Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/96—Esters of carbonic or haloformic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/205—Radicals derived from carbonic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• This anti-allergy drug is marketed by the company UCB (which is also the originator of the drug) and/or Pfizer under the brand nameZyrtec®, as a dihydrochloride salt (often referred to as "cetirizine hydrochloride”) .
• the drug is indicated for the relief of symptoms associated with seasonal allergic rhinitis or perennial allergic rhinitis, as well as for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older.
• Cetirizine has one asymmetric carbon, therefore it may be resolved into enantiomers.
• the pharmaceutically active enantiomer in the racemic cetirizine is the levocetirizine, which is the (R) enantiomer of cetirizine.
• a medicament comprising levocetirizine was launched in the first quarter of 2001 in Germany followed by a pan-European launch.
• Levocetirizine is also marketed as the dihydrochloride salt, under the brand name Xyzaal®.
• Cetirizine was disclosed in US 4,525,358 (EP 58146).
• Levocetirizine was specifically disclosed in GB2225321.
• the method of use of levocetirizine has been disclosed in US 5,698,558 (EP 663828).
• Levocetirizine may be obtained by resolution of the cetirizine enantiomers as generally suggested, e.g., in WO 94/06429. However, the effectiveness of such process is apparently not high and therefore it is preferred to make levocetirizine from an enantiopure intermediate.
• the compound (1) may be obtained as a racemate or as a single enantiomer, particularly as the (R) enantiomer. It is known that the racemic compound (1) can be resolved into enantiomers by a fractional crystallization, preferably by the crystallization of salts with L- tartaric acid, (see US 5,478,941). This makes the compound (1) an important intermediate, particularly in the synthesis of an enantiomerically pure (4).
• the compound (5a) is an extremely toxic compound ("mustard gas"), and second the reaction is accompanied with a large amount of side products arising particularly from the self-condensation of the compound (5).
• the use of an N- protected bis-haloethylamine is clearly preferable.
• other potentially useful N- protected compounds e.g. a carbonyl, alkyl or a triphenylmethyl protecting group, have been reported as unsatisfactory.
• US 5,478,941 and EP 955295 teach that the above mentioned N-tosyl compound of formula (2) is the only useful compound for the coupling reaction with (1).
• the protected analogues (a carbonyl, alkyl, or trityl protecting group) caused important racemization of the compound (1) during the coupling reaction and/or the formation of undesired by-products.
• the present invention relates to the discovery of a convenient process and intermediates for making levocetirizine from achiral precursors. Accordingly a first aspect of the invention relates to a process for the making of levocetirizine, which comprises:
• Z is C1-C20 straight or branched alkyl/cycloalkyl /aralkyl/alkylaryl group, whereby each of which groups can be optionally substituted by one to four halogen, alkoxy, amino, and/or nitro groups and whereby the group Z comprises at least one chiral carbon atom
• said pair being characterised by a single conformation on the chiral carbon(s) within the group Z and either R- or S- conformation on the chiral carbon outside the group Z
• the step a) comprises i) reacting a racemic compound of formula (1) with a compound of formula (7) in the presence of a base,
• X is a leaving group reactive with an amine, for instance a halo group such as chloro or bromo group; or a sulphonyl group such as mesyloxy, besyloxy or tosyloxy group; and preferably X is a chloro group; and Z is as defined above.
• the step a) comprises ii) reacting the compound of the formula (4) with a haloformate of the formula ( 9) wherein X is a halogen group, preferably a chloro-group and and Z are the same as defined above
• the compound of a formula (8) intois an acid addition salt with a suitable inorganic or organic acid, and one diastereomer of such salt is obtained by fractional crystallization from a suitable solvent.
• the diastereomer obtained by the above fractional crystallization is the diastereomer of the compound of formula (8) with R-conformation on the chiral carbon outside the group Z.
• the group Z is a menthyl group ( 2-isopropyl- 5-methylcyclohexyl group), preferably with the conformation (1R,2S,5R) or ( 1S,2R,5S).
