WO2010070593A2 - Esters de malonate - Google Patents

Esters de malonate Download PDF

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WO2010070593A2
WO2010070593A2 PCT/IB2009/055786 IB2009055786W WO2010070593A2 WO 2010070593 A2 WO2010070593 A2 WO 2010070593A2 IB 2009055786 W IB2009055786 W IB 2009055786W WO 2010070593 A2 WO2010070593 A2 WO 2010070593A2
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malonate
formula
alkyl
chiral
compound
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PCT/IB2009/055786
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WO2010070593A3 (fr
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Benjamin Simon Davies
Mark M. Guzman
Carlos A. Martinez
Paul Oliver Mcdaid
Padraig Mary O'neill
Elango Shanmugam
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Pfizer Ireland Pharmaceuticals
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/19—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton
    • C07C255/22—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton containing cyano groups and at least two carboxyl groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to certain 2-(1 -cyanoalkyl)-malonate esters, and to methods and materials for preparing these esters. More specifically, the invention relates to 2-((1 S)-1-cyano-3-methylbutyl)-malonate esters. These malonates are particularly useful for preparing pregabalin, a ⁇ -amino acid that exhibits binding affinity to the human ⁇ 2 ⁇ calcium channel subunit.
  • pregabalin is the active agent in Lyrica®, which is approved for the treatment of epilepsy, neuropathic pain, fibromyalgia and generalized anxiety disorder. It exhibits antiseizure activity, as discussed in U.S. Patent US 5,563,175, and anti-nociceptive activity, as discussed in U.S. Patent US 6,001 ,876. It is hypothesised that the pharmacological activity of pregabalin is the result of binding to the alpha-2-delta ( ⁇ 2 ⁇ ) subunit of a calcium channel. Pregabalin is also described as having utility in other conditions, such as physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, and various psychiatric disorders, including anxiety, depression, mania, and bipolar disorder.
  • pregabalin is the (S)-enantiomer, and a key consideration in the commercial manufacture of pregabalin is the strategy by which optically pure material is obtained. 2. Manufacturing methods involving resolution
  • Pregabalin has been prepared in various ways.
  • a common strategy shared by many syntheses has been the resolution of the final product or of an earlier intermediate into its R- and S-enantiomers.
  • Such methods may involve an azide intermediate (e.g., U.S. Patent US 5563175), or a Hoffman synthesis (e.g. U.S. Patents US 5629447, and US 5616793).
  • a route involving a malonate intermediate e.g., U.S. Patents US 6046353, US 5840956, and US 5637767) has also been utilised (Scheme 1 ).
  • This route starts with the condensation of isovalderaldehyde with diethyl malonate to give an ⁇ , ⁇ -unsaturated diethyl ester, which is reacted with cyanide to give a ⁇ -cyanodiester (CNDE).
  • CNDE ⁇ -cyanodiester
  • This intermediate is subsequently hydrolysed, decarboxylated and reduced to give racemic pregabalin which is resolved with S-(+)-mandelic acid.
  • asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-aminomethyl-5-methylhexanoic acid has also been used to prepare pregabalin, see e.g. U.S. Patent US 6891059.
  • the cyano precursor is subsequently reduced to give pregabalin.
  • the asymmetric hydrogenation employs a chiral catalyst that is comprised of a transition metal bound to a bisphosphine ligand, such as (R 1 R)-Me-DUPHOS.
  • biphosphine ligands may be difficult and costly to prepare.
  • Asymmetric hydrogenation also requires the use of special equipment capable of handling H 2 , which can add to the capital costs of carrying out a large-scale synthesis.
  • Pregabalin has also been synthesized directly using a chiral auxiliary, (4f?,5S)-4- methyl-5-phenyl-2-oxazolidinone: see, e. g., U.S. Patents US 6359169, US 6028214, US 5847151 , US 5710304, US 5684189, US 5608090, and US 5599973.
  • these methods provide pregabalin in high enantiomeric purity, they are less desirable for large-scale synthesis because they employ comparatively costly reagents (e. g., the chiral auxiliary) that are difficult to handle, as well as special cryogenic equipment to reach required operating temperatures, which can be as low as -78 0 C.
  • a stoichiometric amount of the chiral oxazolidinone auxiliary was needed to prepare the ⁇ , ⁇ -unsaturated oxazolidinone derivative, as was a samarium-based catalyst, making this route financially unviable and environmentally undesirable, especially for a large-scale synthesis.
