USOO8283487B2

(12) United States Patent (10) Patent No.: US 8,283,487 B2 Ben Moha-Lerman et al. (45) Date of Patent: Oct. 9, 2012

(54) PROCESSES FOR THE PREPARATION AND 2003/0176398 A1 9/2003 Gallop et al. PURIFICATION OF GABAPENTIN 2004/0077553 A1* 4/2004 Gallop et al...... 514, 19 2005/O154057 A1 7/2005 Estrada et al. ENACARBL 2007/0049627 A1 3, 2007 Tran (75) Inventors: Elena Ben Moha-Lerman, Kiryat Ono FOREIGN PATENT DOCUMENTS (IL); Tamar Nidam, Yehud (IL); Meital WO WO O2/10O347 12/2002 Cohen, Petach-Tikva (IL); Sharon WO WO 2005/0377.84 4/2005 Avhar-Maydan, Givataym (IL); Anna Balanov, Rehovot (IL) OTHER PUBLICATIONS X. Yuan et al. “In Situ Preparation of Zinc Salts of Unsaturated (73) Assignee: Teva Pharmaceutical Industries Ltd., Carboxylic Acids to Reinforce NBR' J. Applied Polymer Science, Petach-Tikva (IL) vol. 77, p. 2740-2748 (2000). - r J. Alexander et al. “(Acyloxy)alkyl Carbamates as Novel Biorevers (*) Notice: Subject to any disclaimer, the term of this ible Prodrugs for Amines: Increased Permeation through Biological patent is extended or adjusted under 35 Membranes”.J. Med. Chem. 1988, 31, pp. 318-322. U.S.C. 154(b) by 249 days. S.M. Rahmathullah et al. “Prodrugs for Amidines: Synthesis and Anti-Pneumocystis carinii Activity of Carbamates of 2.5-Bis(4- (21) Appl. No.: 12/626,682 amidinophenyl)furan” J. Med. Chem. 1999, 42, pp. 3994-4000. (22) Filed: Nov. 26, 2009 * cited by examiner (65) Prior Publication Data Primary Examiner — Joseph K. McKane US 2010/O160665 A1 Jun. 24, 2010 Assistant Examiner — Alicia L Otton (74) Attorney, Agent, or Firm — Arent Fox LLP Related U.S. Application Data (60) Provisional application No. 61/118,265, filed on Nov. (57)57 ABSTRACT 26, 2008, provisional application No. 61/208,565, Gabapentin enacarbil was prepared and purified from inter filed on Feb. 24, 2009, provisional application No. mediates such as 1-haloalkyl carbamate or carbonate and 61/180,265, filed on May 21, 2009, provisional diacid acetal skeleton. For example, a 1-haloalkyl carbonate application No. 61/240,793, filed on Sep. 9, 2009. or carbamate was prepared by combining a C to Co alcohol or C to Co primary amine, a solvent selected from the group (51) Int. Cl. consisting of acetonitrile, C to C, ketone, Cs to Coether, C. C07C 27L/16 (2006.01) to C, ester, Cs to Cohydrocarbon and a combination thereof; (52) U.S. Cl...... 560/115 a 1-haloalkyl haloformate of the following formula: (58) Field of Classification Search ...... None See application file for complete search history. O R (56) References Cited ls 1. X O X U.S. PATENT DOCUMENTS 4,760,057 A 7, 1988 Alexander 6.255,526 B1 7/2001 Pesachovich et al. wherein each X is independently selected from Br, I, or Cl; R. 6,818,787 B2 11/2004 Gallop et al. is alkyl or H; and a C to C tertiary amine. 7,227,028 B2 6/2007 Gallop et al. 7,232,924 B2 6, 2007 Raillard et al. 20 Claims, No Drawings US 8,283,487 B2 1. 2 PROCESSES FOR THE PREPARATION AND tion for colonic absorption. After its absorption in the blood, PURIFICATION OF GABAPENTN GBPE is rapidly converted to GBP. ENACARBL A coupling process of 1-haloalkyl carbamates or carbon ates with carboxylic acid is used in synthetic chemistry and CROSS-REFERENCE TO RELATED particularly in medicinal chemistry, as exemplified in J. Med. APPLICATIONS Chem. 1999, 42, pages 3994-4000 and J. Med. Chem. 1988, 31, pages 318-322, as a way to construct the diacid-acetal This application claims the benefit of U.S. Provisional skeleton. The process is described in scheme 1 below: Patent Application Ser. Nos. 61/118,265, filed Nov. 26, 2008: 61/208,565, filed Feb. 24, 2009: 61/180,265, filed May 21, 10 2009; and 61/240,793, filed Sep. 9, 2009, which are incorpo Scheme 1 rated herein by reference. O R O -- He FIELD OF THE INVENTION R2N ls ls ul 15 Y O X R OH Y: O. NH R3: Alkyl The present invention relates to the preparation of 1-ha X: Cl; Br; I loalkyl carbamate or carbonate and diacid acetal skeleton, R: Alkyl, H intermediates in the preparation of gabapentin enacarbil, as R2: Alkyl well as processes for preparing and purifying gabapentin O R O enacarbil. isN 1 O - O 1 R3 BACKGROUND OF THE INVENTION

Gabapentin (“GBP), 1-(aminomethyl)cyclohexaneacetic 25 The use of a coupling agent in the process depicted above acid is described according to the following formula: is known in the art with the use of coupling agents such as mercury acetate, mercury oxide and silver oxide. This is exemplified in U.S. Pat. No. 6,818,787 (“the 787 patent”). The 787 patent describes a process for preparing GBPE HOC NH2 according to scheme 1 using silver oxide (AgO) as a cou 30 pling agent. The process for preparing compound 18 from compound 16 described in the 787 patent and illustrated in scheme 2 below is a two step process, where compound 17 is CoH7NO2 prepared separately. Mw 17124 35 GBP is a white to off-white crystalline solid with a pKal of 3.7 Scheme 2 and a pKa2 of 10.7. GBP is marketed by Pfizer under the trade R1.13 DR. 14 O 4-Nitrophenol name NeurontinR). Ho GBP is used in the treatment of cerebral diseases such as 40 Yul is epilepsy. In animal models of analgesia, GBP prevents allo C O C dynia (pain-related behavior in response to a normally (15) NO innocuous stimulus) and hyperalgesia (exaggerated response 13 14 to painful stimuli). GBP also decreases pain related responses R13 R14 O - N - after peripheral inflammation. Animal test systems designed 45 X us Acetone to detect anticonvulsant activity, proved that GBP prevents C O O seizures as do other marketed anticonvulsants. (16) Gabapentin enacarbil (“GBPE), 1-(o-isobutanoyloxy NO ethoxy)carbonyl-aminomethyl-1-cyclohexane acetic acid, R13 R 14 O RCO),Mor is a transported prodrug of GBP and is described according to 50 X us R2CONR the following formula: I O O M = Ag., m = 1; (17) M = Hg, m = 2 NO O CH3 O HO ls -i. CH3 55 l R13 R 14 ul N O O R25 -X, O H O CH3

60 GBPE and processes for its preparation are described in CHNO6 U.S. Pat. Nos. 6,818,787, 7,232,924 and 7,227,028, which are MW 329.39 incorporated herein by reference. Like any synthetic compound, gabapentin enacarbil can GBPE was developed to improve some of the bioavailabil contain extraneous compounds or impurities. These impuri ity limitations that are known in GBP. GBPE is recognized by 65 ties may include unreacted starting materials, by-products of high-capacity transport proteins expressed all along the intes the reaction, products of side reactions, and/or degradation tinal tract, making it suitable for Sustained-release formula products. US 8,283,487 B2 3 4 Impurities in gabapentin enacarbil or any active pharma comprising: combining a C to Co alcohol or C to Co ceutical ingredient (API) are undesirable and, in extreme primary amine; a solvent selected from the group consisting cases, might be harmful to a patient being treated with a of acetonitrile, C to C, ketone, Cs to Coether, C to C, ester, dosage form of the API. Cs to Co. hydrocarbon and a combination thereof a 1-ha There is a need in the art for an improved process for loalkyl haloformate of the following formula: preparing GBPE and its intermediates, and processes for puri fying GBPE. O R SUMMARY OF THE INVENTION 10 ----, The present invention encompasses a process for preparing 1-haloalkyl carbonate or carbamate comprising: combining C to Co alcohol or C to Co primary amine, a solvent wherein each X is independently selected from Br, I, or Cland selected from the group consisting of acetonitrile, C to C, R is alkyl or H; and a C to C tertiary amine to obtain a 15 reaction mixture; and adding carboxylic acid to the reaction ketone, Cs to Coether, C to C, ester, Cs to Cohydrocarbon mixture in the presence of a coupling agent selected from the and a combination thereof; a 1-haloalkyl haloformate of the group consisting of Cu(OAc), Zn(OAc), Cu2O, CuO. following formula: CeO, NiO, ZnO and Cu(OCCHMe). In another embodiment, the present invention further O R encompasses a process for preparing AEC-NP comprising: combining 4-nitrophenol with toluene, 1-chloroethyl chloro formate, a base selected from the group consisting of TEA ----, and TBA; and adding isobutyric acid in the presence of a coupling agent, such as ZnO. wherein each X is independently selected from Br, I, or Cl; R. 25 In another embodiment, the present invention encom is alkyl or H; and a C to C tertiary amine. passes a process for preparing GBPE comprising preparing In another embodiment, the present invention encom passes a process for preparing 1-chloroethyl 4-nitrophenyl 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate (AEC-NP) carbonate (“CEC-NP) comprising: combining 4-nitrophe and further converting it to GBPE. nol, toluene, 1-chloroethyl chloroformate and a tertiary 30 In yet another embodiment, the present invention encom amine selected from the group consisting of tributyl amine passes a process for preparing GBPE comprising: preparing (“TBA”) and triethylamine (“TEA"). 