• the invention provides a process for converting the racemic compound (4) into enantiomers, such process comprising the steps of
• Z is C1-C20 straight or branched alkyl/cycloalkyl /aralkyl/alkylaryl group, whereby each of which groups can be optionally substituted by one to four halogen, alkoxy, amino, and/or nitro groups and, whereby the group Z comprises at least one chiral carbon atom said pair being characterised by a single conformation on the chiral carbon(s) within the group Z and either R- or S- conformation on the chiral carbon outside the group Z b) resolving the pair of diastereomers of the compound (8) into single diastereomers having either R- or S- conformation on the chiral carbon outside the group Z c) converting , such as by hydrolysis, the single diastereomer of the compound (8) into single enantiomer of the compound (4)
• the Z group in the above process is preferably a (-) menthyl or a (+)-menthyl group.
• the compounds of formula (8) particularly any and each of diastereomers thereof inclusive mixtures of said diastereomers, form a particular aspect of the present invention.
• Each of the above formulas includes acid addition salts of the compounds.
• the preferred compound of the formula (8) is the compound of the formula (8a), a single diastereomer thereof, as well as an acid addition salt thereof, particularly the sulfate salt.
• Another aspect of the invention relates to the compounds of formulas (7) and (9).
• X is chloro and Z is (+)-menthyl or (-)-menthyl group .
• Still another aspect of the invention relates to the use of the compounds of formula (8) and (7) in the making of levocetirizine and/or the compound of formula (4).
• the present invention deals with an alternate process for making the single, preferably (R), enantiomer of a compound of formula (4), which is the key intermediate in the synthesis of pharmaceutically useful compound levocetirizine .
• the process is characterized by using a specific optically active substituent in the course of the synthesis, which allows to resolve one of the intermediates in the synthesis of (4) into enantiomers without a need of using any optically active acid.
• any process of making levocetirizine via the intermediate (4) requires the use of optically active acids as resolution agents, the finding that such acids are no more necessary is surprising.
• the optically active substituent is preferably used in the synthesis of compound (4), the process can essentially serve two functions at once.
• the chiral carbon in the methyl group bridging two phenyl groups in the compounds (1), (4) and (8) is called " chiral carbon outside group Z" , regardless whether group Z is actually present.
• All chemical formulas having such chiral carbon present include both mixtures of the enantiomers such as a racemate as well as single enantiomers.
• the "enantiomerically pure " enantiomers or diastereomers are compounds with at least 90% optical purity, preferably at least 95% optical purity, and including at least 98% and at least 99% optical purity.
• all chemical formulas, e.g., (1) to (8) include the acid addition salts thereof unless explicitly stated to the contrary.
• a compound of the formula (8) is provided as a pair of diastereomers .
• the compound of the formula (8) comprises a chiral group Z, which is C1-C20 straight or branched alkyl/cycloalkyl /aralkyl/alkylaryl group, whereby each of which groups can be optionally substituted by one to four halogen, alkoxy, amino, and/or nitro groups.
• the group Z comprises at least one chiral carbon atom.
• the chiral carbon atom(s) in the group Z have the substituents oriented in a single way . i.e.
• the chiral carbon outside the group Z may have an orientation of substituents in either R- or S- configuration .
• the compound (8) is provided as a pair of diastereomers ; if, for example, the group Z comprises one chiral carbon with the orientation (R) of substituents , the pair of diastereomers of the compound (8) have the conformation (R,R) and/or (S,R), resp. .
• the group Z is the menthyl group (2-isopropyl- 5-methylcyclohexyl group ).
• This group has three chiral carbons allowing for 8 stereoisomers ; any single combination of spatial arrangement of substituents is allowable, provided however that the resulting conformation is singular; i.e. always a single stereoisomer must be used.
• the menthyl group should have the same conformation as has the natural (-) menthol, i.e. (1R,2S,5R),
• menthyl group will be denoted herein as (-)-menthyl group, or the opposite conformation corresponding to (+)-menthol, i.e. ( 1S,2R,5S), such menthyl group will be denoted herein as (+)- menthyl group .
• Another example of a suitable group Z is camphenyl group.
• the compound (8) may be obtained by various ways.
• the compound (8) is obtained by a reaction of the racemic compound (4) with a haloformate of the formula (9)
• X is a halo group such as chloro or bromo group and preferably X is a chloro group; and Z is as defined above.
• the Z represents a single stereoisomer of a menthyl group, particularly (-)menthyl group , and X represents chlorine.