  • pregabalin Still further improved syntheses of pregabalin are sought. It is especially desirable to provide a process which is cost effective and safe. In particular, it is important to provide a synthesis of pregabalin which can be carried out on a commercial scale and which uses readily available starting materials and cheap reagents.
  • pregabalin in an enantiomerically enriched form, wherein the 3S-enantiomer is present in excess.
  • a process for the large-scale manufacture of pregabalin which uses a compound of formula (I) which is enriched in the desired 3S-enantiomer as an early intermediate would bring about significant benefits. For instance, later intermediates formed in subsequent steps of the synthesis would themselves be enantiomerically enriched in the required 3S-enantiomer.
  • the overall yield of pregabalin would substantially increase as there would be fewer molecules with the incorrect stereochemical configuration reacting in subsequent steps. Processing to remove the undesired 3F?-enantiomer and subsequent disposal of this waste would also be minimised.
  • One method for the synthesis of the compounds of formula (I) that we describe in this specification requires a conjugate addition reaction in the presence of a chiral catalyst, particularly a chiral phase transfer catalyst.
  • Phase transfer catalysis is primarily employed in the reaction of an anion, which is usually soluble in water and not in organic solvents, with an organic substrate which is not usually soluble in water.
  • the advantages of phase transfer catalysis are manifold. Higher reactivity may be achieved as the reactants are in the same phase with less hydration in an ion pair.
  • a PTC e.g. a quaternary ammonium catalyst
  • almost any anion may be extracted into almost any organic medium, giving flexibility in choosing or eliminating the solvent.
  • the PTC may also bring about a lower energy of activation, allowing for reduced reaction temperature and time.
  • Asymmetric phase transfer catalysis using chiral tetraalkylammonium salts or crown ethers may be used for the nucleophilic addition of an inorganic anion to prochiral electrophiles (see K. Maruoka and T. Ooi, Angew. Chem. Int. Ed. 2007, 46, 4222).
  • the asymmetric hydrocyanation of aldehydes using a phase transfer catalyst has been reported (see, e.g., S. Julia and A. Ginebre, Tetrahedron Lett. 1979, 2171 ).
  • the Strecker reaction, i.e. the hydrocyanation of imines, using a PTC has also been carried out asymethcally (see, e.g., T. Ooi, Y.
  • the sulfonate can then be displaced with a nucleophilic agent.
  • Oxygen-, sulphur- and nitrogen-based nucleophiles have all been reported (e.g Effenberger & Stelzer, Chem. Berichte 1993,126, 779-786; Effenberger et al., Tetrahedron Asymmetry 1996, 7 , 607-618; Effenberger & Gaupp, Tetrahedron Asymmetry 1999,10, 1765-1775).
  • the invention provides a compound of formula (I),
  • R 1 and R 2 are the same or different and are each independently selected from hydrogen, Ci-Ci 2 -alkyl, C 3 -Ci 2 cycloalkyl, aryl-Ci-C 6 -alkyl and aryl, said alkyl, cycloalkyl and aryl being optionally substituted by one or more groups selected from halo, C r C 6 -alkoxy and tri(CrC 3 -alkyl)silyl; or wherein R 1 and R 2 together are -C(R 3 )(R 4 )-, where R 3 and R 4 are the same or different and are each independently H or d-C ⁇ -alkyl optionally substituted by one or more groups selected from halo, d-C ⁇ -alkoxy and tri(Ci-C3-alkyl)silyl; or R 3 and R 4 together are -(CH 2 ) n - where n is 2, 3, 4, 5 or 6; wherein the 3S-enantiomer is present
  • R 1 and R 2 are the same or different and are each independently selected from Ci-Ci 2 -alkyl and benzyl. More preferably R 1 and R 2 are the same. Yet more preferably R 1 and R 2 are selected from Ci-C 4 -alkyl.
  • R 1 and R 2 are both ethyl.
  • R 1 and R 2 together are -C(R 3 )(R 4 )-; and R 3 and R 4 are the same or different and are each independently H or d.C ⁇ -alkyl; or R 3 and R 4 together are -(CH 2 ) n - where n is 2, 3, 4, 5 or 6. More preferably, R 3 and R 4 are both H or both methyl, or R 3 and R 4 together are -(CH 2 ) n - where n is 4 or 5.
