Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B57/00—Separation of optically-active compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/42—Separation; Purification; Stabilisation; Use of additives
  • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
  • C07C51/493—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification whereby carboxylic acid esters are formed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/48—Separation; Purification; Stabilisation; Use of additives
  • C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
  • C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation

Definitions

• This invention relates to ⁇ -aryl propionic acids (also referred to as profens) and more particularly to the conversion of racemic profens to optically pure profens.
• Profens are a structural class of nonsteroidal antiinflammatory drugs consisting of ⁇ -aryl propionic acids bearing variously substituted aromatic groups.
• Ibuprofen (2-[4'-isobutylphenyl]propionic acid), Formula 1, and naproxen (2-[6'-methoxy-2'- naphthyl]propionic acid), Formula 2, are the best known members of the class.
• Profens contain a chiral center alpha to the aromatic ring.
• Naproxen and its sodium salts are currently sold in enantiomerically pure form.
• Ibuprofen and other profens, such as ketoprofen and flurbiprofen, are sold as racemates.
• Numerous companies have investigated methods to produce chiral or enantiomerically enriched profens under commercially suitable conditions.
• chiral profens or aryl propionic acids are isolated via techniques such as diastereomeric salt resolutions, chemical and kinetic resolutions, preferential crystallization, asymmetric synthesis using chiral auxiliaries, and asymmetric syntheses using chiral catalysts. These techniques are often labor intensive and require solvents.
• Ibuprofen (Formula 1) is a well known non-steroidal anti-inflammatory (NSAI) drug, and is a racemic mixture of the S-(+) and R-(-)-enantiomers. Studies have indicated that the S-(+)-isomer is the pharmacologically active form. In the human body the R-(-)-isomer is also converted to S-(+)-isomer. Avgerinos et al. Chirality. Vol. 2, 249 (1990). Consequently, there is a growing interest in the commercialization of optically pure S-(+)-ibuprofen.
• NSAI non-steroidal anti-inflammatory
• U.S. Patent 5,015,764 (Assignee: Ethyl Corp.) discloses a process whereby racemic ibuprofen is converted into a mixture of diastereomeric salts. The two isomeric salts are then separated by fractional crystallization.
• U.S. Patent 4,994,604 (Assignee: Merck & Co.) uses S-lysine for the resolution of racemic ibuprofen. Other methods such as enzymatic resolution and chromatography have also been suggested for the resolution. The disadvantage with such processes is that they are time-consuming, and the yields are generally low.
• U.S. Patent 4,874,473 discloses a process for separating the diastereomers, cis/trans permethric acid esters or acid chlorides, menthol/isomenthol and the methyl esters of cis/trans caromaldehyde acid.
• the process involves adding a chiral resolving agent or auxiliary to the diastereoisomers and extractively distilling. Both isomers are isolated. Although diastereomers are separated, there is no suggestions of a process which produces a pure enantiomer.
• Such separation of the chiral auxiliary requires extra processing steps and equipment and often consumes chemicals and generates wastes in stoichiometric quantities. Furthermore, additional process equipment and energy are often needed to alternate between radically different conditions (temperature, solvent, pH, etc.) for racemization and resolution.
• Another object of the present invention is to provide a process for optical resolution of profens with a chiral resolving agent that is separated and recovered from the resolved profen without detectable decomposition or loss of configurational purity of either the profen or the chiral resolving agent.
• Figure 1 illustrates the distillative separation of diastereomeric esters obtained from racemic ibuprofen and chiral, optically active alcohols.
• the invention relates to a process for the preparation of a chiral ester comprising contacting an ⁇ -aryl propionic acid having at least one benzylic chiral carbon center with a -C JQ alkanol having at least one chiral carbon center to form an ester having at least two points of chirality, at least one of said points of chirality being enriched in one stereochemical configuration over the other.
