Title of Invention

A PROCESS FOR SYNTHESIZING A COMPOUND

Abstract

The present invention relates to a process for synthesizing a compound represented by formula or a pharmaceutically acceptable salt thereof, wherein R 1 and R2 independently are H, C1-1O alkyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl being substituted or unsubstituted, comprising deprotecting a compound of formula II: wherein P is a carboxyl protecting group, p* is H, H2+, or a protecting group which is removable by hydrogenolysis, and R1 and R2 are as described above by hydrogenolysis in the presence of a prereduced metal catalyst and base to give the compound of formula I, followed by purifying and isolating the compound of formula I, in a known manner.

Full Text

TITLE OF THE INVENTION IMPROVED PROCESS FOR CARBAPENEM SYNTHESIS BACKGROUND OF THE INVENTION The present invention relates to a process for synthesizing carbapenem intermediates and compounds. The carbapenems are among the most broadly effective antibiotics making them useful in the treatment of a wide range of bacterial infections. The continuing emergence of bacteria exhibiting resistance to existing therapeutic agents has made development of new carbapenems an important part of our strategy in addressing this problem. The process developed for the manufacture of the carbapenem antibiotics disclosed herein is known to make use of a palladium-catalyzed hydrogenolysis of a p-nitrobenzyl ester. The reaction is conducted at pH 6.5 to 8.5 to minimize degradation of the product. Filtration in this pH range to remove the solid catalyst following the reaction results in a solution containing unacceptably high levels of palladium. This problem has been solved in the past by adjusting the pH to below 6 prior to filtration. This pH adjustment, however, results in degradation of the product and introduces salts, which must be removed prior to isolation of the product. This invention relates to a process that utilizes prereduced catalysts to achieve a significantly lower level of solubilized metal derived from the catalyst following the reaction. or a pharmaceutically acceptable salt thereof, is disclosed, wherein R and R independently are H, C1-10alkyl, aryl or heteroaryl, substituted or unsubstituted, comprising deprotecting a compound of formula 11: by hydrogenolysis in the presence of a prereduced metal catalyst, purifying and isolating the compound of formula I, wherein P is a carboxyl protecting group, P* is H, H^"*", or a protecting group which can be removed by hydrogenolysis such as carbobenzyloxy (CBZ), or p-nitrobenzyl carbamoyl (PNZ), and R^ and R" are as described above. These and other aspects of the invention can be realized upon complete review of the application. DETAILED DESCRIPTION OF THE INVENTION The invention is described herein in detail using the terms defined below unless otherwise specified. The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight or branched, and when of sufficient size, e.g., C3_i5 may be cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl. Alkyl also includes an alkyl group substituted with a cycloalkyl group such as cyclopropylmethyl. Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following: wherein: x' and y' = from 0-10; and w and z = from 0-9. When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable. Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like. Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with one to three groups. The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 to 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms. The heteroaryl group is optionally substituted with up to three groups. Heteroaryl includes aromadc and partially aromatic groups which contain one or more heteroatoms. Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine. Examples of partially aromatic groups are tetrahydroimidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below. Substituted alkyl, aryl and heteroaryl, and the substituted portions of aralkyl, aralkoxy. heteroaralkyl, heteroaralkoxy and like groups are substituted with from 1-3 groups selected from the group consisting of: halo, hydroxy, cyano, acyl, acylamino, aralkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, alkyl, alkoxy, aryl, aryloxy, aralkoxy, amino, alkylaxnino, dialkylamino, carboxy, trifluoromethyl and sulfonylamino. Halo means CI, F, Br and I selected on an independent basis. A preferred process for synthesizing a compound represented by formula la: by hydrogenolysis in the presence of a prereduced