  • the enantiomeric excess is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99%.
  • the invention provides a method for the preparation of a compound of formula (I) as defined above comprising reacting a compound of formula (II)
  • the catalyst is a chiral phase transfer catalyst and the reaction is carried out in a two-phase system comprising water and a water- immiscible solvent.
  • the invention provides a method for the preparation of a compound of formula (I) as defined above comprising reacting a compound of formula (111/4) or (IMS)
  • R 3 is selected from CrC 4 alkyl, Ci-C 4 perfluoroalkyl, and phenyl optionally substituted with CrC 4 alkyl, halo or NO2; and X 1 is selected from Cl and Br with a compound of formula (IV)
  • the invention provides method for the preparation of pregabalin, comprising the steps of:
  • alkyl means a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • aryl means a phenyl or naphthyl group.
  • aryl-alkyl means a straight-chain or branched-chain saturated aliphatic hydrocarbon radical in which an aryl group is substituted for an alkyl hydrogen atom.
  • An example of an aryl-alkyl group is benzyl.
  • cycloalkyl means a saturated carbocyclic ring containing the specified number of carbon atoms.
  • carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Enantiomeric excess is a measure, for a given sample, of the excess of one enantiomer in excess of its antipode and is expressed as a percentage. Enantiomeric excess is defined as:
  • er is the ratio of the more abundant enantiomer to the less abundant enantiomer.
  • optionally substituted with reference to an alkyl or aryl group means that a hydrogen atom of the alkyl or aryl group may be replaced by one of the groups listed. The substitution may be made at any position within the alkyl or aryl group. When the optional substitution is with "one or more groups” then any number of hydrogen atoms of the alkyl or aryl group, up to a maximum equal to the number of hydrogens present in the alkyl or aryl group, may be replaced, and each replacement is independent of the others.
  • perfluoroalkyl means an alkyl group as defined above wherein all the hydrogen atoms have been replaced by fluorine.
  • perfluoroalkyl radicals include trifluoromethyl, pentafluoroethyl and heptafluoroisopropyl.
  • R 1 and R 2 are different then the compounds of formula (I) have a second chiral centre.
  • some embodiments of R 1 and R 2 may include additional chiral centres.
  • Reference herein to compounds of formula (I) being in enantiomerically enriched form is intended to relate only to the stereochemistry at the 3-position (as indicted in the formula above).
  • the compounds of formula (I) may thus include single diasteroisomers and mixtures thereof. However, it will generally be preferred that these additional chiral centres be avoided.
  • R 1 and R 2 to be the same, and to be achiral groups.
  • Compounds of formula (I) of particular interest include:
  • the compounds of formula (I) may be prepared according to the methods described herein.
  • a compound of formula (II) is allowed to react with a cyanide source in the presence of a chiral catalyst.
  • the chiral catalyst is a chiral phase transfer catalyst and the reaction is carried out in a two-phase system comprising water and a water-immiscible solvent.
  • Chiral phase transfer catalysts may be ephedrine, quinine, quinidine, cinchonidine, cinchonine, crown ether or tartrate derivatives. They may be chiral tetraalkylammonium salts, chiral crown ethers, chiral phosphonium salts, chiral cinchonidinium salts, chiral cinchoninium salts, chiral quininium salts, chiral azepinium salts.
  • the chiral phase transfer catalysts may also be non-racemic chiral quaternary ammonium ions, i.e., nitrogen bonded to four carbons, which present an asymmetric environment, causing differentiation between the two enantiotopic faces of a prochiral carbon atom, typically an sp 2 -hydbridised carbon atom.
  • the quaternary ammonium moiety may be embedded in an asymmetric bicyclic or polycyclic scaffold which provides a rigid or semi-rigid environment.
  • the catalyst may bear substituents which may also affect catalyst reactivity and which may provide enhanced enantioselectivities.