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate (AEC-NP) In yet another embodiment, the present invention encom according to the process above and further converting it to passes a process for preparing GBPE comprising preparing GBPE. 1-haloalkyl carbonate or carbamate and further converting it 35 In one embodiment, the present invention further encom to GBPE. passes a process for preparing gabapentin enacarbil compris In one embodiment, the present invention encompasses a ing: combining gabapentin with a solvent selected from the process for preparing diacid acetal skeleton having the fol group consisting of acetonitrile, C to C, ketone, Cs to Co lowing structure: ether, C to C, ester, Cs to Cohydrocarbon and a combination 40 thereof; a base selected from a group consisting of C to C. tertiary amine, KCO, KHCO, NaCO and NaHCO; and O R O AEC-NP. In one embodiment, the present invention encompasses a isN 1 O - O 1 R3 purification process of GBPE comprising reducing the NP 45 and NP derivatives in GBPE, followed by acidic extractions. wherein Y is O or NH, R is alkyl or H. R. is alkyl and R is In another embodiment, the present invention encom alkyl or a substituted aromatic hydrocarbon mono-substituted passes a process comprising: combining GBPE containing at ortho- or para-positions with a moiety selected from the NP and/or NP derivatives with a polar solvent or an aromatic group consisting of halo. —C(halo), —CF, —CN. 50 solvent to obtain a solution, adding gaseous H or formic acid OCN, -SCN, - N - NO = S(O).O. , S(O),OH, salt in the presence of Pd/C or Pt/C to the solution; and —S(O).R', OS(O)O –OS(O).R', OP(O)(OR), extracting with an acid to obtain GBPE. C(O)R', C(S)R', C(O)OR', C(O)NR'R'', C(O) In yet another embodiment, the present invention encom O C(S)OR, N(R)C(O)NR'R", N(R)C(S)NR'R", passes a process comprising: dissolving GBPE containing NP N(R)C(NR)N(R)'R" and C(NR')NR'R, wherein each R, 55 and/or NP derivatives in C-C carboxylic acid or HCl to R" and R" are independently selected from the group consist obtain a solution; adding a metal selected from the group ing of hydrogen and alkyl comprising: combining a carboxy consisting of iron, Zinc and magnesium to the solution; and lic acid with 1-haloalkyl carbamates or carbonates in the extracting with acid. presence of a coupling agent selected from the group consist In yet another embodiment, the present invention encom ing of Cu(OAc), Zn(OAc), CuO, CuO, CeO2, NiO, ZnO 60 passes a process comprising: loading GBPE on a column and Cu(OCCHMe). filled with cross-linked dextrangel in toluene; and eluting In another embodiment, the present invention encom GBPE with toluene or a toluene? hexane solution to obtain passes a process for preparing 1-(isobutyryloxy)ethyl 4-ni GBPE. trophenyl carbonate (AEC-NP) comprising: combining In one embodiment, the present invention encompasses a CEC-NP with isobutyric acid in the presence of zinc oxide. 65 one-pot process for preparing GBPE comprising: combining In another embodiment, the present invention encom C to Co alcohol or C to Co primary amine; a solvent passes a one-pot process for preparing diacid acetal skeleton selected from the group consisting of acetonitrile, C to C, US 8,283,487 B2 5 6 ketone, Cs to Coether, C to C, ester, Cs to Cohydrocarbon methyl, ethyl, n-propyl, isopropyl. n-butyl, t-butyl, and isobu and a combination thereof; a 1-haloethyl haloformate of the tyl. The term “alkyl is specifically intended to include following formula: groups having any degree or level of Saturation, i.e., groups having exclusively single carbon-carbon bonds, groups hav ing one or more double carbon-carbon bonds, groups having O R one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. As used herein, the term “one-pot' refers to a process done ----, without isolating the process intermediates from the reaction 10 solvent or mixture. wherein X is independently selected from Br, I, or C1 and R. As used herein, the term “carboxylic acid refers to a is methyl; and a C to C tertiary amine; adding isobutyric compound having the following formula: acid in the presence of a coupling agent selected from the group consisting of Cu(OAc), CdCOAc), Zn(OAc), Cu2O, CuO, CeO, CdC). NiO, ZnO and Cu(OCCHMe); adding 15 gabapentin and a base selected from a group consisting of: C to C tertiary amine, KCO, KHCO, NaCO and NaHCO -> to obtain GBPE; reducing the GBPE, followed by acidic extraction, concentrating the Solvent and adding hexane, hep wherein R is alkyl. Preferably, R is selected from the group tane or a solution of heptane and EtOAc to obtain a precipi consisting of methyl, ethyl and isopropyl. Preferably, the tate. carboxylic acid is isobutyric acid. In another embodiment, the present invention further As used herein, the term “CEC-NPrefers to 1-chloroethyl encompasses a one-pot process for preparing GBPE compris 4-nitrophenyl carbonate having the following structure: ing: combining 4-nitrophenol, toluene, 1-chloroethyl chloro formate and a base selected from the group consisting of TEA 25 and TBA; adding isobutyric acid in the presence of ZnO; adding GBP and a base selected from the group consisting of TEA and KCOs; adding potassium formate in the presence of palladium over carbon; and adding hexane, heptane or 30 Crrr. heptane/EtOAc.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term “AEC-NP” refers to 1-(isobutyry loxy)ethyl 4-nitrophenyl carbonate having the following As used herein, the term “1-haloalkyl carbamate or carbon Structure: ate' refers to a compound having the following formula: 35

O R R2 ls ls 40 N O X Crs wherein Y is O or NH, X is independently selected from Cl, Br, or I, R is alkyl or H, and R is alkyl or a substituted As used herein, the term “NP refers to nitrophenol. aromatic hydrocarbon. Preferably, R is alkyl or a substituted 45 As used herein, the term “room temperature” refers to a aromatic hydrocarbon mono-Substituted at ortho- or para temperature of about 15°C. to about 30°C., preferably, about positions with a moiety selected from the group consisting of 20° C. to about 25° C. As used herein, the term “reduced pressure” refers to a pressure less than atmospheric pressure, more preferably, of 50 about 10 mbar to about 50 mbar. C(O)CR', C(O)NR'R", C(O)C , C(S)OR', N(R) As used herein, the term “protected gabapentin” refers to C(O)NR'R", N(R)C(S)NR'R", N(R)C(NR)N(R)'R" and gabapentin possessing a protecting group on its carboxylic —C(NR)NR'R, wherein each R, RandR" are independently moiety, preventing gabapentin from acting as a nucleophile. selected from the group consisting of hydrogen and alkyl. Suitable protecting groups are well known in the art. Optionally, R. Rand R", together with the atom to which they 55 As used herein, the term “substantially pure GPBE refers are attached, form a cycloheteroalkyl or substituted cyclohet to GBPE having an assay of about 95% or more, measured eroalkyl ring. More preferably, R is a substituted aromatic versus its standard. Preferably, “substantially pure GBPE hydrocarbon substituted with a moiety selected from the has an assay of about 97% or more, more preferably, of about group consisting of —NO. —S(O)O— —S(O)OH and 99% or more, even more preferably, of about 99.3% or more, —S(O).R', most preferably, R is p-nitrophenyl. Preferably, 60 most preferably, of about 99.8% or more. Y is O and R is a linear alkyl. As used herein, the term “GBPE-mix' refers to a nearly As used herein, the term “alkyl refers to saturated or equimolar mixture of GBPE and NP and/or NP derivatives. unsaturated, straight or branched hydrocarbon chain or cyclic As used herein, the term “HPLC refers to High-perfor monovalent hydrocarbon radical consisting of carbon and mance liquid chromatography. hydrogenatoms, having from 1 to 6 carbon atoms, and which 65 As used herein, the term "NP derivatives’ refers to chemi is attached to the rest of the molecule by a single bond. cal structures containing a nitrophenol moiety. The term “NP Examples of alkyl groups include, but are not limited to, derivatives” includes, for example, CEC-NP and AEC-NP. US 8,283,487 B2 7 8 As used herein, the term “% area by HPLC' refers to the Typically, the C to Co alcohol is a C to Co aromatic area in an HPLC chromatogram of one or more peaks com alcohol, more preferably, phenol, more preferably, a Substi pared to the total area of all peaks in the HPLC chromatogram tuted phenol, even more preferably, phenol substituted with a expressed in percent of the total area. nitro group, most preferably, 4-nitrophenol. Preferably, the The present invention refers to a process for preparing C to Co primary amine is a C to Co primary aromatic 1-haloalkyl carbonate or carbamate, such as CEC-NP. pref amine, more preferably, aniline. erably avoiding the use of Solvents such as tetrahydrofuran Preferably, the solvent is toluene. (“THF) and chloroform which are used in the prior art. THF Optionally, the solution of the Co alcohol or Co pri is expensive and might form peroxides in the presence of mary amine in the solvent is cooled before the addition of the oxygen, which are explosive. Chloroform is a toxic solvent 10 1-haloalkyl haloformate and the C to C tertiary amine. which is not recommended as well. Preferred processes of the Preferably, the cooling is to a temperature of about 15° C. to invention use a recoverable base which makes the process about 0°C., more preferably, to a temperature of about 10°C. environmentally friendly, and improves the cost efficiency of to about 0°C., most preferably, to a temperature of about 5° the process compared to the prior art; the use of TEA and THF 15 C. together, as described in the prior art, prevents the base from Preferably, the 1-haloalkyl haloformate is 1-chloroalkyl being recovered. The combination of toluene and TEA used haloformate, more preferably, 1-chloroethyl chloroformate. according to preferred embodiments of the present invention Preferably, the C to C tertiary amine is tributyl amine allows easier separation of TEA*HCl formed during the pro (“TBA”) or triethylamine ("TEA). cess, by filtration. Such a procedure has economic and envi The use of TEA in a combination with toluene is advanta ronmental advantages, since the isolated TEA*HC1 can be geous as TEA.HC1 can be removed by filtration without the recovered. need of extraction, and allows obtaining the 1-haloalkyl car The present invention encompasses a process for preparing bonate or carbamate more efficiently. 