metal catalyst, purifying and isolating the compound of formula la, wherein P is a carboxyl protecting group, P* is H, H2+, or a protecting group which can be removed by hydrogenolysis such as carbobenzyloxy (CBZ), orp-nitrobenzyl carbamoyl (PNZ), and X+ is a charge-balancing group. By using a prereduced catalyst, the levels of solubilized metal derived from the catalyst are significantly lower compared with the use of an unreduced catalyst. The level of solubilized metal is negligible in the sense that it is possible to isolate the compound of formula I containing pharmaceutically acceptable levels of the metal derived from the catalyst, said levels would expose a patient to no more than about 50 micrograms per day of the metal, preferably no more than 25 micrograms per day. Examples of the metal catalysts are those described herein. In another aspect of the invention a process for synthesizing a compound represented by formula I: or a pharmaceuticaliy acceptable salt thereof, containing pharmaceutically acceptable levels of a metal derived from a metal catalyst is disclosed, wherein R and R" independently are K, C1-10 alkyl, aryl or heteroaryl, said alkvL aryl or heteroaryl being substituted or unsubstituted, comprising deprotecting a compound of formula 11: by hydrogenolysis in the presence of a prereduced metal catalyst, purifying and isolating the compound of formula I, wherein P is a carboxyl protecting group, P"^ is H, H?"^, or a protecting group which can be removed by hydrogenolysis, and R' and R"" are as described above. A preferred aspect of this process is realized when it is conducted with a compound of formula Ha to produce a compound of formula la. Accordingly, the present invention provides a process for synthesizing a compound represented by formula or a pharmaceutically acceptable salt thereof, wherein R and R independently are H, Ci-io alkyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl being substituted or unsubstituted, comprising deprotecting a compound of formula II: wherein P is a carboxyl protecting group, P is H, H2+, or a protecting group which is 1 9 removable by hydrogenolysis, and R and R are as described above by hydrogenolysis in the presence of a prereduced metal catalyst and base to give the compound of formula I, followed by purifying and isolating the compound of formula I, in a known manner. The compounds of formula I and la' can be obtained as shown below in Flow Sheets A-1 and A-2, respectively. Compounds 1,1 a, 2 and 2a can be obtained in accordance with techniques such as those disclosed in U.S. Patent Nos. 5,034,384, granted on July 23,1991; 5,952,323, granted on September 14,1999; 4,994,568 granted on February 19,1991; 4,269,772 granted on May 26,1981; 4,350,631 granted on September 21,1982; 4,383,946 granted on May 17,1983; 4,414,155 granted on November 8,1983; U.S. Patent No. 6,063,931, granted May 16, 2000; EP-A-562855; Tetrahedron Lett, 21,2783 (1980);/ Am. Chem, Soa 102, 6161 (1980);/. Am, Chem. Soc. 108, 4675 (1986) and 5,478,820 granted on December 26,1995, The teachings of these references are incorporated herein by reference. Compounds of formula I and la and derivatives thereof and processes thereof are disclosed in U.S. Patent Nos. 5,872,250, granted February 16, 1999 and 6,180,783, granted January 30, 2001, both incorporated herein by reference. The compounds of formula II or Ila' or salts thereof are produced by reacting the enol phosphate 1 or la and thiol 2 or 2a in the presence of a base. This reaction is typically conducted at reduced temperature, e.g., about -30°C to about -70°C, preferably about -40°C to about -60°C. Bases which are suitable for the above reaction include organic as well as inorganic bases. Preferred bases for use herein are secondary and tertiary amines such as diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), guanidines such as 1,1,3,3-tetramethylguanidine (TMG), N,N,N',N'N'.tetraethylcyclohexylguanidine (TECHG), N,N',N",N"-dicyclohexyldiethylguanidine (DCDEG) and amidines such as 1,8-dia2abicyclo[4.3,0]undec-7-ene (DBU) and 1,5-diazabicyclo [4.3.0]non-5-ene (DBN). Most preferable bases are the guanidine bases and even more preferred is TMG. An antioxidant is optionally added. Preferred antioxidants are PR3, wherein R3 belongs to the group consisting of C1-8 alkyl, aryl or heteroaryl, or aromatic phenols such as BHT (butylated hydroxy toluene) and BHA (butylated hydroxy anisole). Most preferred antioxidant is PBUj. The reaction can be conducted in a polar organic solvent, e.g., N-ethylpyrrolidinone (NEP), N-methylpyrrolidinone, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetonitrile, propionitrile, or a mixture thereof and the like. The preferred solvent is N-ethylpyrrolidinone (NEP). After coupling, the carbapenem can be stabilized by combining the carbapenem with a carbon dioxide source. Stabilization can be conducted according to the teachings in U.S. Patent No. 6,180,783, granted January 30,2001 and incorporated by reference herein. The carbapenem is subjected to deprotection, thus removing the 3- carboxyl protecting group yielding I or la. In the claimed invention, hydrogenolysis is conducted in the presence of a prereduced metal catalyst. The preferred reaction involves H2 gas with a prereduced palladium (Pd on carbon) catalyst. The reaction can be conducted under hydrogen over a broad pressure range, preferably above 40 psi. A base such as sodium hydroxide or sodium bicarbonate can be added during the reaction to control pH. Sufficient sodium bicarbonate can be present at the start of the reaction to control the pH. Preferably, the reaction is conducted in the presence of a source of carbon dioxide such as sodium bicarbonate to give the stabilized form 3 or 3a where X* is a charge-balancing group. Suitable catalysts are those which contain a metal known to be useful for catalytic hydrogenation such as palladium (Pd), platinum (Pt), and rhodium (Rh), preferably Pd. The metal catalyst can be a salt or metal powder or supported on a wide range of solid supports known to be useful in catalytic hydrogenation reactions including alumina, silica, calcium carbonate, barium carbonate, barium sulfate, strontium carbonate, polymers, or carbon, preferably activated carbon. The catalyst is used in an amount that is at least 5 mol% relative to the carbapenem substrate. A pre-reduced catalyst is formed by chemical treatment with a reducing agent prior to addition of the substrate. Suitable reducing agents include those known to be useful for the reduction of metal catalysts such as formate, borohydride, and hydrogen, preferably hydrogen. The reduction can be performed in manufacture of the catalyst or just prior to use. The pH can be controlled during reduction by addition of a base. Preferred bases are sodium hydroxide or sodium bicarbonate. Carbon dioxide sources, as used herein, refer to carbon dioxide eas as well as compounds which can produce carbon dioxide in solution. Representative examples include carbonates and bicarbonates, such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. Preferably, the carbon dioxide source is sodium bicarbonate. The sodium bicarbonate can be purchased or obtained by mixing sodium hydroxide and carbon dioxide at a pH above about 6.5. The carbon dioxide source can altemadvely be included in the reaction medium prior to or added during the deprotection reaction. Examples of suitable 3-carboxyl protecting groups are those which can be removed by hydrogenolysis. Examples of such protecting groups are: benzhydryl, o-nitrobenzyl,p-nitrobenzyl, 2-naphthylmethyI, and benzyl. A preferred carboxyl protecting group is p-nitrobenzyl (PNB). Many other suitable protecting groups are known in the art. See, e.g., T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., 1981 (Chapters 2 and 5). Numerous salt-forming ions are recited in Berge, S. M., et al. J, Pharm. Sci. 66(1): 1-16 (1977), the teachings of which are incorporated herein by reference. The charge balancing group X+ maintains overall charge neutrality. Preferably X+ represents a pharmaceutically acceptable salt-forming cation. Preferred salt-forming cations are selected from the group consisting of: sodium, potassium, calcium and magnesium. More preferably the salt-forming cation is a member selected from the group consisting of: Na"*", Ca+2 and K"*". The salt-forming cations mentioned above provide electronic balance and overall charge neutrality. From zero to three positively charged counterions may be present depending upon the number of charged moieties on the carbapenem. The number of negatively charge groups is largely a function of pH, since these groups become protonated as the pH is lowered. For every positively charged functional group on the molecule, a negadvely charged counterion is present to provide overall charge neutrality. Different counterions may also be included in the overall reacdon composition. Hence, for example, calcium and sodium could be included together in the reaction to provide overall charge neutrality. The counterions can thus be varied within