  • the chiral phase transfer catalyst is selected from: (-)- ⁇ /-Benzyl- ⁇ /-methylephedrinium halide; (-)- ⁇ /-Dodecyl- ⁇ /-methylephedhnium halide; (-)- ⁇ /, ⁇ /-Dimethylephedrinium halide; ⁇ /-Benzylcinchonidinium halide; O-Allyl- ⁇ /-benzylcinchonidinium halide; ⁇ /-(9-Anthracenylmethyl)cinchonidinium halide; O-Allyl- ⁇ /-(9-anthracenylmethyl)cinchonidinium halide; ⁇ /-Benzylquininium halide; ⁇ /-(4-Thfluoromethylbenzyl)cinchoninium halide; O,O'-Diallyl- ⁇ /,/V-(2,7-naphthalenediyldimethyl)
  • Catalysts such as (trifluoromethylbenzyl)cinchoniniunn halide and 3,5- bis(thfluoromethyl)benzyl cinchoninium halide, are especially preferred. More preferably, the chiral phase transfer catalyst is (trifluoromethylbenzyl)cinchoninium bromide or 3,5-bis(thfluoromethyl)benzyl cinchoninium bromide.
  • the catalyst may be used in an amount ranging from 0.05 to 1.1 equivalents per molar equivalent of the compound of formula (II) without negatively affecting the e.e. Preferably a 0.05-0.20 molar equivalent is used. This may be especially advantageous as the catalyst may be expensive and/or not readily available. In addition, the present invention envisages that the catalyst may be recovered and reused.
  • the reaction of the compound of formula (II) with a cyanide source is carried out in a two-phase system.
  • the compound of formula (II) may itself provide one of the phases and may be used neat, i.e. undissolved in an additional solvent. More typically, the reaction is carried out in a two-phase system comprising water and a water- immiscible solvent.
  • a suitable amount of a compound, e.g. a glycol, which lowers the freezing point of the aqueous phase of the reaction mixture may be added.
  • the water-immiscible solvent is a solvent which provides good recoveries of the organic materials. It is also preferred that a solvent with medium polarity is used.
  • a solvent which is not inert under the reaction conditions may be advantageous to use.
  • a water-immiscible ketone may also be used to bring the cyanide anion into the organic phase as a cyanohydhn.
  • suitable solvents include hydrocarbons such as toluene, xylene and mesitylene, ethers such as methyl-/-butyl ether, 2-methyltetrahydrofuran, chlorinated solvents such as dichloromethane and chlorobenzene, water-immiscible ketones such as methyl ethyl ketone, diethyl ketone and alcohols such as /-amyl alcohol, 3- pentanol, n-butanol, isobutanol. More preferably the water-immiscible solvent is selected from methyl-/-butyl ether and /-amyl alcohol. Most preferably, the solvent is methyl-/-butyl ether.
  • the solvent is preferably toluene or dichloromethane.
  • cyanide sources may be used to provide the cyanide anion required for the reaction. They include acetone cyanohydrin and TMSCN. More usually, the cyanide source is a cyanide salt of an alkali metal, preferably sodium or potassium.
  • the reaction may be carried out at a temperature in the range of -78 to 8O 0 C, more preferably in the range -20 to 4O 0 C, and still more preferably in the range 0-30 0 C.
  • a lipophilic proton source to the reaction mixture.
  • the proton source may be added in any quantity, a stoichiometric quantity being the typical amount.
  • Typical lipophilic proton sources are long-chain alcohols, such as 1 -octanol.
  • the reaction of the compound of formula (II) with a cyanide source may be carried out in continuous, semi-continuous or batch fashion.
  • the compounds of formula (II) may be prepared from isovaleraldehyde and a malonate of formula (IV), for example as described in U.S. Patents US 6046353, US 5840956, and US 5637767.
  • the compounds of formula (I) may be prepared by reacting a compound of formula ( ⁇ A) or (IMS) with a malonate derivative of formula (IV) in the presence of a base.
  • R 3 is selected from d-C 4 alkyl, d-C 4 perfluoroalkyl, and phenyl optionally substituted with CrC 4 alkyl, halo or NO2.
  • Preferred embodiments of R 3 include methyl, trifluoromethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl and 2-, 3- and4-nitrophenyl.
  • X 1 is selected from Cl and Br.
  • the base may be any suitable base. Suitable bases are those that deprotonate the malonate to a sufficient degree to allow the reaction to proceed, but which do not react with the various functional groups present in the starting materials and the product. Examples of suitable bases include alkali metal carbonates (such as caesium carbonate) and alkali metal hydrides (such as sodium hydride). Alkali metal alkoxides (such as sodium ethoxide and potassium t-butoxide) may also be suitable provided that they do not lead to transestehfication products.