1-haloalkyl carbonate or carbamate comprising: combining Preferably, C to C tertiary amine is added drop-wise, C to Co alcohol or C to Co primary amine, a solvent 25 followed by the addition of 1-haloalkyl haloformate. selected from the group consisting of acetonitrile, C to C, Preferably, following the addition of C to C tertiary ketone, Cs to Coether, C to C, ester, Cs to Cohydrocarbon amine, a mixing step (e.g., stirring, shaking, etc.) is per and a combination thereof; a 1-haloalkyl haloformate of the formed. Preferably, the mixing is for about 30 minutes to following formula: about 10 hours. Preferably, the mixing is at a temperature of 30 about 10°C. to about 100° C., more preferably, the mixing is at about room temperature. O R Optionally, for example when TBA is used, the 1-haloalkyl carbonate or carbamate is isolated. Preferably, the isolation comprises: washing the solution with HCl, water and brine to ----, 35 obtain a two-phase system; separating the phases; and remov ing the solvent (e.g., toluene). The solvent can be removed by wherein each X is independently selected from Br, I, or Cl; R. methods known in the art, such as evaporation. is alkyl or H; and a C to C tertiary amine. The present invention encompasses a process for preparing Preferably, the Co alcohol has the formula R Y H CEC-NP comprising: combining 4-nitrophenol, solvent wherein Y is O. and the Co primary amine has the formula 40 (preferably toluene), 1-chloroethyl chloroformate and a ter R YH wherein Y is N. tiary amine selected from the group consisting of TBA and Preferably, R is alkyl or a substituted aromatic hydrocar TEA. bon. Preferably, R is alkyl or a substituted aromatic hydro The present invention also encompasses a process for pre carbon mono-Substituted at ortho- or para-positions with a paring GBPE comprising: preparing 1-haloethylcarbonate or moiety selected from the group consisting of halo, 45 carbamate according to the process described above and fur —C(halo), —CF, —CN, —OCN, —SCN, - N - NO. ther converting it to GBPE. The process parameters are, pref —S(O).O. , —S(O),OH, -S(O).R', OS(O)O , —OS erably, the same as those described above. (O).R', OP(O)(OR), C(O)R', C(S)R', C(O)CR', The present invention also encompasses a process for pre C(O)NR'R'', C(O)C , C(S)OR', N(R)C(O) paring GBPE comprising: preparing CEC-NP according to NR'R", N(R)C(S)NR'R", N(R)C(NR)N(R)'R" and 50 the process described above and further converting it to —C(NR)NR'R, wherein each R, RandR" are independently GBPE. The process parameters are, preferably, the same as selected from the group consisting of hydrogen and alkyl. those described above. Optionally, R. Rand R", together with the atom to which they The present invention refers to a coupling process for pre are attached, form a cycloheteroalkyl or substituted cyclohet paring diacid acetal skeleton of 1-haloalkyl carbamate or eroalkyl ring. More preferably, R is a substituted aromatic 55 carbonate with carboxylic acid, according to scheme 3 below: hydrocarbon Substituted with a group selected from the group consisting of: - NO. —S(O)O— —S(O)OH and —S(O).R', most preferably, R is p-nitrophenyl. Scheme 3 Preferably, the 1-haloalkyl carbonate is CEC-NP. O R O Preferably, the process comprises dissolving C to Co 60 alcohol or C to Co primary amine in a solvent selected from R2-n ls ls -- ls -a- the group consisting of acetonitrile, C. to C, ketone, Cs to Y O X R3 OH Coether, C. to C, ester, Cs to Cohydrocarbon and a com O R O bination thereof, followed by the addition of a C to C. tertiary amine and 1-haloalkyl haloformate. Preferably, the 65 isN 1 O - O 1 R3 C to C tertiary amine is a C to C tertiary amine, more preferably, TEA. US 8,283,487 B2 10 in the presence of new coupling agents, whereinY is O or NH, Preferably, the carboxylic acid used in the process is isobu X is independently selected from Cl, Br, or I, R is alkyl or H. tyric acid. R is alkyl and R is alkyl or a Substituted aromatic hydrocar Preferably, the 1-haloalkyl carbonate is CEC-NP. bon. More preferably, R is alkyl or a substituted aromatic Optionally, prior to the combining step, the coupling agent hydrocarbon mono-Substituted at ortho- or para-positions 5 is added to a solution of carboxylic acid and a solvent selected with a moiety selected from the group consisting of halo, from the group consisting of acetonitrile, C to C, ketones, —C(halo), —CF, —CN, —OCN, —SCN, - N - NO. Cs to Coethers, C. to C, esters, Cs to Cohydrocarbons and —S(O)O— —S(O)OH, -S(O) R', —OS(O)O— —OS a combination thereof. Preferably, the solvent is toluene. (O).R', OP(O)(OR), C(O)R', C(S)R', C(O)CR', Preferably, the process is done at a temperature of about 60° C(O)NR'R'', C(O)C , C(S)OR', N(R)C(O)NR'R", 10 C. to about 110°C., more preferably, at a temperature of about N(R)C(S)NR'R", N(R)C(NR')N(R)'R" and C(NR) 75° C. Preferably, the process is done for about 1 hour to NR'R, wherein each R, R and R" are independently selected about 24 hours, more preferably, for about 10 hours. The from the group consisting of hydrogen and alkyl. Optionally, 1-haloalkyl carbamate or carbonate is preferably added to the R, R and R", together with the atom to which they are reaction mixture comprising the coupling agent, solvent and attached, form a cycloheteroalkyl or substituted cyclohet 15 eroalkyl ring. More preferably, R is a substituted aromatic carboxylic acid. hydrocarbon substituted with a moiety selected from the Typically, during the process, water is formed. Optionally, group consisting of —NO. —S(O)O— —S(O)OH and the water is removed. Preferably, the removal is done by a —S(O).R. Most preferably, R is p-nitrophenyl. Dean Stark apparatus or molecular sieves. Preferably, the Coupling agents used in the art include mercury acetate, removal of water is prior to the addition of the 1-haloalkyl mercury oxide and silver oxide. Such coupling agents possess carbamate or carbonate. several disadvantages, as these agents are expensive and thus The process may be done under neat conditions. Prefer increase the raw material costs of the final product. In addi ably, the process comprises: dissolving 1-haloalkyl carbam tion, mercury is highly toxic. In the 787 patent, the carboxy ate or carbonate in carboxylic acid; and adding a coupling lic acid is added as silver isobutyrate, prepared separately. In 25 agent selected from the group consisting of Cu(OAc), contrast, preferred processes of the invention for the prepa Zn(OAc), CuO, CuO, CeO2, NiO, ZnO and ration of the diacid acetal skeleton from 1-haloalkyl carbon Cu(OCCHMe). More preferably, the coupling agent is ate or carbamate, such as the preparation of AEC-NP from ZnO. The process under neat conditions is preferably done at CEC-NP, includes an in-situ formation of the zinc-carboxy a temperature of about 60° C. to about 110°C., more prefer late salt, thus making the process more efficient than that of 30 ably, at about 60° C. the 787 patent. In addition, the yield of the preferred pro Preferably, the amount of carboxylic acid used is about 50 cesses of the present invention is superior to that of the 787 equivalents to about 80 equivalents relative to the 1-haloalkyl process. carbamate or carbonate. More preferably, the amount of car The present invention encompasses a process for preparing boxylic acid used is about 60 equivalents relative to the 1-ha diacid acetal skeleton having the following structure: 35 loalkyl carbamate or carbonate. Preferably, the ratio of the coupling agent to 1-haloalkyl carbamate or carbonate is about 0.7 equivalents to about 10 O R O equivalents, more preferably, of about 1 equivalent to about 3 equivalents, most preferably, of about 1 equivalent. is 1 - 1 40 Preferably, the process may be done in the presence of a N O O R3 catalyst. The catalyst may be selected from the group consist ing of NaI, NaBr, tetrabutylammonium bromide (“TBAB), wherein Y is O or NH, R is alkyl or H. R. is alkyl and R is tetrabutylammonium iodide (“TBAI), KBr, KI, LiBr and alkyl or a Substituted aromatic hydrocarbon comprising: LiI. Preferably, the catalyst is