• Another embodiment of the invention relates to a process for selectively preparing S-(+)-aryl propionic acids from racemic aryl propionic acids comprising (a) reacting racemic aryl propionic acid having a chiral benzylic carbon with a C,-C 20 optically active alkanol to produce a mixture of diasteromeric esters; (b) fractionally distilling said mixture under suitable conditions such that the diastercomer incorporating the S-form of the aryl propionic acid distills off into the distillate, while the diastereomer incorporating the R- form of the propionic acid accumulates in the distillation residue; (c) racemizing the benzylic profen carbon in the distillation residue under suitable conditions to regenerate a substantially 1:1 mixture of the diastereomeric esters; and (d) optionally hydrolyzing the distillate to provide the desired S(+)-enriched aryl propionic acid as well as the C r C 20 optically active alkanol for recycle.
• a preferred embodiment of the present invention relates to a process for selectively preparing S-(+)-ibuprofen, or salts thereof, from racemic ibuprofen, comprising (a) reacting racemic ibuprofen with the appropriate enantiomer of an optically active alcohol to produce a mixture of diastereomeric esters; (b) distilling said mixture under suitable conditions such that the diastereomer incorporating the S-form of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the R-form of ibuprofen accumulates in the distillation residue; (c) racemizing benzylic carbon in the distillation residue under suitable conditions to regenerate a substantially 1:1 mixture of diasteromer esters; and, (d) optionally hydrolyzing the distillate of step (b) to S-(+)-ibuprofen.
• This process may also be employed for the selective preparation of R-(-)-ibuprofen or salts thereof, by (a) reacting racemic ibuprofen with the other enantiomer of the optically active alcohol to produce another mixture of diastereomeric esters; (b) distilling the mixture of diastereomeric esters under suitable conditions such that the diastereomer incorporating the R-form of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the S-form accumulates in the distillation residue; (c) racemizing the distillation residue under suitable conditions to regenerate a substantially 1:1 mixture of diastereomeric esters; and, (d) optionally, hydrolyzing the distillate of step (b) to R-(-)-ibuprofen.
• the present invention may also be used to optically enrich a chiral alkanol by (a) esterification with an optically active aryl propionic acid; (b) distillative separation of the resulting diastereomeric esters; and (c) hydrolysis of one or both of the separated diastereomeric esters.
• a compound is said to be asymmetric or chiral if it has two isomers which are mirror images of each other but which are not superimposable. Such isomers are said to be enantiomers.
• An atomic center in a chiral compound is a chiral center if the chiral compound has two enantiomers for which the geometrical configurations of atoms directly bonded that atomic center differ only in the sense of being non-superimposable mirror images.
• the two non-superimposable mirror image geometrical configurations of a chiral center are called geometrical, optical, or stereochemical configurations.
• asymmetric and chiral do not imply any excess of one enantiomer or configuration over another. Isomers of a chiral compound which differ only by the stereochemical conf ⁇ guration(s) at one or more chiral centers are stereoisomers. If a chiral compound has more than one pair of enantiomerically related stereoisomers, each pair of enantiomerically related stereoisomers is called a diastereomer. Enantiomeric, configurational, or diastereomeric purity is the quantity of a particular enantiomer, configuration, or diastereomer as a percentage of all enantiomers, configurations, or diastereomers, respectively, where "all" usually means "both".
• enantiomeric, configurational, or diastereomeric excess is the difference between the two enantiomeric, configurational, or diastereomeric purities.
• Optical purity and enantiomeric excess are interchangeable terms with identical meanings.
• a sample is considered to be optically active if it contains more of one enantiomer than the other enantiomer of a chiral compound.
• a sample of a chiral compound is racemic if it has little or no optical activity, optical purity, or enantiomeric excess (ee).
• Figure 1 illustrates a multistep process to isolate the desired profen enantiomer, with ibuprofen illustrated for exemplary purposes, wherein esterification of racemic ibuprofen with an optically pure (S)-alkanol is employed, followed by fractional distillation of the resulting diastereomeric esters, racemization of the benzylic carbon of the unwanted RS diastereomer, and hydrolysis of the S.S-diastereomer.
• S optically pure
• the present invention discloses a process to make S-(+)-ibuprofen or R-(-)- ibuprofen from racemic ibuprofen in yields exceeding 50% of the racemate feed without the need to separate the chiral resolving agent or the auxiliary from the undesired enantiomer.
