ID xl50 mm, 3.5 micron) at 40 0 C with flow rate of 1.0 mL/min and run time of 10.0 min. UVmax of between 254 and 280 nm.
• Solvents Solvent (A) a mixture of 80% H 2 O, 0.05% TFA, Solvent (B) 20% MeCN; Gradient (B) 20%/0.0 min, 20%/1.0 min, 90%/6.0 min, 90%/8.0 min, 55%/9.O min, 20%/10.0 min.
• Solvents Solvent (A) 90% IPA, Solvent (B) 10% hexane.
• Solvents Solvent (A) 25% IPA, Solvent (B) a mixture of 75% hexane and 0.05% TFA. Retention time: 5.1 min/N-acetyl-D-leucine, 6.0 min/N- acetyl-L-leucine.
• the suspension mixture was heated to 88 ⁇ 2 °C, then the temperature was gradually increased to 112 ⁇ 2 °C at a rate of 2 0 C per 5 min..
• the reaction was refluxed for 4 hours and water (108 mL) was collected by the Dean-Stark trap.
• ⁇ PLC and LC-MS were used to monitor the progress of the reaction to >95% completion.
• the solvent was removed by distillation under reduced pressure and the resulting material was cooled to below 40 0 C to produce a thick yellow semi-solid of the Schiff base.
• a re-slurry method can be use to obtain purer material.
• 667.0 g of Compound 4 with 96% d.e. was re-slurried in a mixture of MeOH/EtOAc (1.0 L/0.2 L), following the above described resolution process.
• 610.0 g of pure salt 4 with 98% d.e.. Several batches can be combined and re-slurried if necessary.
• the reaction was cooled to 20 0 C and the white solid was isolated by filtration. A filter with a large surface area was used since the potassium salt 10a was a semi- gelatinous material in CH 2 Cl 2 and thus the filtration was a slow process. The filtration cake was washed with CH 2 Cl 2 (2.0 L x 2) and dried to afford the potassium salt 10a for recycle (see EXAMPLE 6).
• the progress of the reaction was determined by HPLC, LC-MS and TLC (MeOH/CH 2 Cl 2 , 5%/95%). A longer reaction time (up to 6 hours) may be needed if there is more than 3 to 5% of the starting Compound 7 present.
• the yellowish slurry was stirred for 30 min and acidified with 3 N HCl solution (0.7 L) to a pH of about 8-9.
• the solid was isolated by filtration and washed with H 2 O (0.5 L x 2).
• the wet filter cake was dried by air-suction and then placed in an oven under house vacuum at 60 0 C for 16 hours.
• a floor stand 6 Liter Parr pressure reactor was equipped with a thermocouple controller, a mechanic overhead stirrer, a cooling coil, nitrogen/hydrogen/vacuum lines and an emergency relief disc.
• This vessel was charged with Compound 8 (319.2 g, 0.81 mol) and CH 3 OH (1.8 L) with fast agitation due to the thick slurry that was formed under nitrogen.
• a solution of 6 N hydrochloride (0.136 L) was added over 3 min. (this addition was an exothermic process and the temperature of the resulting clean homogenous solution was about 29 0 C) followed by the addition of 5% Pd/C (115.2 g, 6.6% mol of Pd) over 1 min.
• the system was closed and first purged with nitrogen (1380 hPa) (x 3) and then hydrogen (1380 hPa) (x 2).
• the reaction was carried out at 23-28 0 C under hydrogen pressure (3447 hPa.) with moderate agitation (400 rpm) for 4 hours.
• the progress of the reaction was determined by HPLC, LC-MS and TLC (MeOH/CH 2 Cl 2 , 1/9).
• the reaction mixture was transferred to a filtration bottle by vacuum, the catalyst was removed by filtration through a Celite® 545 short cartridge, and the filter cake was washed with CH 3 OH (0.2 L x 4).
• the Pd catalyst is an air-sensitive flammable metal, thus the surface of the filter cake should never be allowed to become dry.
• the organic phase was condensed to dryness to afford the (S)-enantiomer enriched free base mixture (R- ⁇ S'-enantiomers, 15 % / 85 % to 35 % / 65 %), which was used for the epimerization step (see EXAMPLE 7).
• the aqueous phase (6.0 L) was cooled in an ice bath and acidified with concentrated HCl solution (37%, 1.3 L) to a pH of about 1 with fast agitation. The addition of HCl solution should be slow since this addition was an exothermic process.
• EXAMPLE 7 (STEP 7)
• the present invention is further directed to a process for epimerization of a (S)- enantiomer enriched (lS)-l-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-lH- ⁇ - carboline mixture (R- ⁇ S-enantiomers, mixture ranging from 15%/85% to 35%/65%) to a near racemic ( ⁇ )-l-(2,3-dihydrobenzofuran-5-yl)-2,3,4,9-tetrahydro-lH- ⁇ -carboline mixture (R- ⁇ S-enantiomers, mixtures ranging from 44% / 56% to 50 % / 50%) '
• R- ⁇ S-enantiomers mixtures ranging from 44% / 56% to 50 % / 50%
• the addition was an exothermic process and the temperature of the solution was about 30 0 C after the addition, while the heterogeneous mixture became a homogenous solution.
