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.