• the invention more generally relates to a process for the preparation of a chiral ester comprising contacting an ⁇ -aryl propionic acid having at least one benzylic chiral carbon center with a C r C 20 alkanol having at least one chiral carbon center to form an ester having at least two points of chirality, at least one of said points of chirality being enriched in one stereochemical configuration over the other.
• the ⁇ -aryl propionic acid may be selected from the group consisting of naproxen, ketoprofen, flurbiprofen, fenoprofen, indoprofen, pirprofen, suprofen, ibuprofen, cycloprofen, and minoxiprofen, wherein ibuprofen and naproxen are most preferred.
• the present invention relates to a process for selectively preparing S-(+)-aryl propionic acids from racemic ⁇ -aryl propionic acids comprising (a) reacting racemic aryl propionic acid having a chiral benzylic carbon with a C r C 20 optically active alkanol to produce a mixture of diasteromeric esters; (b) fractionally distilling said mixture under suitable conditions such that the diastereomeric ester incorporating the S-form of the aryl propionic acid distills off into the distillate, while the diastereomeric ester in incorporating the R-form of the propionic acid accumulates in the distillation residue; and, (c) racemizing the benzylic profen carbon atom in the distillation residue under suitable conditions to regenerate a substantially 1 :1 mixture of the diastereomeric esters.
• the process further comprises, optionally, hydrolyzing the distillate of step (b) under suitable conditions to yield S-(+)-ary 1 propionic acids
• R-(-)-ibuprofen or salts thereof, from racemic ibuprofen comprising (a) reacting racemic ibuprofen with the other enantiomer of the optically active alcohol to produce a mixture of diastereomeric esters; (b) distilling said mixture under suitable conditions such that the diastereomer incorporating the R-form of ibuprofen selectively distills off into the distillate, while the diastereomer incorporating the S-form accumulates in the distillation residue; (c) racemizing the distillation residue under suitable conditions to regenerate a mixture of diastereomeric esters; and, (d) optionally, hydrolyzing the distillate of step(b) to R-(-)- ibuprofen.
• the resolution of racemic ibuprofen proceeds by reacting the racemate with a substantially pure optically active alcohol (or alkanol as also referred herein) to produce a mixture of two diastereomeric esters. If the optically active alcohol is an (S)-alcohol, for example, then the resulting diastereomers will have the (S,S) and the (R,S) configurations.
• the alkanol generally consists of C 4 -C, 2 S-(+)-alkanol.
• alkanols include, but are not limited to: S-(+)-2-butanol, 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 3 -methyl- 1-butanol, 3-hepanol, 3-hexanol, 2-amino-l-propanol, menthol, isomenthol, nopol, and 2-methylcyclo- pentanol, 2-methyl-l-butanol, menthol, isomenthol, nopol, trans 2-methyl cyclopentanol, trans 2-methylcyclohexanol, and cis 2-methylcyclohexanol with a preference given to 2-butanol.
• Use of enantiomerically pure alkanol is preferred for optimal success of the inventive distillative resolution process. Methods of making chiral 2-alkanols are reported in the literature.
• the chiral alcohol is chosen such that the corresponding two diastereomers will have sufficient thermal stability and difference in volatility to permit their separation by fractional distillation.
• Such distillative separation is typically achieved at pressures of about 0.1 to 100 mm Hg absolute pressure, and preferably at about 0.2 to 10.0 mm Hg absolute pressure.
• the alcohol is preferably employed in slight excess. Generally about 5-30 mole %, more preferably about 10-20 mole % excess relative to the propionic acid.
• Diastereomeric esters of racemic ibuprofen with several chiral acyclic and cyclic alcohols may be prepared, and the relative boiling points or volatilities of the esters may be estimated by processes known to those of skill in the art, such as, gas liquid chromatography .
• a pair of relatively low boiling diastereomers having a relatively large difference in boiling points would be preferred for the distillative separation.
• the esterification reaction may proceed by conventional methods.