  • alkali metal carbonates such as caesium carbonate
  • alkali metal hydrides such as sodium hydride
  • Alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide
  • Suitable solvents are those in which the stating materials and the base have sufficient solubility to allow the reaction to proceed, but which do not adversely react with the reactants.
  • suitable solvents include nitriles (such as acetonitrile) and ethers (such as tetrahydrofuran, 2-methyltetrahydrofuran and 1 ,2-dimethoxyethane).
  • Alcohols such as ethanol may also be suitable solvents provided that they do not lead to transestehfication products. Solvent mixtures are also contemplated.
  • the reaction may be carried out at any temperature between the freezing point and the boiling point of the solvent. Preferred temperatures are in the range of 20 0 C to 80 0 C, and particularly 40°C to 60 0 C.
  • the base may react with the malonate before the compound of formula (111/4) or (IMS) is added.
  • a compound of formula (111/4) wherein R 3 is phenyl or substituted phenyl is reacted with the sodium salt of diethyl malonate in a polar solvent at about 50°C to provide the compound of formula (I) wherein R 1 and R 2 are both ethyl.
  • the compounds of formula (Ml/4) and (IMS) should be enantiomerically enriched, with the (S)-enantiomer present in excess.
  • the compounds of formula (Ml/4) and (IMS) should be in the form of the substantially pure (S)-enantiomer.
  • the compounds of formula (Ml/4) can be prepared according to the published methods (supra) from (S)-2-hydroxy-4-methylpentanenitrile ((S)-isovaleraldehyde cyanohydrin) by reaction with an appropriate sulfonyl chloride or sulfonic acid anhydride. (R 3 SO 2 ) 2 O (IMA)
  • the compounds of formula (IMS) can be prepared according to the published methods (supra) from (R)-2-hydroxy-4-methylpentanenitrile ((R)-isovaleraldehyde cyanohydrin) by reaction with an appropriate halogenating agent (for example thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxybromide and triphenylphosphine/carbon tetrabromide).
  • an appropriate halogenating agent for example thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus oxybromide and triphenylphosphine/carbon tetrabromide.
  • Both the (R)- and (S)-enantiomers of isovaleraldehyde cyanohydrin are known and may be prepared by a number of methods.
  • a preferred method is to react isovaleraldehyde with a cyanide source (such as an alkali metal cyanide or acetone cyanohydrin) in the presence of a hydroxynitrile lyase enzyme.
  • a cyanide source such as an alkali metal cyanide or acetone cyanohydrin
  • suitable enzymes include (S)-hydroxynitrile lyases from Hevea brasiliensis, Manihot esculenta, and Sorghum bicoloran ⁇ (R)-hydroxynitrile lyase from Prunus amygdalus.
  • the enantiomehcally enriched compounds of formula (I) are useful intermediates for the manufacture of pregabalin. Starting from the compounds of formula (I) it is necessary to perform three transformations in order to get to pregabalin:
  • WO 2006/000904 also describes the reduction of the monoester of the ⁇ -cyanodiacid intermediate, to form a lactam which is subsequently hydrolysed to give enantiopure pregabalin.
  • Other approaches from the monoester of the the ⁇ -cyanodiacid intermediate are discussed in Organic Process Research and Development, Vol. 12 (3), 2008, 392-398. The skilled reader will be able to modify the methods described in the art as necessary.
  • yield losses associated with the production of an undesired enantiomer may be substantially reduced or even be eliminated altogether.
  • DIW De-ionised water dd Doublet of doublets ddd Doublet of doublets of doublets dt Doublet of triplets eq or eq. Equivalent e.e. or ee Enantiomeric excess
  • MA-ene-malonate was prepared using the procedure described in: Tsuno, K. Sugiyama, H. Ago, Heterocycles 1994, 38, 2631.
  • Isovaleraldehyde (11.2 ml, 104.5 mmol, 1.05 eq) and Meldrum's acid (14.4 g, 99.9 mmol, 1 eq) were dissolved in MTBE (500 ml).
  • Piperidine (0.2g) and glacial acetic acid (0.2 g) were added. The mixture was heated to reflux temperature and water was removed using a Dean- Stark collector. After about 3 h, 1.5 ml of water had collected and overnight distillation did not increase this amount.
  • the crown ether PTC catalyst was prepared according to the procedure described in: K. Naemura, M. Ueno, Bull. Chem. Soc. Jpn. 1990, 63, 3695.