• the reaction mixture was warmed to gentle reflux at 38 ⁇ 2 °C for 16 hours.
• the progress of the reaction was determined by chiral HPLC analysis.
• the final R-/S- ratio of the racemized mixture was in the range of 44 %/56 % to 50 % / 50 %. More TFA (0.2-0.5 equivalent) was added and the reaction mixture was refluxed for an extended time. The solution was cooled to 20 0 C and agitated vigorously while a 7% NaOH solution (4.3 L, 7.5 mol) was added over a 20 min period. After phase separation, the organic phase was washed with brine (2.0 L) and concentrated to dryness. The resulting material was placed in an oven under house vacuum at 60 °C for 16 hours.
• the white solid was isolated by filtration, washed with cold D.I. H 2 O (I Lx 2), dried by air-suction and then placed in a vacuum oven under house vacuum at 60 °C for 16 hours. There was obtained 410.0 g (80% yield) of recovered iV-acetyl-D-leucine 10 as an off-white solid with a high optical purity (>97% e.e.). The structure of the recovered resolving agent 10 was also confirmed by 1 H-NMR and LC-MS analyses.
• a 22 Liter 4-neck vessel was equipped with a thermocouple controller, an overhead mechanic stirrer and two 2.0 Liter addition funnels.
• the vessel was charged with D.I. H 2 O (2.45 L) and D-leucine (99% e.e., 917.Og, 7.0 mol) with agitation.
• Acetic anhydride (99%, 2142.0 g, 21.0 mol) and a 20 JV solution of NaOH in H 2 O (2.45 L, 49.0 mol) were added simultaneously over a 3 to 4 hour period, while the reaction temperature was maintained between 5 to 15 0 C.
• the addition rates of the alkaline solution and acetic anhydride were adjusted along with wet ice cooling to maintain the reaction temperature.
• the pH of the reaction mixture was maintained slightly alkaline (pH 8-9) and measured every 10 to 15 min with pH indicator strips. The progress of the reaction was determined by HPLC and LC-MS. After the addition was completed, the mixture was agitated for 1 hour and then acidified cautiously with a 37% HCl solution (4.76 L, 49.0 mol) over a 30-min period. A white solid precipitated and the slurry was stirred for 2 hours at about 5 0 C to about 15 0 C. The resulting solid was isolated by filtration, washed with D.I.
• the present invention is further directed to a synthesis process to provide scalable quantities of (3R)-3-(2,3-dihydro-benzofuran ⁇ 5-yl)-2-pyridin-2-yl- 1,2,3,4- tetrahydro-pyrrolo[3,4-b]quinolin-9-one methanesulfonic acid salt Compound 12 as shown below in Scheme HI. More particularly, the present invention is directed to the large scale Buchwald-Hartwig coupling of 2-bromopyridine and a pyrroloquinolone compound of formula (A) to provide an intermediate Compound 11 (represented in WO 01/87882 as Compound 136). The intermediate Compound 11 is then carried forward as described herein to provide Compound 12.
• the THF used had a water content in a range of from about 0.01 % w/w to about 0.1% w/w and led to the same rate and yields as the product dried over sodium/benzophenone.
• the best ligand for this reaction was found to be ( ⁇ )-BINAP. Entry 5
• the THF used had a water content in a range of from 0.01% w/w to 0.1% w/w) and led to the same rate and yields as the product dried over sodium/benzophenone.
• the best ligand for this reaction was found to be ( ⁇ )-BINAP.
• the diaminocarbene palladium complexes exhibited lower activity.
• the elution gradient was 5% acetonitrile / 95% NH 4 OAc (0.5% in water) ramping to 95% acetonitrile / 5% NH 4 OAc (0.5% in water) over 16 min, at a flow rate of 1.2 mL/min, then kept 95% acetonitrile / 5% NH 4 OAc (0.5% in water) for 3 min.
• Optical purities were measured by Capillary Electrophoresis employing a 57 cm uncoated fused silica column (75 ⁇ m LD., 375 ⁇ m O.D., UV wavelength of 200 nm) at 20 0 C.
• the mobile phase consisted of a 5OmM phosphate buffer, at pH 3.0; the chiral selector of 1OmM DM-beta-CD. Each run lasted 30 min.
• a 500 Liter glass-lined reactor was charged with 1.6 kg of compound 11 (3.04 mol, 2110 ppm Pd) and 288.9 L of methanol. After heating to 60 0 C, the mixture was stirred (75 rpm) for 1 hour at this temperature. Then, 106 g of Norit A Supra and 10.6 g of dicalite were added. The mixture was stirred for another 20 min. and thereafter filtered. The cake was washed with 5 L of methanol. The solvent was reduced to 110 L, at 50 0 C, and then transferred to a 100 Liter glass-lined reactor where the mixture volume was reduced to 35 L, at 60 0 C.