• the preferred compound for the reaction with the compound (4) is a menthyl chloroformate of the formula (9a).
• the reaction between compound (4) and (9) generally proceeds in an inert , preferably water immiscible, solvent , e.g. in a hydrocarbon or a halogenated hydrocarbon , preferably under presence of a base, which may be advantageously an organic base, for instance a primary, secondary or tertiary amine.
• a base which may be advantageously an organic base, for instance a primary, secondary or tertiary amine.
• the reaction temperature may be ambient or close to ambient ( 0- 50C) .
• the side product (a salt of the amine) is conventionally removed by an extraction by water and the product is optionally isolated from the organic layer, e.g. by a removal of the solvent.
• the crude product may be purified, if necessary, or may be used in the next step in the crude state.
• the compound (8) may also be isolated as an acid addition salt.
• the racemic compound of formula (1) reacts, generally in a liquid phase, with the compound of the general formula (7) to yield the compound of formula (8).
• Z is the same group as defined above ; preferably, Z is a menthyl group.
• the compound (7) contains two equal leaving groups X that are reactive with the primary amine in the compound (1) to form the piperazine ring.
• groups X may be represented by a halogen group, or a sulphonyl group such as mesyloxy, besyloxy, anisylsulfonyloxy or tosyloxy group; preferably X is a chloro-group.
• the reaction between compounds (1) and (7) proceeds in the presence of a base, which is preferably an organic base.
• a liquid organic base is employed, whereby the liquid organic base serves also as the solvent of the reaction.
• the preferred liquid organic base is diisopropylethylamine.
• the reaction preferably proceeds at an enhanced temperature, e.g., at a temperature between 50-150°C, suitably at reflux.
• potassium iodide may be added as an initiator .
• the reaction progress may be monitored by a suitable analytical technique, e.g. HPLC.
• the reaction mixture containing the product (8) may be used for the next step (advantageously, after removal of amine salts formed and/or after removal of at least part of the solvent) or is elaborated to isolate the reaction product (8).
• the reaction mixture is partitioned between an aqueous and organic phase (whereby the organic solvent may be conveniently a hydrocarbon or a chlorinated hydrocarbon) and the product is isolated from the organic phase.
• the crude product may be purified, if necessary, or may be used in the next step in the crude state.
• the compound (8) may also be isolated as an acid addition salt.
• the pair of diastereomers of the compound (8) is resolved to obtain a single diastereomer , preferably having the chiral methyl group in the (R)-conformation; i.e., in the correct orientation for completing a levocetirizine synthesis.
• the compound (8) may be resolved into single diastereomers without a need of any resolution agent, i.e. , e.g., without a need of an optically active acid.
• a suitable process comprises a fractional crystallization of the compound (8) from a suitable solvent.
• Another suitable process comprises chromatography on a suitable column , such as HPLC.
• the compound (8) is first converted into a suitable acid addition salt before the fractional crystallization by contacting with a suitable acid in a suitable solvent, which may be the same or different from the solvent used for the crystallization.
• Suitable acid addition salts are, without limitation, a hydrochloride, a hydrobromide, sulfate, phosphate, acetate, formate, maleate, fumarate , tartrate or oxalate etc.
• a suitable solvents for the fractional crystallization are, without limitation, water, an C1-C6 aliphatic alcohol, a C3-C8 aliphatic ketone, a C2-C8 aliphatic or cyclic ether , C2-C10 ester , C1-C4 nitrile, and mixtures thereof.
• one diastereomer of the compound (8) preferentially precipitates and the second one preferentially remains in the solution.
• the word preferentially illustrates the fact that the precipitate and/or solute does not comprise 100%, but comprises a majority, such as more than 70% of the desired enantiomer.
• the conformation of the diastereomer in the precipitated / crystallized product depends on the choice of the group Z, on the solvent and on the nature of the compound (8), i.e. whether the compound (8) is a base or a salt.
• the solid product obtained by crystallization may be advantageously , but not necessarily, the product with the desired (R)-orientation on the chiral carbon atom outside the chiral group Z. It may be isolated by filtration and optionally washed and dried. The second of the pair of diastereomers that remained in the solution may be isolated by evaporation of the solvent.
• the fractional crystallization of any of the obtained fraction may be repeated.