  • a solution of (2R,3/ : ?)-butane-2,3-cliol (0.27 ml_, 3.0 mmol, 1.0 eq.) and pentaethylene glycol bis(p-toluenesulfonate) (1.8 g, 3.3 mmol, 1.1 eq) in THF (160 mL) was added dropwise over 10 hours to a suspension of sodium hydride (180 mg, 7.5 mmol, 2.5 eq.) and potassium tetrafluoroborate (425 mg, 3.3 mmol, 1.1 eq.) in refluxing THF (160 mL).
  • the crude product was dissolved in 50/50 dichloromethane/heptane and passed through a short silica gel column eluting with 50/50 dichloromethane/heptane, and the resultant fraction was evaporated under reduced pressure to give a pale yellow oil.
  • the organic phase was dried (MgSO 4 ) and evaporated to a pale orange oil which solidified on standing.
  • the crude product was dissolved in 50/50 dichloromethane/heptane and passed through a short silica gel column eluting with 50/50 dichloromethane/heptane, the resultant fraction was evaporated under reduced pressure to give a pale yellow oil which solidified on standing.
  • Examples 1 to 20 relate to the phase-transfer catalysis method.
  • Et-ene-malonate (Preparation 1 : 20 mg, 0.09 mmol, 1.0 eq.), a catalyst, if used, (0.018 mmol, 0.2 eq.), 1.2 ml_ water and 0.4 ml_ organic solvent were mixed in a small vial.
  • Aqueous NaCN or KCN (0.05 ml_ of a 2M solution, 0.1 mmol, 1.1 eq.) was added and the vial sealed. The mixture was stirred rapidly at room temperature overnight, then allowed to settle and the organic layer was sampled by HPLC. Alternatively, the reaction may be carried out at 0 °C but no difference in the enantiomeric excess obtained was observed.
  • the catalysts used are referred to by various numbers which correspond to the following table. The same numbering is used to refer to the catalysts in subsequent tables.
  • Example 2 The procedure of Example 1 was used, except that KCN was used as the cyanide source, the catalyst was used in stoichiometric quantities and dichloromethane was used as the organic solvent.
  • the conversion of Et-ene-malonate to CNDE was determined by 1 H NMR and the ee of CNDE was measured by chiral HPLC.
  • Table 3 Effect of using a stoichiometric quantity of catalyst on the extent of conversion of Et-ene-malonate and enantiomeric excess of the R or S enantiomer obtained
  • Example 2 Effect of solvent on the enantiomeric excess of the R ox S enantiomer obtained
  • the procedure of Example 1 was used, except that KCN was used as the cyanide source and the organic solvent was varied according to the table below.
  • the ee of CNDE was measured by chiral HPLC.
  • Example 3 The procedure of Example 3 was used on a scale of 200 mg Et-ene-malonate. NaCN was used as the cyanide source and the catalyst used was ⁇ /-(4- trifluoromethylbenzyl)cinchonininium bromide (catalyst 10, 0.2 eq).
  • Example 2 The procedure of Example 1 was used, except that KCN was used as the cyanide source, and the organic solvent was varied according to the table below.
  • the catalyst used was ⁇ /-(4-trifluoromethylbenzyl)cinchonininium bromide (catalyst 10, 0.2 eq).
  • a stoichiometric quantity of 1-octanol was also added to the reaction mixture.
  • the reactions were repeated several times on a scale of 20 mg of Et-ene- malonate, also carried out in duplicate on 200 mg Et-ene-malonate, giving S-CNDE of 23% and 33% ee.
  • the ee of CNDE was measured by chiral HPLC.
  • Example 2 The procedure of Example 1 was used, with 0.2 g Et-ene-malonate, 1.1 eq of NaCN, 4 ml_ of MTBE, 12 ml_ H 2 O, 1 eq of 2-octanol being employed.
  • the mol% of catalyst, ⁇ /-(4-trifluoromethylbenzyl)cinchonininium bromide (catalyst 10) was varied according to the Table below.
  • Example 1 The procedure of Example 1 was used on a scale of 200mg of Et-ene-malonate. NaCN (1.1 eq.) was used as the cyanide source, and MTBE (4 ml_) was used as the solvent. The catalyst used was ⁇ /-(4-Trifluoromethylbenzyl)cinchonininium bromide (0.2 eq.). The level of water was varied according to the table below.