wide limits. Generally, the counterion or counterions are pharmaceutically acceptable cationic species. The compounds formed in the present invention have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers. The processes of synthesizing all such isomers, including optical isomers, are included in the present invention. Purification and isolation of compounds of formula I and la can be achieved via a combination of several operations: extractions using solvents such as dichloromethane to remove residual organic solvents, chromatography using hydrophobic resin chromatography (eluting with 0.05 M sodium bicarbonate at about 5°C), nanofiltration for concentration of the process stream followed by crystallization of the pure drug (See U.S.S.N. 09/093813, filed 6/9/1998, incorporated herein by reference). Alternatively, the column chromatography and nanofiltration operations can be eliminated when the extraction is carried out with an appropriate alcohol. A preferred extraction is carried out with the appropriate alcohol in the presence of an ion-pairing reagent. The process described below allows a direct crystallization of carbapenem compounds after this type of extraction. The extractions can be conducted by methods generally known in the art. A preferred extraction process is discussed in U.S.S.N 09/487,044 filed 1/19/2000, which is incorporated herein by reference. An example of the extraction involves extracting a solution containing a compound of formula I, la, 3, or 3a, or a pharmaceutically acceptable salt thereof, wherein each X is a charge-balancing group and is present or absent as necessary to provide overall charge neutrality, with an alcohol, crystallizing and collecting a compound of formula I or la' from the resultant aqueous phase. It is preferable that the extraction is conducted in the presence of an ion-pairing reagent and that pH of the aqueous phase is maintained between neutral and mildly basic pH (pH 7 to 9) according to the teachings of WO 9745430. It is also preferable that the extraction is performed while I or la is stabilized in the form, 3 or 3a. After extraction, the stabilized form 3 or 3a is readily converted to a salt form of I or la under neutral to mildly acidic conditions (pH 7 to 5). The pH is adjusted to produce the appropriate salt form of I or la for isolation by crystallization. Alternatively, there can be multiple extractions with, for example the example solvents being isoamyl alcohol (lAA) /DPP solution in the first extraction, and lAA in a second extraction. It is preferable to use equipment that is capable of multi-stage extraction such as mixer-settler cascade, spray tower, baffle tower, packed tower, perforated plate tower, mechanically agitated extractor, pulsed extractor, reciprocating plate extractor, or centrifugal extractor for optimal performance. Most preferable is the use of a multi-stage centrifugal extractor. The preferred equipment is dependent on scale; CINC (Costner Industries Nevada Corporation) liquid-liquid centrifugal separators are preferred for laboratory scale operation; whereas, a Podbielniak® centrifugal extractor is preferred for large scale operation. Use of these multi-stage centrifugal extractor provides unexpected benefits. For example, the ion pairing reaction of TMG with diphenyl phosphate (DPP) is used to reduce the TMG level in the process stream prior to the isolation of the compound of formula J, la, 3 or 3a. In addition to this purification, the residual reaction solvent, N-ethyl pyrrolidinone (NEP) must be removed from the process stream, and the process stream must be concentrated four fold to allow successful crystallization of the compound of formula I, la, 3 or 3a. All three of these processing requirements are accomplished simultaneously via a rapid, muUi-stage, counter-current centrifugal extraction, which minimizes the soluble product degradation during processing. The alcohol useful for the present invention includes but is not limited to iso-amyl alcohol, tert-amyl alcohol, 1-butanol, 2-butanol, 1-octanol, 1-hexanol, 1-heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol, 2-methyl-l-pentanol, 2-ethyl-l-butanol, 4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, 2-methylcyclohexanol, preferably 1-butanol or iso-amyl alcohol. Preferred ion-pairing reagents for use in the present invention are C6-24 carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids and the like and their salts. Most preferred ion-pairing reagents are the sodium salts of diphenylphosphoric acid, stearic acid