• the present invention is further directed to a process for the oxidative rearrangement of the ⁇ -carboline derivatives of Formula VII to the quinolone derivatives of Formula VIII.
• the rearrangement can be performed on an arylated ⁇ - carboline derivative of Formula VII (which can yield the final compound directly).
• the oxidative rearrangement may be performed on a benzyl-protected compound of Formula VII.
• the resulting quinolone can then be deprotected and subsequently arylated.
• the oxidative rearrangement is preferably performed on a protected ⁇ -carboline, wherein the protecting group is selected from benzyl, tert-butoxycarbonyl or benzyloxycarbonyl.
• ARC, RC 1 and Phi-tec adiabatic calorimetry experiments were conducted using an ARC calorimeter, manufactured by CSI Columbia Scientific Ind., a RC 1 calorimeter, manufactured by Mettler Toledo and a Phi-tec calorimeter, Model No. Phi-tec II, manufactured by HeI.
• reaction mixture had shown a thermal instability at relatively low temperatures.
• An experiment in a ARC calorimeter on the N-benzyl protected ⁇ -carboline of Formula VII reaction mixture showed an exothermic decomposition starting at 39 0 C, with increased decomposition and pressure build up at 60 °C.
• MTSR refers to "maximum temperature of the synthetic reaction”
• the MTSR was determined by adding the starting temperature of 55°C and the added heat production of about 92°C (adiabatic temperature rise), to yield the MTSR of 147°C.
• the MTSR depends on the amount of unreacted starting materials at the moment of the cooling failure.
• the RC 1 experiment revealed that the reaction enthalpy was about 500 kJ/mole, but as the reaction was slow, the specific heat release was only 1.5 W/L and could easily be cooled in a production plant. However, there was about 90% thermal accumulation, so this is in fact a batch process and batch processes are not easy to control.
• the reaction or exothermic decomposition started at 52°C with a total, Phi-tec corrected, adiabatic temperature rise of 192°C.
• the self heat rate was 0.56 0 C/ min., with a maximum of 102°C/min. at 150 0 C.
• the adiabatic reaction temperature should not exceed 7O 0 C, thus avoiding a runaway reaction (uncontrolled chemical reaction).
• the residue of the reaction contained 20-30% of the keto-lactam (3R)-3-(2,3-dihydro-benzofuran-5-yl)-2,7-dioxo-l,2,3,5,6,7-hexahydro- benzo[e][l,4]diazonine-4-carboxylic acid tert-butyl ester
• Compound 14 which on treatment with KOH was quantitatively converted to (3R)-3-(2,3-dihydro ⁇ benzofuran-5- yl)-9-oxo-l,3,4,9-tetrahydro-pyrrolo[3,4-b]quinoline-2-carboxylic acid tert-butyl ester Compound 15.
• DMD can be used to epoxidize the 2,3,4,9-tetrahydro- lH-carbazole Compound 17 to provide a 2,3,4,5-tetrahydro-lH-carbazol[4a,9a- b]oxirane Compound 18 in equilibrium with the hydroxy-imine intermediate Compound 19.
• the intermediate can be converted to the keto-lactam 3,4,5,6- tetrahydro-lH-benzo[b]azonine-2,7-dione Compound 20 in good yields by further oxidation with mCPBA.
• the epoxide Compound 18 can be formed in situ from acetone and OXONE ® at controlled pH (as described in Adam, W.; Chan, Y.-T.; Cremer, D.; Gauss, J.; Scheutzow, D.; Schlinder, M.; 7. Org. Chem. 1987, 52, 2800-2803; (b) Murray, R.W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853).
• Compound 16 was oxidized using OXONE ® and mCPBA to provide the keto- lactam (3i?)-3-(2,3-dihydro-benzofuran-5-yl)-2,7-dioxo-l,2,3,5,6,7-hexahydro- benzo[e][l,4]diazonine-4-carboxylic acid benzyl ester Compound 21.
• the keto-lactam Compound 21 was isolated by crystallization from ethylacetate with an overall yield of 36% on a 46 mole scale.
• reaction mixture contained up to 60 - 70% (HPLC area percent) of the hydroxy-imine (identification by LC-MS) and again most of the impurities started to form upon addition of mCPBA.
• the mixture was stirred for another 2 hours at a temperature of from about 51 0 C to about 42 0 C.
• Water (18 mL) was added and the layers were separated while keeping the temperature at about 35 0 C to about 40°C.
• acetone 107 mL was added and the mixture was cooled to a temperature of from about 20 0 C to about 25 0 C.
• a solution of mCPBA (71%, 5.34 g, 0.217 mole) in dichloromethane (62 mL) was added over a period of about 15 minutes at a temperature of from about 0 °C to about 5 0 C.
• the mixture was stirred for another 1.5 hour at a temperature of from about 0 0 C to about 5 0 C and then washed successively with water (76 mL) and with a solution OfNaHCO 3 (6 g) in water (76 mL).

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