  • Example 1 The procedure of Example 1 was used to investigate the effect of temperature.
  • the catalyst used was ⁇ /-(4-trifluoromethylbenzyl)cinchonininium bromide (catalyst 10, 0.2 eq.).
  • the temperature at which the reaction was carried out varied according to the table below. Each reaction was carried out in duplicate using 200mg Et-ene- malonate, 1.1 eq of NaCN and 20 mol% catalyst, 12ml_ water and 4ml_ MTBE.
  • Example 1 Effect of increasing the amount of NaCN
  • the procedure of Example 1 was used to investigate the effect of using 1.5 eq NaCN.
  • the catalyst used was ⁇ /-(4-trifluoromethylbenzyl)cinchonininium bromide (catalyst 10, 0.1 eq.).
  • the reaction was carried out using 200 mg Et-ene-malonate and MTBE (4 ml_) as the organic solvent.
  • Example 10 The procedure of Example 10 was used to obtain dibenzyl 2-(1 -cyano-3-methyl- butyl)malonate as a racemate by using /7Bu 4 NBr as the catalyst. The reaction did not go to completion. However, the product was obtained clean after chromatography.
  • Example 10 The procedure of Example 10 was used, using ⁇ /-(4-trifluoromethylbenzyl)- cinchonininium bromide (catalyst 10, 0.051 eq.) as the phase transfer catalyst (PTC).
  • PTC phase transfer catalyst
  • the amounts of MTBE and water were varied according to Table 11.
  • Example 12 The procedure of Example 12 was used.
  • the PTC was varied according to Table 12, the numbering used for the various catalysts is the same as that used in Table 1 , with the exception of PTC 17, 18 and 19, which do not appear in Table 1. Entry A in Table 11 gives details of the amounts of MTBE and water which were used.
  • Table 13 Catalysts used in the hydrocya nation of Bn-ene- malonate
  • Figure 4 shows values obtained for the amounts of benzylalcohol, Bn-ene-malonate (the starting material) and Bn-CN-malonate obtained. These values are derived from three separate concentration calibrations for benzylalcohol, Bn-ene-malonate and Bn-CN-malonate. Consequently there is quite a margin for error in combining three calibrations as well as the fact that the phase separation in the reactions made sampling difficult, hence some % values will be overestimated. In cases where there was little conversion, the % ee may also not be an accurate reflection of the actual % ee obtained. As shown in Table 12 and Figure 4, the chinchonidinium catalysts were the slightly more selective set of PTC agents used. Example 14 Hydrocyanation of Et-ene-malonate with PTCs 17, 18 and 19.
  • Et-ene-malonate (0.1 g, 0.438 mmol, 1 eq) and PTC 17, 18 or 19 (see Table 13) (0.024 mmol, 0.05 eq) were weighed out into a vial and were slurried with MTBE (2 ml_).
  • NaCN (0.032 g, 0.657 mmol, 1.5 eq) was dissolved in water (6 ml_) and was added. The mixture was vigorously stirred overnight. The layers were allowed to stand and separate and then about 50 ⁇ l_ of the organic layer was removed and was diluted with about 1 ml_ IPA for HPLC analysis, which was carried out using the HPLC assay described in Example 1. The results obtained are summarised in Table 15.
  • MA-ene-malonate MA-CN-malonate MA-ene-malonate (Preparation 2; 0.2 g, 0.94 mmol, 1 eq) and the PTC (0.094 mmol, 0.1 eq) were weighed out into a vial and were slurried with MTBE (4 ml_).
  • NaCN (0.07 g, 1.41 mmol, 1.5 eq) was dissolved in water (12 ml_) and was added. The mixture was vigorously stirred overnight. The mixture was then acidified to pH 1 with 1 M aqueous HCI and the product was extracted out with DCM (3 x 5 ml). The organic layer was dried over Na2SO 4 , filtered (a sample was removed for HPLC analysis) and the solvent was removed in vacuo.
  • Solvent A Heptane (0.1 % TFA)
  • Solvent B Propan-2-ol (0.1 % TFA)
  • Example 16 The procedure of Example 16 was used, with the exception that the aqueous layer was buffered. The reactions were also run in DCM instead of MTBE, as the poor solubility of the product makes it difficult to handle in MTBE. It is to be noted that since the product is very acidic and the reaction generates NaOH, the final pH differs form the pH of the buffer solution used as follows:
  • Example 16 The procedure of Example 16 was used. Water was not used; instead, amyl alcohol was used as a solvent. The NaCN was also used as a solid, rather than as an aqueous solution.