• the preferred compound (8a) is fractionally crystallized as a base or is converted into a salt with sulfuric acid. If crystallized as a base, e.g. from an etheral solvent, the product with the desired (R) orientation preferentially remains in the solution . On the other hand , the sulfate salt crystallizes ( e.g. from ethyl acetate and/or acetonitrile) as a solid preferentially with the (R) orientation, while the (S)-diastereomer is concentrated in the solution.
• the single diastereomer of the compound (8) is subjected to a hydrolysis/solvolysis of the carbamate group.
• the hydrolysis is advantageously performed by an aqueous or alcoholic acid or by an aqueous alkali.
• the acid may be , e.g., hydrochloric or sulfuric acid.
• the "aqueous alkali" comprises an aqueous solution or suspension of lithium, sodium, potassium or calcium hydroxide or carbonate.
• the reaction may proceed in the presence of an inert co-solvent.
• reaction product comprising the single, preferably the (R)- enantiomer of the compound (4) is then advantageously extracted by a water-insoluble organic solvent , preferably by ethyl acetate and/or toluene, and isolated from the organic phase.
• a water-insoluble organic solvent preferably by ethyl acetate and/or toluene
• Side products if any, may be efficiently removed if the above extraction is done under acidic or alkaline conditions.
• the formed compound of formula (4) is isolated from the reaction mixture, and/or purified. It may be isolated as a free base or may be isolated after converting it into an acid addition salt with an organic or inorganic acid that is isolatable as a solid, preferably crystalline, product.
• An advantageous salt in this respect is the oxalate salt as it may be isolated as a stable crystalline material.
• the oxalate salt of the compound (4) is a suitable form that allows storage of the compound (4), particularly the (R)- enantiomer thereof, for an enhanced period of time.
• the single enantiomer of the compound (4) may be however isolated also as a free base, which is preferably a solid product, for instance by a suitable extraction process.
• the reaction mixture is partitioned between an organic layer and acidified aqueous layer (in which the product concentrates), the aqueous layer is neutralized, the free base of (4) is extracted by an organic solvent and isolated from this solvent.
• the compound of formula (7) may be obtained, for instance, by the condensation of the compound (5)
• N,N-bis(2-chloroethyl) (-) menthyl carbamate of the formula (7a) is thus obtained by the reaction of the bis(2- chloroethyl)amine with a (-)menthylchloroformate of formula (9a).
• N,N-bis(2-chloroethyl) (+) menthyl carbamate by the reaction of the bis(2-chloroethyl)amine with a (+)menthylchloroformate.
• the reaction is advantageously performed in an inert solvent, e.g., in a hydrocarbon solvent or a halogenated hydrocarbon solvent, preferably in the presence of a base.
• the compound of formula (7) may be obtained from bis (2- hydroxyethyl) amine and a haloformate (9) according to the scheme
• Z * is (lS)-(-)-menthyl
• a mixture containing 5.48 g ( ⁇ ) Carbamate (8a) in 25 ml isopropyl ether were stirred at 4O 0 C for
• the isolated solid was suspended in 10 ml isopropyl ether. The suspension was stirred for 2 hours at 4 0 C. The solid was isolated again by filtration and dried.
• the isolated solid was suspended in 20 ml isopropyl ether. The suspension was stirred ambient temperature for 4 hours. The solid was isolated again by filtration and dried.
• Z * is (l S)-(-)-menthyl
• a mixture containing 3.91g ( ⁇ ) Carbamate in 10 ml isopropyl ether was refluxed for 1 hour. Then it was stirred at ambient temperature for 4 hours. Solid was collected by filtration and dried. Enriched carbamate was suspended in 5 ml isopropyl ether. The suspension was refluxed for 1 hour. Then it was stirred at ambient temperature for 4 hours. Solid was collected by filtration and dried at 4O 0 C under vacuum. The isolated carbamate compound (1.22g) had a 97.2% in S enantiomeric purity.
• Step 3 Resolution of the compound (8a) less soluble more soluble

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Citations (9)

• 2008
  • 2008-11-21 WO PCT/EP2008/009977 patent/WO2010057515A1/en active Application Filing
• 2009
  • 2009-11-20 NL NL1037485A patent/NL1037485C2/en not_active IP Right Cessation

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