• a useful process in connection with the present invention is to reflux the racemic ibuprofen and the optically active alcohol in the presence of an acid catalyst.
• Suitable acids include, but are not limited to sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, and hydrochloric acid.
• Solid acid catalyst e.g., acidic ion exchange resins (Amberlyst®, etc., Nafion®) may also be employed.
• the catalyst is generally employed in amounts of about 1 - 10 wt % based on the propionic acid.
• the esterification reaction may proceed in the presence of a solvent. If the alcohol is a liquid, such may itself act as the solvent.
• Suitable solvents for the esterification procedure include, but are not limited to, -C 12 aliphatic hydrocarbons, aromatic hydrocarbons, and ethers such as hexane, cyclohexane, heptane, octane, cyclooctane, nonane, decane, decalin, benzene, toluene, xylene, ethyl benzene, di-isopropyl ether, di-n-propyl ether, dibutyl ether, anisole, diphenyl ether, and the like.
• the solvent may be employed in amounts from about half to about ten times the weight of the propionic acid.
• the esterification reaction is preferably carried out at a temperature of about 50-200 °C, preferably about 100-150 °C, and most preferably at reflux temperature. It is preferred that the water formed during the reaction be removed by distillation as an azeotrope.
• the esterification reaction is preferably carried out over about 0.5-10 hours and more preferably over about 1-4 hours with an acid catalyst as described above, in an amount of about 0.01-0.1 moles and more preferably about 0.02-0.06 moles per mole of propionic acid.
• the ester product may be isolated and analyzed by conventional methods such as gas chromatography (GC), high performance liquid chromatography (HPLC), infrared spectroscopy (IR) and the like for completion of the reaction.
• the distillation is preferably carried out by continuous injection of the mixture of diastereomers into an intermediate position of a low-pressure drop fractional distillation column with continuous removal of distillation overhead (distillate) and distillation bottoms (residue) from the top and the bottom of the distillation column, respectively. All distillation overhead (distillate) fractions and all distillation residue (bottoms) fractions are considered to be distillation products.
• the distillation overhead is enriched in the S,S diastereomer and the distillation residue is enriched in the R,S diastereomer.
• the distillation overhead is enriched in the R,R diastereomer and the distillation residue is enriched in the S,R diastereomer.
• the stereochemical configuration of the chiral alcohol component of the ester is preferably selected to permit recovery of ⁇ -arylpropionic acid enriched in the desired enantiomer from the distillation overhead and to permit racemization of benzylic carbon enriched in the undesired configuration in the distillation residue.
• optically pure ⁇ -arylpropionic acids can be used as chiral resolving agents or auxiliaries to resolve racemic alcohols.
• distillation of the mixture of diastereomeric esters prepared from S-(+)-ibuprofen and racemic 2-alkanol eg. 2- octanol
• 2-alkanol eg. 2- octanol
• Separate hydrolysis of the distillate and the residue would yield optically enriched S-2-alkanol and optically enriched R-2-alkanol, respectively, in addition to S-(+)- ibuprofen for recycle to esterification.
• the S-2-octyl ester of S-(+)-ibuprofen was found to undergo acid-catalyzed hydrolysis without compromising the configurational purity of the benzylic carbon.
• a ([A] v [B] 1 )/([A],[B] v ) where the subscripts v and 1 denote concentrations in vapor and liquid phases, respectively, which are in equilibrium.
• the reflux ratio is the ratio of overhead condensate returned to the distillation column to the overhead condensate withdrawn from the distillation and not returned to the column.
• the distillation is carried out preferably at about 50°C-250°C and about 0.01-100 mm Hg absolute pressure with a reflux ratio of about 1:1 - 100:1, and more preferably at about 100°C-200°C and about 0.2-10 mm Hg absolute pressure with a reflux ratio of about 5 : 1 -20 : 1.
• the alcohol component of the ester and the distillation temperature, pressure, reflux ratio, and column height, diameter, packing, and injection point are interrelated factors which can be optimized by one skilled in the art of distillation.