NaBr, NaI or KI. Preferably, the combining a carboxylic acid with 1-haloalkyl carbamates or 45 amount of catalyst is about 0.5 equivalents. Preferably, when carbonates in the presence of a coupling agent selected from the 1-haloalkyl carbonate is a 1-chloroalkyl carbonate, the the group consisting of Cu(OAc), Zn(OAc). CuO. CuO. catalyst mentioned above is used. Preferably, where the 1-ha CeO, NiO, ZnO and Cu(OCCHMe). The process is done loalkylcarbonate is a 1-bromoalkyl, the catalyst is selected according to scheme 3. Preferably, R is alkyl or a substituted from the group consisting of NaI, KI, and LiI. aromatic hydrocarbon mono-Substituted at ortho- or para 50 The process preferably further comprises an isolation step. positions with a moiety selected from the group consisting of Prior to the isolation step, a mixing step is preferably per formed. Prior to the isolation step, a cooling step is preferably performed. Preferably, the cooling is to about room tempera ture. Preferably, the stirring is for about 1 hour to about 16 C(O)CR', C(O)NR'R", C(O)C , C(S)OR', N(R) 55 hours, more preferably, for about 2 hours. Preferably, the C(O)NR'R", N(R)C(S)NR'R", N(R)C(NR)N(R)'R" and isolation is done by evaporation to obtain a residue. The —C(NR)NR'R, wherein each R, RandR" are independently residue may be further recovered. The recovery may be done selected from the group consisting of hydrogen and alkyl. by dissolving the residue in ethyl acetate, followed by wash Optionally, R. Rand R", together with the atom to which they ing with Saturated Sodium bicarbonate and brine to obtain a are attached, form a cycloheteroalkyl or substituted cyclohet 60 two-phase system. The organic layer may be separated, fol eroalkyl ring. More preferably, R is a substituted aromatic lowed by drying it over magnesium Sulfate and evaporating it hydrocarbon substituted with a moiety selected from the to obtain the final product. group consisting of —NO. —S(O)O— —S(O)OH and The present invention also encompasses a process for pre —S(O).R', most preferably, R is p-nitrophenyl. paring AEC-NP comprising: combining CEC-NP with isobu Preferably, the coupling agent is ZnO. Preferably, the 65 tyric acid in the presence of a coupling agent, preferably, amount of the coupling agent is about 1 equivalent. ZnO. The process parameters are the same as those described Preferably, the diacid acetal skeleton is AEC-NP. above. US 8,283,487 B2 11 12 The present invention encompasses efficient and low cost 1-haloalkyl haloformate and C to C tertiary amine. Prefer processes for the preparation of AEC-NP. The process can be ably, the cooling is to a temperature of about 15° C. to about performed as a one-pot process, allowing for increased effi 0° C., more preferably, to a temperature of about 10° C. to ciency and application on an industrial scale. The one-pot about 0°C., most preferably, to a temperature of about 5°C. process allows the use of a single solvent during the entire Preferably, the C to C tertiary amine is tributylamine or process, thus avoiding the need to remove or separate the triethylamine. solvent. Preferably, C to C tertiary amine is added drop-wise, The present invention encompasses a one-pot process for followed by the addition of 1-haloalkyl haloformate. preparing diacid acetal skeleton comprising: combining a C Preferably, following the addition of C to C tertiary to Co alcohol or C to Co primary amine; a solvent selected 10 amine, a stirring step is performed. Preferably, the stirring is from the group consisting of acetonitrile, C to C, ketone, Cs for about 30 minutes to about 10hours. Preferably, the stirring to Co. ether, C to C, ester, Cs to Co. hydrocarbon and a is at a temperature of about 10° C. to about 100° C., more combination thereof; a 1-haloalkylhaloformate of the follow preferably, the stirring is at about room temperature. ing formula: Preferably, when the tertiary amine is TBA, prior to the 15 carboxylic acid addition, the reaction mixture is washed with HCl and water. The organic phase is further combined with O R the carboxylic acid in the presence of the coupling agent, as described above. Preferably, when the tertiary amine is TEA, prior to the ----, carboxylic acid addition, a filtration step is performed. The obtained filtrate is preferably combined with the carboxylic wherein each X is independently selected from Br, I, or Cland acid in the presence of the coupling agent, as described above. R is alkyl or H; and a C to C tertiary amine to obtain a Preferably, the coupling agent is ZnO. Preferably, the reaction mixture; and adding carboxylic acid to the reaction amount of the coupling agent is about 1 equivalent. mixture in the presence of a coupling agent selected from the 25 Preferably, the diacid acetal skeleton is AEC-NP. group consisting of Cu(OAc), Zn(OAc), Cu2O, CuO. Preferably, the carboxylic acid used in the process is isobu CeO, NiO, ZnO and Cu(OCCHMe). Most preferably, the tyric acid. Solvent is toluene. Preferably, the 1-haloalkyl carbonate is CEC-NP. Preferably, the Co alcohol has the formula R Y H Preferably, the addition of the carboxylic acid in the pres wherein Y is O. and the Co primary amine has the formula 30 ence of the coupling agent is done at a temperature of about R YH wherein Y is N. Preferably, R is alkyl or a substi 60° C. to about 110°C., more preferably, at a temperature of tuted aromatic hydrocarbon. More preferably, R is alkyl or a about 75° C. Preferably, the addition of the carboxylic acid in substituted aromatic hydrocarbon mono-substituted at ortho the presence of the coupling agent is done for about 1 hour to or para-positions with a moiety selected from the group con about 24 hours, more preferably, for about 10 hours. sisting of halo, —C(halo), —CF, —CN, OCN, SCN, 35 Preferably, the amount of carboxylic acid used is about 50 —N, NO. —S(O)O— —S(O)2OH. —S(O) R', —OS equivalents to about 80 equivalents relative to the 1-haloalkyl (O)O OS(O).R', OP(O)(OR), C(O)R', C(S)R', carbamate or carbonate. More preferably, the amount of car C(O)CR', C(O)NR'R", C(O)C , C(S)OR', N(R) boxylic acid used is about 60 equivalents relative to the 1-ha C(O)NR'R", N(R)C(S)NR'R", N(R)C(NR)N(R)'R" and loalkyl carbamate or carbonate. —C(NR)NR'R, wherein each R, RandR" are independently 40 Preferably, the ratio of the coupling agent to 1-haloalkyl selected from the group consisting of hydrogen and alkyl. carbamate or carbonate is of about 1 equivalent to about 10 Optionally, R. Rand R", together with the atom to which they equivalents, more preferably, of about 1 equivalent to about 3 are attached, form a cycloheteroalkyl or substituted cyclohet equivalents, most preferably, of about 1 equivalent. eroalkyl ring. More preferably, R is a substituted aromatic Preferably, the addition of the carboxylic acid in the pres hydrocarbon substituted with a moiety selected from the 45 ence of the coupling agent may be done in the presence of a group consisting of —NO. —S(O)O— —S(O)OH and catalyst. The catalyst is preferably selected from the group —S(O).R', most preferably, R is p-nitrophenyl. consisting of NaI, NaBr, tetrabutylammonium bromide Preferably, the 1-haloalkyl carbonate is CEC-NP. (“TBAB), tetrabutylammonium iodide (“TBAI), KBr, KI, Preferably, the process comprises dissolving C to Co LiBr and LiI. Preferably, the catalyst is NaBr, NaI or KI. alcohol or C to Co primary amine in a solvent selected from 50 Preferably, the amount of catalyst is about 0.5 equivalents. the group consisting of acetonitrile, C. to C, ketone, Cs to Preferably, when the 1-haloalkyl carbonate is a 1-chloro Coether, C to C, ester, Cs to Co. hydrocarbon and a com alkyl carbonate, the catalyst mentioned above is used. Pref bination thereof, followed by the addition of 1-haloalkyl erably, where the 1-haloalkylcarbonate is a 1-bromoalkyl, the haloformate and C to C tertiary amine to obtain a reaction catalyst is selected from the group consisting of NaI, KI, and mixture, and adding carboxylic acid to the reaction mixture in 55 LiI. the presence of a coupling agent selected from the group The present invention further encompasses a process for consisting of Cu(OAc), Zn(OAc), CuO, CuO, CeO2, NiO, preparing AEC-NP comprising: combining 4-nitrophenol ZnO and Cu(OCCHMe). with toluene, 1-chloroethyl chloroformate, a base selected Preferably, the C to Co alcohol is a C to Co aromatic from the group consisting of TEA and TBA.; and adding alcohol, more preferably, phenol, more preferably, a Substi 60 isobutyric acid in the presence of a coupling agent, such as tuted phenol, even more preferably, phenol substituted with a ZnO. nitro group, most preferably, 4-nitrophenol. Preferably, the The present invention also encompasses a process for pre C to Co primary amine is a C to Co primary aromatic paring GBPE comprising preparing AEC-NP according to the amine, more preferably, aniline. processes described above and further converting it to GBPE. Preferably, the solvent is toluene. 