or dodecylbenzenesulfonic acid. A hydrogenator is charged with 63 g of 10% Pd on carbon catalyst (dry weight) in 1.8 L of water. The vessel is placed under hydrogen then vented and placed under nitrogen. Sodium hydroxide (68 g, 50%) is charged adjusting the pH to about 7.5 with carbon dioxide. The enol phosphate (170 g) and the thiol (86 g) are dissolved in i.3"L of N-ethylpyrrolidinone (NEP). The mixture is cooled to below -40°C and 1,1,3,3-tetramethylguanidine (109 g) is added. After 3 hours, the reaction mixture is WE CLAIM: L A process for synthesizing a compound represented by formula or a pharmaceutically acceptable salt thereof, wherein R^ and R^ independently are H, CMO alkyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl being substituted or unsubstituted, comprising deprotecting a compound of formula II: wherein P is a carboxyl protecting group, P is H, H2+, or a protecting group which is removable by hydrogenolysis, and R and R are as described above by hydrogenolysis in the presence of a prereduced metal catalyst and base to give the compound of formula I, followed by purifying and isolating the compound of formula I, in a known manner. 2. The process as claimed in claim 1 wherein the protecting group is carbobenzyloxy or p-nitrobenzyl carbamoyl (PNZ). 3. The process as claimed in claim 1 wherein one of R or R is hydrogen and the other is an aryl substituted with CO2H. 4. The process as claimed in claim 1 wherein the prereduced metal catalyst is a palladium, platinum or rhodium catalyst. 5. The process as claimed in claim 4 wherein the metal catalyst is a salt or metal powder or supported on solid supports selected from the group consisting of alumina, silica, calcium carbonate, barium carbonate, barium sulfate, strontium carbonate, polymers, or carbon. 6. The process as claimed in claim 5 wherein the metal catalyst is prereduced palladium on carbon. 7. The process as claimed in claim 1 wherein the base is bicarbonate or hydroxide and carbon dioxide mixed to make bicarbonate. 8. The process as claimed in claim 6 further comprising purifying the compound using hydrophobic resin chromatography. 9. The process as claimed in claim 8 further comprising concentrating the compound in solution using a nanofiltration membrane. 10. The process as claimed in claim 9 further comprising crystallizing the compound. 11. The process as claimed in claim 1 wherein the purification step consists of treatment with activated carbon. 12. The process as claimed in claim 6 further comprising extracting a solution containing a compound of formula 1 or 3: or a pharmaceutically acceptable salt thereof, wherein each X is a charge-balancing group, and R1 and R2 are as described above with a C4-10 alcohol, purifying and isolating the compound of formula I from the resulting aqueous phase. 13. The process as claimed in claim 12 wherein the extraction is conducted with an alcohol in the presence of an ion-pairing reagent, while maintaining a pH of the aqueous phase between neutral and mildly basic. 14. ' The process as claimed in claim 13 wherein the extraction is conducted using a multi-stage extractor. 15. The process as claimed in claim 14 wherein the extraction is conducted using a multi-stage countercurrent centrifugal extractor. 16. The process as claimed in claim 13 wherein the alcohol is iso-amyl alcohol, tert-amyl alcohol, 1 -butanol, 2-butanol, 1 -octanol, 1 -hexanol, 1 -heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol, 2-methyl-l-pentanol, 2-ethyl-1-butanol, 4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, or 2-methylcyclohexanol. 17. The process as claimed in claim 16 wherein the alcohol is iso-amyl alcohol or 1-butanol. 18. The process as claimed in claim 13 wherein the ion-pairing reagent comprises C6-24 carboxylic acids; phosphoric acids, phosphinic acids, sulfonic acids or their salts. 19. The process as claimed in claim 17 wherein ion-pairing reagent is a sodium salt of diphenylphosphoric acid, stearic acid or dodecylbenzenesulfonic acid. 20. The process as claimed in claim 12 wherein the extracted solution contains a compound of formula I. 21. The process as claimed in claim 12 wherein the extracted solution contains a compound of formula 3. 22. A process for synthesizing a compound represented by formula la: or a pharmaceutically acceptable salt thereof, comprising deprotecting a compound of formula Ila: wherein P is a carboxyl protecting group, P is H, H2+, or a protecting group which is removable by hydrogenolysis, and X+ is a charge-balancing group, by hydrogenolysis in the presence of a prereduced metal catalyst and base to give a compound of formula la, followed by purifying and isolating the compound of formula la, in a known manner. 