• the yield of the predominate diastereomer in the distillate can be increased to much greater than 50% of the total feed mixture by recycle of the distillation residue back to the distillation column after racemization of the benzylic carbon in the residue.
• Processes for using an acid or base catalyst to racemize ibuprofen enantiomers are known.
• U.S. Patent 5,015,764 discloses racemization of ibuprofen enantiomers using bases.
• racemizations require solvents, low operating temperatures, and long reaction times and therefore are not easily integrated with a fractional distillation process.
• the distillation residue might require cooling and dilution with solvent, and then, after racemization of benzylic carbon, reheating and distillative removal of solvent prior to recycle to the distillation column.
• cooling, dilution, reheating, and solvent stripping all add extra processing steps and increase process equipment and energy requirements.
• a solvent is not always necessary for this racemization.
• the distillation residue is directly treated with the appropriate amount of the carbonate in a slurry at temperatures of about 70 °C to about 200 °C for a sufficient length of time, usually about 0.5-5 hours, for substantially complete racemization.
• the racemization process of the present invention is preferably carried out in the absence of added solvent by mixing a slurry of 0.05-0.25 moles of carbonate catalyst per mole of ester at about 80°C-200°C, more preferably about 120°C-160°C, for a length of time sufficient to achieve substantially complete racemization of benzylic carbon, which is about 0.1- 24 hours and more typically about 1-6 hours.
• substantially complete may be determined by an analysis by GC to show a mixture of two diastereomers (RS) and (SS) in a ration (1:1) or 50:50.
• solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, polyethylene glycol, diisopropyl ether, tetraethyleneglycol dimethyl ether, toluene, and the like, may be used.
• the racemization may also be carried out with other basic catalysts, including but not limited to tertiary amines such as poly(4-vinylpyridine), 4-(dimethylamino)pyridine, and l,4-diazabicyco[2.2.2]octane as well as alkoxide salts such as the sodium or, preferably, potassium salts of t-butoxide or, preferably, the optically pure alkoxide corresponding to the alkanol component of the ester.
• tertiary amines such as poly(4-vinylpyridine), 4-(dimethylamino)pyridine, and l,4-diazabicyco[2.2.2]octane
• alkoxide salts such as the sodium or, preferably, potassium salts of t-butoxide or, preferably, the optically pure alkoxide corresponding to the alkanol component of the ester.
• Hydrolysis of profen esters such as the 2-butyl and 2-octyl ester of ibuprofen is preferably carried out with about 0.5-4.0 moles and more preferably about 0.5-2.0 moles of water per mole of ester, about 0.01- 1.0 moles and more preferably about 0.05-0.3 moles of acid catalyst (hydrochloric acid, sulfuric acid, preferably methanesulfonic acid, and more preferably p-(toluenesulfonic acid) per mole of ester, solid acid catalyst (e.g., acidic ion exchange resins, e.g., Amberlyst®, Nafion®, etc) and about 0.5-5.0 grams of water-miscible organic solvent (e.g., polyethylene glycol, acetic acid, or, preferably, tetraethylene glycol dimethyl ether (TEGDE)) per gram of ester at about 50 °C-200 °C and more preferably about 100 °C- 150
• the following are intended as illustrative but not limiting examples of the present invention.
• the experimental work was carried out with the S,S 2-butyl and S,S 2-octyl esters of ibuprofen.
• the first capital letter denotes the configuration of the chiral center in ibuprofen; the second denotes the configuration of the chiral center in the alcohol.
• Esterification Optimization of the esterification conditions reduced alkene formation to less than 1% at high ibuprofen conversion (85-90%) and reasonable reaction times (2 hours).
• the preferred ibuprofen/alcohol/MSA (methanesulfonic acid) molar ratio was 1,0/1.1/0.04.
• TEG DME tetra(ethylene glycol) dimethyl ether
• PTSA p-toluenesulfonic acid
• FIGURE 1 DISTILLATION OF DIASTEREOMERIC IBUPROFEN ESTERS

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• 1996
  • 1996-04-22 JP JP8533346A patent/JPH11505525A/ja active Pending
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