65 The present invention encompasses an efficient process for Optionally, the solution of the Co alcohol or Co pri the preparation of gabapentin enacarbil which lowers the mary amine in the solvent is cooled before the addition of the amount of gabapentin equivalents used in the process. Pref US 8,283,487 B2 13 14 erably, the mole equivalent of gabapentin to the diacid acetal Preferably, the aromatic solvent is selected from the group skeleton is less than about 1.9 equivalents, more preferably, consisting of toluene, o-Xylene, m-Xylene and p-Xylene. Most about 1 to about 1.9 equivalents, more preferably, about 1 to preferably, the solvent is toluene. about 1.5 equivalents. Preferably, the formic acid salt is ammonium formate or The present invention further encompasses a process for potassium formate. preparing gabapentin enacarbil comprising: combining gaba Preferably, the formic acid salt is added with water. Pref pentin with a solvent selected from the group consisting of erably, the ratio of the formic acid saltwater (mole:mole) is of acetonitrile, C to C, ketone, Cs to Coether, C. to C, ester, Cs about 1:1 to about 1:20, more preferably, of about 1:1 to about to Co. hydrocarbon and a combination thereof: a base 1:10, most preferably, of about 1:3 to 1:6. 10 Preferably, the gaseous H is added at a pressure of about 1 selected from a group consisting of C to C tertiary amine, to 6 atmospheres, more preferably, at a pressure of about 3 KCO, KHCO, NaCO, and NaHCO; and AEC-NP. atmospheres. AEC-NP may be obtained by any method known in the art, preferably, according to the process described in the present Preferably, prior to the extraction, a reaction mixture is invention. obtained. Preferably, the reaction mixture is maintained and 15 further filtered. The maintaining step may be done for about 2 Preferably, the solvent is toluene. hours to about 24 hours, more preferably, for about 2 hours to Preferably, the base is KCO or NaCO. about 12 hours. Preferably, the maintaining step is done with Preferably, the C to C tertiary amine is TBA or TEA. stirring. Preferably, when H gaseous is used in the process, Preferably, when the base is KCO, KHCO, NaCO or the stirring is at about room temperature to about 60°C., more NaHCO, the base is added with water. preferably, at about room temperature. Preferably, when for Optionally, when the base is a C to C tertiary amine, mic acid salt is used in the process, the stirring is at about prior to the addition of the base, chlorotrimethylsilane may be room temperature to about 60°C., more preferably, at about added. 450 C. Preferably, following the addition of the base, a stirring Prior to the extraction step, the reaction mixture may be step is performed. Preferably, the stirring is at about 10°C. to 25 filtered and optionally further dried. The drying may be done about 100° C. Preferably, when the base is a C to C tertiary by evaporation. amine, the stirring is at about room temperature. Preferably, The acidic extraction may be done by adding HCl and when the base is KCO, KHCO, NaCO or NaHCO, the brine, optionally with water, to obtain a two phase system; stirring is at a temperature of about 40°C. to about 60° C. separating the phases and removing the solvent from the Preferably, AEC-NP is added with the same solvent used in 30 organic phase. Preferably, the solvent is removed by evapo the process. ration. When the polar solvent is MeOH or EtOH, prior to the Preferably, following the addition of AEC-NP, a stirring washing step, the solvent is preferably removed to obtain a step is performed. Preferably, the stirring is for about 2 hours residue, and toluene is preferably added to obtain a solution. to about 48 hours, more preferably, for about 7 hours. Pref 35 In another embodiment, the purification process is a Single erably, the stirring is at a temperature of about 10°C. to about Electron Transfer (“SET) process comprising: dissolving 100° C., more preferably, at about room temperature. GBPE containing NP and/or NP derivatives in C-C car GBPE obtained according to the process above may con boxylic acid or HCl to obtain a solution; adding a metal tain NP and/or NP derivatives. Optionally, the obtained selected from the group consisting of iron, Zinc and magne GBPE is GBPE-mix. 40 sium to the Solution; and extracting with acid. Optionally, GBPE is recovered. Preferably, when the base Preferably, the C-C carboxylic acid is acetic acid. is a C to C tertiary amine, the recovery comprises: washing Preferably, the metal is iron. Preferably, the iron is pow with HCl and water to obtain a two-phase system; separating dery. the phases; and removing the solvent from the organic phase. Preferably, prior to the extraction step, a reaction mixture is Preferably, when the base is KCO, KHCO, NaCO or 45 obtained. The reaction mixture may be stirred, preferably at a NaHCO, the recovery comprises: washing with water to temperature of about 10° C. to about 100° C., more prefer obtain a two-phase system; separating the phases, acidifying ably, at about 45°C. The stirring may be done for about 1 hour the aqueous phase with HCl and extracting with toluene. to about 24 hours, more preferably, for about 2.5 hours. Fol The present invention provides a purification process of lowing the stirring step, the reaction mixture is cooled. The GBPE comprising reducing the NP and NP derivatives in 50 cooling may be done to about room temperature. GBPE, followed by acidic extractions. Preferably, the The extraction may be done by adding water and toluene to obtained product contains less than about 0.1% area by obtain a two phase system; separating the phases; washing the HPLC, preferably less than about 0.05% area by HPLC, more organic phase with HCl, water and brine; drying the organic preferably, no detectable level of NP and/or NP derivatives in phase; and removing the solvent. The drying may be done GBPE by HPLC. The reduction may be done by either hydro 55 over sodium sulfate. The removal of the solvent may be done genating with gaseous H. by transfer hydrogenation, with by evaporation. The evaporation may be done at reduced formic acid salt or by Single Electron Transfer (“SET). The pressure. acidic extraction may be done with any acid known in the art, The product obtained from the purification process above preferably, HC1. is preferably pure from NP and its derivatives. In a preferred embodiment, the purification process com 60 The present invention provides another purification pro prises: combining GBPE containing NP and/or NP deriva cess of GBPE comprising loading GBPE on a column filled tives with a polar solvent or an aromatic solvent to obtain a with cross-linked dextrangel (e.g., Sephadex LH-20, which is solution, adding gaseous Horformic acid salt in the presence reported to have a bead size of about 25-100 microns, or other of Pd/C or Pt/C to the solution; and extracting with an acid to similar resin) in toluene; and eluting GBPE with toluene or a obtain GBPE. 65 toluene/hexane solution to obtain GBPE. Preferably, the Preferably, the polar solvent is selected from the group cross-linked dextrangel is cross-linked dextrangel having a consisting of MeCH and EtOH. bead size about the same as Sephadex LH-20. Preferably, the US 8,283,487 B2 15 16 obtained product contains less than about 0.1% area by HPLC, preferably less than about 0.05% area by HPLC, more O R preferably, no detectable level of NP and/or NP derivatives in GBPE by HPLC. -s-s Preferably, when a toluene/hexane solution is used, the ratio of the toluene to hexane is about 1:1 to about 10:1, more wherein X is independently selected from Br, I, or C1 and R. preferably, about 4:1. is methyl; and a C to C tertiary amine; adding isobutyric Optionally, the above purification process may be repeated. acid in the presence of a coupling agent selected from the The present invention further encompasses a one-pot reac 10 group consisting of Cu(OAc), CdCOAc), Zn(OAc), Cu2O, tion for the preparation of GBPE. In preferred embodiments CuO, CeO, CdO, NiO, ZnO and Cu(OCCHMe); adding this process is efficient, time saving, and results in a higher gabapentin and a base selected from a group consisting of: C yield than that of the prior art. The process may be illustrated to C tertiary amine, KCO, KHCO, NaCO and NaHCO according to the scheme below. to obtain GBPE; reducing the GBPE, followed by acidic 15 extraction, concentrating the solvent and adding hexane, hep tane or a solution of heptane and EtOAc to obtain a precipi OH TEA, tate. 1-Chloroethyl chloroformate Preferably, the Co alcohol has the formula R Y H He wherein Y is O, and the Co primary amine has the formula Toluene R YH wherein Y is N. Preferably, R is alkyl or a substi ON tuted aromatic hydrocarbon. More preferably, R is alkyl or a NP substituted aromatic hydrocarbon mono-substituted at ortho O O C Isobutyric acid, or para-positions with a moiety selected from the group con ZnO, KI He 25 sisting of halo. —C(halo), —CF, —CN, —OCN, —SCN, O —N, NO. —S(O)O— —S(O)OH, -S(O)R', —OS ON (O)O-, - OS(O).R', —OP(O)(OR), C(O)R', C(S)R', CEC-NP C(O)CR', C(O)NR'R", C(O)O C(S)OR', N(R) C(O)NR'R", N(R)C(S)NR'R", N(R)C(NR)N(R)'R" and O O O Gabapentin 30 - C(NR)NR'R, wherein each R, RandR" are independently He Base: TEA or selected from the group consisting of hydrogen and alkyl. O O K2CO3/water