23. The process as claimed in claim 22 wherein the P protecting group, is carbobenzyloxy or p-nitrobenzyl carbamoyl (PNZ). 24. The process as claimed in claim 22 wherein the prereduced metal catalyst is a palladium, platinum or rhodium catalyst. 25. The process as claimed in claim 24 wherein the metal catalyst is a salt or metal powder or supported on solid supports selected from the group consisting of alumina, silica, calcium carbonate, barium carbonate, barium sulfate, strontium carbonate, polymers, or carbon. 26. The process as claimed in claim 25 wherein the metal catalyst is prereduced palladium on carbon. 27. The process as claimed in claim 22 wherein the base is bicarbonate or hydroxide and carbon dioxide mixed to make bicarbonate. 28. The process as claimed in claim 22 wherein the purification step consists of treatment with activated carbon. 29. The process as claimed in claim 25 further comprising purifying the compound using hydrophobic resin chromatography. 30. The process as claimed in claim 28 further comprising concentrating a solution of the compound using a nanofiltration membrane. 31. The process as claimed in claim 29 further comprising crystallizing the compound. 32. The process as claimed in claim 26 further comprising purifying the compound by extracting a solution containing a compound of formula la or 3a: pharmaceutically acceptable salt thereof, wherein each X"^ is a charge-balancing group, with a C4.10 alcohol, crystallizing and collecting a compound of formula la* from the resulting aqueous phase. 33. The process as claimed in claim 32 wherein the extraction is conducted with an alcohol in the presence of an ion-pairing reagent while maintaining a pH of the aqueous phase between neutral and mildly basic. 34. The process as claimed in claim 33 wherein the extraction is conducted using a multi-stage extractor. 35. The process as claimed in claim 34 wherein the extraction is conducted using a multi-stage countercurrent centrifugal extractor. 36. The process as claimed in claim 33 wherein the alcohol is iso-amyl alcohol, tert-amyl alcohol, 1 -butanol, 2-butanol, 1 -octanol, 1 -hexanol, 1 -heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol, 2-methyl-l-pentanol, 2-ethyl-1 -butanol, 4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, or 2-methylcyclohexanol. 37. The process as claimed in claim 36 wherein the alcohol is iso-amyl alcohol or 1-butanol. 38. The process as claimed in claim 33 wherein the ion-pairing reagent comprises C6-24 carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids or their salts. 39. The process as claimed in claim 38 wherein the ion-pairing reagent is a sodium salt of diphenylphosphoric acid, stearic acid or dodecylbenzenesulfonic acid. 40. The process as claimed in claim 32 wherein the extracted solution contains a compound of formula 3a: 41. The process as claimed in claim 32 wherein the extracted solution contains a compound of formula la: 42. A process for synthesizing a compound represented by formula I: or a pharmaceutically acceptable salt thereof, containing pharmaceutically acceptable levels of a metal derived from a metal catalyst, wherein R and R independently are H, CMO alkyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl being substituted or unsubstituted, comprising deprotecting a compound of formula II: wherein P is a carboxyl protecting group, P is H, H2+, or a protecting group which is removable by hydrogenolysis, and R and R areas described above, hydrogenolysis in the presence of a prereduced metal catalyst and base to give a compound of formula I, followed by purifying and isolating the compound of formula I. 43. The process as claimed in claim 42 for synthesizing a compound represented by formula la: or a pharmaceutically acceptable salt thereof, containing pharmaceutically acceptable levels of a metal derived from a metal catalyst, comprising deprotecting a compound of formula Ua: wherein P is a carboxyl protecting group, P is H, H2+, or a protecting group which is removable by hydrogenolysis in the presence of a prereduced metal catalyst and base to give a compound of formula la, followed by purifying and isolating the compound of formula la. 44. A process for synthesizing a compound substantially as herein described with reference to the accompanying drawings.

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