  • Example 18 The procedure of Example 18 was used. The reaction was run in various NMR solvents in the absence or presence of a PTC, as detailed in Table 17. After overnight stirring, NMR was used to determine whether conversion had occurred. The samples were acidified and a sample taken for HPLC analysis. The results are summarised in Table 17.
  • the organic phase was sampled, diluted with ethanol and analysed by chiral HPLC.
  • PTC 10 gave good selectivity (-29%) in toluene, although a gum also formed. Unfortunately due to a co-running peak, analysis in other solvents was not possible.
  • PTC 8 was the only other catalyst to give enrichment of the later running peak by HPLC - although this was only up to 4% ee.
  • Examples 21 to 23 relate to the cyanohydrin method.
  • a further set of screening reactions was carried out using 2.5eq of sodium hydride and 2.6eq of diethyl malonate at 5O 0 C.
  • a further set of screening reactions was carried out using increasing amounts of sodium hydride in THF at reflux.
  • Diethylmalonate (43.Og, 0.268moles, 1.6eq) was added to a slurry of sodium hydride (10.1g, 60% w/w, 0.251 moles, 1.5eq) in dry THF (65OmL) at ambient temperature over a period of approximately 15 minutes. The slurry was stirred at ambient temperature for approximately 15 minutes. A solution of 2-nosylate cyanohydrin (5Og, 0.168moles) in dry THF (5OmL) was added and the reaction was heated to reflux and stirred for 3 hours. The reaction was allowed to stir to ambient temperature overnight.
  • the IPA was distilled off under vacuum to a batch volume of about 97OmL while maintaining the pot temperature below 35 0 C and once distillation was complete the vacuum was broken at the same temperature with nitrogen.
  • the pot temperature was reduced to 0°C over 2hrs and granulated at the same temperature for 3hrs.
  • the product was isolated by filtration.
  • the product was slurried twice on the filter with 12% water in IPA (205ml_ IPA: 21.9ml_ H 2 O). The product was dried in a vacuum oven.

Abstract

La présente invention concerne un composé de formule (I) sous une forme énantiomériquement enrichie. Dans ladite formule, R1 et R2 sont chacun indépendamment sélectionnés parmi un alkyle éventuellement substitué, un cycloalkyle, un aryle-alkyle et un aryle, le 3S-énantiomère étant présent en excès et l'excès énantiomérique étant au moins égal à 10 %. L'invention concerne également un procédé de préparation, sous une forme énantiomériquement enrichie, du composé de formule (I). L'invention concerne en outre un composé de formule (I) dans un procédé de préparation de prégabaline.
PCT/IB2009/055786 2008-12-19 2009-12-16 Esters de malonate WO2010070593A2 (fr)

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Cited By (8)

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WO2012025861A1 (fr) 2010-08-23 2012-03-01 Pfizer Manufacturing Ireland Procédé de préparation de dérivés d'acide (s)-3-cyano-5-méthylhexanoïque et de prégabaline
WO2016153937A1 (fr) * 2015-03-20 2016-09-29 Stanford University Réactions de carboxylation activées par du carbonate pour la synthèse de composés organiques de valeur
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US10160740B2 (en) 2015-03-20 2018-12-25 The Board Of Trustees Of The Leland Stanford Junior University Carbonate-promoted carboxylation reactions for the synthesis of valuable organic compounds
US10710971B2 (en) 2015-03-20 2020-07-14 The Board Of The Trustees Of The Leland Stanford Junior University Carbonate-promoted carboxylation reactions for the synthesis of valuable organic compounds
WO2017183539A1 (fr) * 2016-04-18 2017-10-26 第一三共株式会社 Procédé de production d'un composé bicyclique à l'aide d'acide de meldrum
CN109232311A (zh) * 2018-10-08 2019-01-18 浙江新和成股份有限公司 一种绿色高效的普瑞巴林合成方法
CN109232311B (zh) * 2018-10-08 2021-02-19 浙江新和成股份有限公司 一种绿色高效的普瑞巴林合成方法

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