Optionally, R, RandR", together with the atom to which they ON are attached, form a cycloheteroalkyl or substituted cyclohet AEC-NP eroalkyl ring. More preferably, R is a substituted aromatic O O KHCO2, 35 hydrocarbon substituted with a moiety selected from the HO ls 10%. Po? C group consisting of —NO. —S(O)O— —S(O)OH and N O O —S(O).R', most preferably, R is p-nitrophenyl. H Preferably, the process comprises dissolving C to Co O alcohol or C to Co primary amine and C to C tertiary 40 amine in a solvent selected from the group consisting of GBPE-Imix: acetonitrile, C to C, ketone, Cs to Coether, C to C, ester, Cs Distillation to Co. hydrocarbon and a combination thereof, followed by of Toluene: the addition of 1-haloalkyl haloformate to obtain a reaction O O Crystallization l mixture, and adding carboxylic acid to the reaction mixture in HO N u O l O Heptane/EtOAc 45 the presence of a coupling agent selected from the group H consisting of Cu(OAc), Zn(OAc), CuO, CuO, CeO2, NiO, O ZnO and Cu(OCCHMe), adding GBP, and a base selected from a group consisting of C to C tertiary amine, KCO, GBPE KHCO, NaCO, and NaHCO, to obtain GBPE: reducing the 50 obtained GBPE, followed by acidic extraction, concentrating the solvent and adding hexane, heptane or a solution of hep O O tane and EtOAc to obtain a precipitate. Preferably, the C to C tertiary amine is a C to C HO N lsO 1. O tertiary amine More preferably, the C to C tertiary amine is H 55 a TEA. O Typically, the C to Co alcohol is a C to Co aromatic alcohol, more preferably, phenol, more preferably, a Substi tuted phenol, even more preferably, phenol substituted with a GBPEcryst nitro group, most preferably, 4-nitrophenol. Preferably, the 60 C to Co primary amine is a C to Co primary aromatic amine, more preferably, aniline. The present invention encompasses a one-pot process for Preferably, the solvent is toluene. preparing GBPE comprising: combining C to Co alcohol or Optionally, prior to the addition of 1-haloethylhaloformate C to Co primary amine; a solvent selected from the group the solution is cooled. Preferably, the cooling is to a tempera consisting of acetonitrile, C to C, ketone, Cs to Coether, C. 65 ture of about 15° C. to about 0°C., more preferably, to a to C, ester, Cs to Cohydrocarbon and a combination thereof. temperature of about 10°C. to about 0°C., most preferably, to a 1-haloethyl haloformate of the following formula: a temperature of about 5°C. US 8,283,487 B2 17 18 Preferably, the 1-haloethyl haloformate is 1-chloroethyl mic acid salt is used in the process, the stirring is at about chloroformate. room temperature to about 60°C., more preferably, at about Preferably, the C to C tertiary amine is tributylamine or 450 C. triethylamine Alternatively, the reduction process is a Single Electron Preferably, the 1-haloethyl haloformate is added drop Transfer (“SET) process comprising: adding a metal W1S. selected from the group consisting of iron, Zinc and magne Preferably, following the addition of C to C tertiary sium; and extracting with acid. amine, a stirring step is performed. Preferably, the stirring is Preferably, the metal is iron. Preferably, the iron is pow at a temperature of about 10° C. to about 100° C., more dery. preferably, the stirring is at about room temperature. 10 Preferably, when the tertiary amine is TEA, prior to the Prior to the extraction step, the reaction mixture may be carboxylic acid addition, a filtration step is performed. The filtered and optionally further dried. The drying may be done obtained filtrate is preferably combined with the carboxylic by evaporation. acid in the presence of the coupling agent, as described above. Optionally, the acidic extraction is done by adding HCl and Preferably, the coupling agent is ZnO. Preferably, the 15 brine, optionally with water, to obtain a two phase system; amount of the coupling agent is about 1 equivalent. separating the phases and removing the solvent from the Preferably, the addition of the carboxylic acid in the pres organic phase. Preferably, the solvent is removed by evapo ence of the coupling agent may be done in the presence of a ration. catalyst. The catalyst may be selected from the group consist When the polar solvent is MeOH or EtOH, prior to the ing of NaI, NaBr, tetrabutylammonium bromide (“TBAB), washing step, the solvent is preferably removed to obtain a tetrabutylammonium iodide (“TBAI), KBr, KI, LiBr and residue, and toluene is preferably added to obtain a solution. LiI. Preferably, the catalyst is NaBr, NaI or KI. Preferably, the Preferably, prior to the extraction step, a reaction mixture is amount of catalyst is about 0.5 equivalents. obtained. The reaction mixture may be stirred, preferably at a Optionally, following the addition of carboxylic acid in the temperature of about 10° C. to about 100° C., more prefer presence of the coupling agent, a heating step is performed, 25 ably, at about 45°C. The stirring may be done for about 1 hour followed by a cooling step. Preferably, the heating is to a to about 24 hours, more preferably, for about 2.5 hours. Fol temperature of about 60° C. to about 100° C., more prefer lowing the stirring step, the reaction mixture is cooled. The ably, about 80° C. Preferably, the cooling is to about room cooling may be done to about room temperature. temperature. Preferably, following the cooling step, water is The extraction may be done by adding water and toluene to added to obtain a two-phase system, the phases are separated, 30 obtain a two phase system; separating the phases; washing the and the organic phase is further washed with aqueous Na2CO3 to obtain a pH of about 6 to about 7 in a two-phase organic phase with HCl, water and brine; drying the organic system. The two-phase system is further separated and the phase; and removing the solvent. The drying may be done organic phase is kept for the next step where GBP is added. over sodium sulfate. The removal of the solvent may be done Preferably, the carboxylic acid used in the process is isobu 35 by evaporation. The evaporation may be done at reduced tyric acid. pressure. Preferably, the base selected from a group consisting of C. The product obtained from the purification process above to C tertiary amine, KCO, KHCO, NaCO and NaHCO is preferably pure from NP and its derivatives. is KCO or NaCO. The concentration may be done by vacuum distillation. As Preferably, the C to C tertiary amine is TBA or TEA. 40 used herein, the term “vacuum distillation” refers to a distill Preferably, when the base is KCO, KHCO, NaCO or lation step under vacuum, at a temperature of about 50° C. to NaHCO, the base is added with water. about 80°C., more preferably, of about 50° C. to about 60° C. Preferably, following the addition of GBP and the base, a Preferably, following the addition of hexane, heptane or stirring step is performed. Preferably, the stirring is at about heptane/EtOAc solution, a cooling step is performed. Prefer 10° C. to about 100° C. Preferably, when the base is a C to 45 ably, the cooling is to a temperature of about room tempera C tertiary amine, the stirring is at about room temperature. ture to about 0°C., more preferably, to about 5°C., to allow Preferably, the reduction is done by hydrogenation, trans precipitation. fer hydrogenation or SET. The present invention further encompasses a one-pot pro In a preferred embodiment, the reduction process com cess for preparing GBPE comprising: combining 4-nitrophe prises: adding gaseous H2 or formic acid salt in the presence 50 nol, toluene, 1-chloroethyl chloroformate and a base selected of Pd/C or Pt/C to the solution; and extracting with an acid to from the group consisting of TEA and TBA.; adding isobu obtain GBPE. tyric acid in the presence of ZnO; adding GBP and a base Preferably, the formic acid salt is added with water. Pref selected from the group consisting of TEA and KCO; add erably, the ratio of the formic acid saltwater (mole:mole) is of ing potassium formate in the presence of palladium over about 1:1 to about 1:20, more preferably, of about 1:1 to about 55 1:10, most preferably, of about 1:3 to 1:6. carbon; and adding hexane, heptane or heptane/EtOAc. Preferably, the gaseous H is added at a pressure of about 1 Having thus described the invention with reference to par to 6 atmospheres, more preferably, at a pressure of about 3 ticular preferred embodiments and illustrative examples, atmospheres. those in the art can appreciate modifications to the invention Preferably, prior to the extraction, a reaction mixture is 60 as described and illustrated that do not depart from the spirit obtained. Preferably, the reaction mixture is maintained and and scope of the invention as disclosed in the specification. further filtered. The maintaining step may be done for about 2 The examples are set forth to aid in understanding the inven hours to about 24 hours, more preferably, for about 2 hours to tion but are not intended to, and should not be construed to, about 12 hours. Preferably, the maintaining step is done with limit its scope in any way. Absent statement to the contrary, stirring. Preferably, when H gaseous is used in the process, 65 any combination of the specific embodiments described the stirring is at about room temperature to about 60°C., more above are consistent with and encompassed by the present preferably, at about room temperature. Preferably, when for invention. US 8,283,487 B2 19 20 INSTRUMENTS Example 3 Water Removing Tool: One-Pot Process for Preparation of AEC-NP Molecular sieves, Dean Stark apparatus. HPLC Reactor was loaded with 4-Nitrophenol (5 g, 35 mmol) dissolved in Toluene (75 ml) followed by addition of triethy lamine (TEA) (3.8 g. 38.5 mmol). The obtained yellow col Column & Packing: Zorbax sb phenyl 100 * 4.6 1.8 ored solution was cooled to 5° C. and then 1-chloroethyl Eluent A: A: 0.025% H2SO4 in water chloroformate (38.5 mmol) was added dropwise. The Eluent B: B: Acetonitrile 10 obtainedjelly-like slurry was stirred for additional 30 min, at Time 96 Eluent A % Eluent B this point according to HPLC no 4-Nitrophenol remained. Gradient O 70 30 The reaction mixture was filtered; the filtrate was loaded to 5 70 30 the reactor followed by addition of Zinc oxide (38.5 mmol), 2O 60 40 45 10 90 15 Potassium iodide (19.3 mmol) and Isobutyric acid (43 ml). Equilibrium time: 8 min The obtained mixture was heated at 80° C. monitored by Flow: 1.0 ml/min HPLC. The reaction was stopped approximately after 10 h. Sample volume: 10 IL Detector: 210 mm The reaction was washed with NaHCO, solution, 20% Column temperature: 25o C. NaSO solution and then with brine. The solvent was Diluent Water:ACN (50:50) evaporated to give the product in 40% to 50% yield. Sample Preparation Example 4 Weigh accurately about 40 mg of sample in a 20 ml volu metric flask. Dissolve with diluent. Preparation of AEC-NP from CEC-NP 25 Method 1-1-chloroethyl 4-nitrophenyl carbonate CEC-NP (1 g, 4 Inject the sample solutions into the chromatograph, con mmol) was dissolved in isobutyric acid (20 ml) followed by tinuing the chromatogram of sample up to the end of the addition of zinc oxide (1 g, 12 mmol) and NaBr (0.41 g, 4 gradient. Determine the areas for each peak in each Solution mmol). The reaction mixture was stirred at 60° C. for 24 using a suitable integrator. 30 hours. The reaction was stopped and evaporated; the residue EXAMPLES was dissolved in EtOAc, washed with saturated NaHCO Solution and then with brine. The organic layer was separated, Example 1 dried over MgSO and evaporated to give the desired product in 60% yield. 35 Preparation of CEC-NP Example 5 Reactor (500 ml) was loaded with 4-Nitrophenol (10 g, Preparation of AEC-NP from CEC-NP 0.07 mol) dissolved in Toluene (150 ml) followed by drop wise addition of 1-chloroethyl chloroformate (13.25 g, 0.09 40 mol) and then Tributylamine (17.3 g, 0.09 mol). The obtained Zinc oxide (1 g, 12 mmol) was added to a solution of solution was stirred at room temperature for additional 30 toluene (40 ml) and isobutyric acid (10 ml) and the flask was min. At this point according to HPLC no 4-Nitrophenol heated at 105° C. The water created in this process was remained. The reaction was washed with 1N HCl (150 ml), removed by Dean Stark apparatus. After 1 h of heating, the water (2* 100 ml) and brine. The aqueous phase was removed 45 temperature was lowered to 60° C. and then 1-1-chloroethyl from the reactor and to the remaining toluenic Solution was 4-nitrophenyl carbonate CEC-NP (1 g, 4 mmol) together evaporated. with NaI (1 g, 6.4 mmol) were added. The reaction mixture was stirred at 60° C. for 24 hours. The reaction was stopped Example 2 and evaporated; the residue was dissolved in EtOAc, washed 50 with saturated NaHCO solution and then with brine. The One-Pot Process for Preparation of AEC-NP organic layer was separated, dried over MgSO and evapo rated to give the desired product in 75% yield. Reactor (500 ml) was loaded with 4-Nitrophenol (10 g, 0.07 mol) dissolved in Toluene (150 ml) followed by drop Example 6 wise addition of 1-chloroethyl chloroformate (13.25 g, 0.09 55 mol) and then Tributylamine (17.3 g, 0.09 mol). The obtained Preparation of GBPE from AEC-NP solution was stirred at room temperature for additional 30 min. At this point according to HPLC no 4-Nitrophenol Gabapentin free base (5.75 g, 0.03 mol) was slurried in remained. The reaction was washed with 1N HCl (150 ml), Toluene (50 ml) followed by addition of chlorotrimethylsi water (2* 100 ml) and brine. The aqueous phase was removed 60 lane (6.5 g., 0.06 mol) and Tributyl amine (11.1 g, 0.06 mol). from the reactor and to the remained toluenic Solution was The resulting mixture was stirred at room temperature to give added Zinc oxide (17 g., 0.21 mol), Sodium iodide (10.5 g. clear solution. Then 1-(isobutyryloxy)ethyl 4-nitrophenyl 0.07 mol) and Isobutyric acid (50 ml). The obtained mixture carbonate AEC-NP (10g, 0.03 mol) in Toluene (20 ml) was was heated at 75° C. monitored by HPLC. The reaction was added and the reaction was stirred at RT for 24 h. The reaction stopped approximately after 10 h. The reaction was washed 65 was washed with 1N HCl (150 ml) and hot water (5* 100 ml). with NaHCO solution and then with brine. The solvent was The toluenic phase was washed with saturated NaHCO and evaporated to give the product in 60% yield. the phases were separated. The aqueous phase was acidified US 8,283,487 B2 21 22 with 1N HCl and extracted with Toluene. The last toluenic Example 12 phase was dried and evaporated to give GBPE. In MeOH (II) Example 7 5 GBPE crude (3.5 g) was dissolved in MeOH followed by Preparation of GBPE from AEC-NP addition of 10% Pd/C (20% wt) and Ammonium formate (1 eq). The resulting reaction mixture was stirred at RT for 2 h to Gabapentin free base (5.75 g, 0.03 mol) was slurried in 24 h. Then the reaction was filtered, and the filtrate was Toluene (50 ml) followed by addition of Chlorotrimethylsi evaporated. The residue was dissolved in toluene and washed lane (6.5 g., 0.06 mol) and Tributyl amine (11.1 g, 0.06 mol). 10 with 1N HCl, brine and the organic phase was evaporated to The resulting mixture was stirred at room temperature to give give GBPE pure from nitrophenol derived impurities. clear solution. Then 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate AEC-NP (10g, 0.03 mol) in Toluene (20 ml) was Example 13 added and the reaction was stirred at RT for 24 h. The reaction was washed with 1 NHCl (150 ml) and water (2*100 ml). The 15 In EtOH (II) toluenic phase was dried and evaporated to give GBPE in quantitative yield. GBPE crude (3.5 g) was dissolved in EtOH followed by Purification of GBPE from NP and its Derivatives addition of 10% Pd/C (20% wt) and Ammonium formate (1 Method A: Hydrogenation: eq). The resulting reaction mixture was stirred at RT for 2 h to 24 h. Then the reaction was filtered, and the filtrate was Example 8 evaporated. The residue was dissolved in toluene and washed with 1N HCl, brine and the organic phase was evaporated to give GBPE pure from nitrophenol derived impurities. In Toluene (I) Method C: Single Electron Transfer: 25 GBPE crude (3.5 g) was dissolved in toluene followed by Example 14 addition of 10% Pd/C (20% wt) and the obtained mixture was hydrogenated at 3 atm for 2 h to 24 h. Then the reaction was GBPE crude (0.5 g) (containing nitrophenol (8%) and filtered, the filtrate was washed with 1N HCl, brine and the derivatives of nitrophenol (about 10%)) was dissolved in organic phase was evaporated to give GBPE pure from nitro 30 acetic acid (6 mL). Iron powder (0.5 g) was added and the phenol derived impurities. mixture was stirred at 45° C. for 2.5 hours. TLC (Hexane/ EtOAc, 1:2) indicated full consumption of nitrophenol. The Example 9 mixture was cooled to 25° C. and diluted with water. GBPE was extracted by toluene. The toluene solution was conse In MeOH (I) 35 quently washed with HCl (1N), water and brine, dried over Sodium sulfate. The solvent was removed at reduced pressure, GBPE crude (3.5 g) was dissolved in MeOH followed by giving the product (0.29 g) as Viscous oil. addition of 10% Pd/C (20% wt) and the obtained mixture was Method D: Filtration on Sephadex LH-20 hydrogenated at 3 atm for 2 h to 24 h. Then the reaction was filtered, and the filtrate was evaporated. The residue was 40 Example 15 dissolved in toluene and washed with 1 NHCl, brine and the organic phase was evaporated to give GBPE pure from nitro GBPE crude (1 g) containing 20% of Nitrophenol (NP) was phenol derived impurities. loaded on column filed with Sephadex LH-20 in Toluene (40 g of stationary phase). GBPE was eluted with Toluene/Hex Example 10 45 ane (4:1) solution monitored by TLC. Fractions containing GBPE were combined together and evaporated to dryness to In EtOH (I) give GBPE and 0.27% of NP. The recovery of GBPE was 97.7%. This experiment can be repeated in order to achieve GBPE crude (3.5 g) was dissolved in EtOH followed by GBPE fraction which contains undetectable levels of NP. addition of 10% Pd/C (20% wt) and the obtained mixture was 50 One-Pot Process for Preparation of GBPE from NP hydrogenated at 3 atm for 2 h to 24 h. Then the reaction was filtered, and the filtrate was evaporated. The residue was Example 16 dissolved in toluene and washed with 1 NHCl, brine and the organic phase was evaporated to give GBPE pure from nitro Method A phenol derived impurities. 55 Method B: Transfer Hydrogenation: Stage 1: 4-Nitrophenol (50 g, 0.36 mol) and Triethylamine ITEA (42 g, 0.415 mol, 1.15 eq) were dissolved in Toluene Example 11 (750 ml, 15V) and the obtained reaction mixture was cooled at 5°C. under N. 1-chloroethyl-chloroformate (59.5g, 0.415 In Toluene (II) 60 mol. 1.15 eq) was added dropwise and then the reaction is allowed to reach room temperature. The reaction progress GBPE crude (3.5 g) was dissolved in toluene followed by was monitored by HPLC, no 4-Nitrophenol was detected addition of 10% Pd/C (20% wt) and Ammonium formate (1 after 1 h. The reaction was filtered, the cake was washed with eq). The resulting reaction mixture was stirred at RT for 2 h to Toluene (2* 100 ml) and the filtrate was returned to the reac 24 h. Then the reaction was filtered, the filtrate was washed 65 tOr. with 1 NHCl, brine and the organic phase was evaporated to Stage 2: Zinc oxide (30 g, 0.36 mol), Potassium iodide (30 give GBPE pure from nitrophenol derived impurities. g, 0.18 mol) and Isobutyric acid (400 ml) were loaded into the US 8,283,487 B2 23 24 reactor and the reaction mixture was heated at 80°C. approxi Stage 4: To the solution of KHCO (46g, 0.54 mol 1.5 eq mately for 8 h. Then the reactor was cooled to RT and the vs. NP in water (29 ml, 1.62 mol 3 eq vs. KHCO, were reaction was washed with water (500 ml). After phase sepa added 10% Pd/C (50% water content, 5 g) and the toluenic ration additional amount of water (1 L) was added and the pH Solution from the previous stage. The reaction was heated at was adjusted to 6.5-7 by portionwise addition of solid 45° C. and was monitored by HPLC. The reaction was NaHCO. The organic phase was washed with 20% NaSO stopped when no 4-Nitrophenol was detected. The reaction (1 L) and with water (2*1 L). After phase separation, assay was cooled to RT and acidified with 2N HCl (500 ml) fol percentage of the desired intermediate in the solution was lowed by filtration on Hyflo bed. The cake was washed with measured. Toluene (2*100 ml) and water (2*100 ml). The phases were Stage 3: To the toluenic phase were added Gabapentin 10 separated and organic phase was washed with water (1 L). (42.91 g, 0.25 mol 1.5 eq vs AEC-NP) and Triethylamine Toluenic phase was stirred at -10°C. for 24 hand then filtered ITEA (25.38 g., 0.25 mol 1.5 eq vs. AEC-NPI) and the on HiFlo bed. After filtration the assay of GBPE in the solu reaction was heated at 40° C. The reaction progress was tion was measured. To the toluenic solution was added monitored by HPLC, when no AEC-NP was detected (ap Na2CO3 aqueous solution 5% molar vs. GBPE) and the proximately after 7h) the reaction was cooled to RT and the 15 biphasic mixture was stirred at RT for 24 h. Then the phases solution was washed with 1N HCl (1 L). The phases were were separated, the organic phase was washed with 1 NHCl separated and the toluenic phase was washed with water (1 L). and then with water. Phases were separated and the yield until Stage 4: To the toluenic phase were added Potassium for this stage was 36% vs. 4-Nitrophenol (NP) based on assay mate (45 g, 0.53 mol 1.5 eq vs. NPI) and 10% Pd/C (50% calculations. water content, 15 g). The reaction was heated at 45° C. and Crystallization stage: The toluenic phase was concentrated was monitored by HPLC. The reaction was stopped when no by vacuum distillation (50-60°C.) to approximately 1-2 Vol 4-Nitrophenol was detected. The reaction was filtered on umes of Toluene (vs. GBPE) followed by addition of Hep Hyflo bed, washed with Toluene (2*100 ml) and the filtrate tane/EtOAc=10:1 (5 V). The crystallization mixture was was washed with 1 NHCl (1 L) and then with water (1 L). The heated up to 80° C. to give clear solution and then slowly yield until this stage was 40% vs. 4-Nitrophenol (NP) based 25 cooled to 40°C. and seeded. The reaction was further slowly on assay calculations. cooled to 5°C. The reaction was kept at this temperature for Precipitation stage: The toluenic phase was concentrated 12 h and the obtained precipitate was collected by filtration. by vacuum distillation (50-60°C.) to approximately 1-2V of Toluene (vs. GBPE) followed by addition of Heptane (20-30 What is claimed is: V) and cooling to RT to form precipitate which was collected 30 1. A process for purifying gabapentin enacarbil (GBPE) by filtration. from a mixture with nitrophenol (NP) and/or NP derivatives comprising reducing the NP and NP derivatives in the mix Example 17 ture, followed by acidic extraction. 2. The process of claim 1, wherein the obtained product Method B 35 contains less than about 0.1% area by HPLC of nitrophenol and less than about 0.1% area by HPLC of any nitrophenol Stage 1: 4-Nitrophenol (50 g, 0.36 mol) and Triethylamine derivative. ITEA (42 g, 0.415 mol, 1.15 eq) were dissolved in Toluene 3. The process of claim 1, wherein the obtained product (750 ml, 15V) and the obtained reaction mixture was cooled contains less than about 0.05% area by HPLC of nitrophenol at 5° C. under N2. Chloroethyl-chloroformate (59.5g, 0.415 40 and less than about 0.05% area by HPLC of any nitrophenol mol. 1.15 eq) was added dropwise and then the reaction was derivative. allowed to reach room temperature. The reaction progress 4. The process of claim 1, wherein the obtained product was monitored by HPLC, no 4-Nitrophenol was detected contains no detectable amount, by area HPLC, of nitrophenol after 1 h. The reaction was filtered, the cake was washed with or any nitrophenol derivative. Toluene (2* 100 ml) and the filtrate was returned to the reac 45 5. The process of claim 1, wherein the reduction is done by tOr. hydrogenating with gaseous H. by transfer hydrogenation Stage 2: Zinc oxide (30 g, 0.36 mol), Potassium iodide (30 with formic acid salt or by Single Electron Transfer (“SET). g, 0.18 mol) and Isobutyric acid (400 ml) were loaded into the 6. The process of claim 1, comprising: combining a mix reactor and the reaction mixture was heated at 80°C. approxi ture containing gabapentin enacarbil, NP, and/or NP deriva mately for 8 h. Then the reactor was cooled to RT and the 50 tives with a polar solvent or an aromatic solvent to obtain a reaction was washed with water (500 ml). After phase sepa Solution, adding gaseous Horformic acid salt in the presence ration the toluenic phase was cooled to 0°C. followed by of Pd/C or Pt/C to the solution; and extracting with an acid. dropwise addition of 18% Na2CO3 aqueous solution till the 7. The process of claim 6, wherein the polar solvent is pH reached 6.5-7. The phases were separated and the organic selected from the group consisting of MeOH and EtOH. phase was washed with 20% Na2S2O3 (500 L) and with 55 8. The process of claim 6, wherein the aromatic solvent is water (2500 L). After phase separation, assay percentage of selected from the group consisting of toluene, o-Xylene, the desired intermediate in the Solution was measured. m-Xylene and p-Xylene. Stage 3: To solution of KCO (53.6 g. 0.38 mol 2 eq vs. 9. The process of claim 8, wherein the aromatic solvent is AEC-NP) in water (250 ml (5V vs. GBPI) was added Gaba toluene. pentin (50 g, 0.29 mol 1.5 eq vs AEC-NP) and the toluenic 60 10. The process of claim 6, wherein the formic acid salt is Solution from the previous stage. The obtained reaction mix ammonium formate or potassium formate. ture was stirred at 40°C. and was monitored by HPLC. When 11. The process of claim 6, wherein the formic acid salt is no AEC-NP was detected (approximately after 10 h) the added with water. reaction was cooled to RT and water (500 ml) was added. The 12. The process of claim 11, wherein the ratio of the formic phases were separated and the aqueous phase was acidified 65 acid saltwater (mole:mole) is of about 1:1 to about 1:20. with 2NHCl and extracted with Toluene (1 L). Toluenic phase 13. The process of claim 6, wherein the gaseous H is added was stirred at -10°C. for 24 hand then filtered on HiFlobed. at a pressure of about 1 to about 6 atmospheres. US 8,283,487 B2 25 26 14. The process of claim 1, comprising dissolving a mix cross-linked dextrangel in toluene; and eluting purified gaba ture containing gabapentin enacarbil, nitrophenol, and/or pentin enacarbil with toluene or a toluene? hexane Solution. nitrophenol derivatives in a C-C carboxylic acid or HCl to 18. The process of claim 17, wherein the cross-linked obtain a solution; adding a metal selected from the group dextran has a bead size of approximately 25-100 microns. consisting of iron, Zinc and magnesium to the Solution; and 19. The process of claim 17, wherein, when a toluene/ extracting with acid to obtain gabapentin enacarbil. hexane solution is used, the ratio of the toluene to hexane is 15. The process of claim 14, wherein the C-C carboxylic about 1:1 to about 10:1. acid is acetic acid. 20. The process of claim 19, wherein the ratio of the tolu 16. The process of claim 14, wherein the metal is iron. ene to hexane is about 4:1. 17. A process for purifying gabapentin enacarbil, compris ing: loading a mixture containing gabapentin enacarbil, nitro 10 phenol, and/or nitrophenol derivatives on a column filled with