Lulu NRR 5,637,767 a 6, 1997 Grote Et Al

Lulu NRR 5,637,767 a 6, 1997 Grote Et Al

USOO8168828B2 (12) United States Patent (10) Patent No.: US 8,168,828 B2 Satyanarayana Reddy et al. (45) Date of Patent: May 1, 2012 (54) PROCESS FOR THE PREPARATION OF PCT Written Opinion of the International Searching Authority, PCT/ PREGABALN IN2008/000174, 3 pp., Date of Mailing: Oct. 11, 2010. Armstrong, A., et al., “Diastereoselective Conjugate Addition of Cyanide to C.B-Unsaturated Oxazolidinoncs: Enantioselective Syn (75) Inventors: Manne Satyanarayana Reddy, thesis of ent-Pregabalin and Baclofen.” SYNLETT, No. 10, pp. 1589 Hyderabad (IN); Srinivasan Thirumalai 1591 (Received Mar. 9, 2006). Rajan, Hyderabad (IN); Sajja “Pregabalin.” Drugs of the Future, 24(8): 8620870, (1999) (no Eswaraiah, Hyderabad (IN); Revu month). Satyanarayana, East Godavari (IN) Mita, T., et al., “Catalytic Enantioselective Conjugate Addition of Cyanide to C.B-Unsaturated N-Acylpyrroles,” J. A.M. Chem. Soc., 127, 514-515 (2005) (no month). (73) Assignee: MSN Laboratories, Limited, Andhra Concellón, J. M. and Concellón, C., “Aldol-type Reactions of Pradesh Hyderabad (IN) Unmasked Iodoacetic Acid with Carbonyl Compounds Promoted by Samarium Diiodidc: Efficient Synthesis of Carboxylic (*) Notice: Subject to any disclaimer, the term of this 3-Hydroxyacids and Their Derivatives.” J. Org. Chem., 71, No. 12, patent is extended or adjusted under 35 4428-4432 (2006) (no month). U.S.C. 154(b) by 0 days. Andruszkiewicz, R., and Silverman, R.B., “A Convenient Synthesis of 3-Alkyl-4-Aminobutanoic Acids.” Communications, pp. 953 (21) Appl. No.: 12/666,133 955(1989). Sammis, G.M. and Jacobsen, E.N., "Highly Enantioseleetive, Cata (22) PCT Filed: Mar. 24, 2008 lytic Conjugate Addition of Cyanide to O.f3-Unsaturated Imides. J. Am. Chem. Soc., 125:4442-4443 (2003). (86). PCT No.: PCT/N2008/000174 Yamamoto, K., et al., “Stereoselective Synthesis of (E)- Alkylideneseuccinates by Palladium-catalyzed Carbonylation.” The S371 (c)(1), Chemical Society of Japan, 58:3397-3398(1985). (2), (4) Date: Dec. 22, 2009 * cited by examiner (87) PCT Pub. No.: WO2009/001372 Primary Examiner — Joseph Kosack PCT Pub. Date: Dec. 31, 2008 Assistant Examiner — Matthew Coughlin (74) Attorney, Agent, or Firm — Hamilton, Brook, Smith & (65) Prior Publication Data Reynolds, P.C. US 2010/O179345 A1 Jul. 15, 2010 (57) ABSTRACT (30) Foreign Application Priority Data The present invention encompasses novel intermediates of pregabalin, namely 3-cyano-5-methylhexanamide (28) and Jun. 25, 2007 (IN) ........................... 1344/CHFA2007 3-(amino methyl)-5 methylhexanamide (29), and processes Jan. 14, 2008 (IN) ............................. 114f CHEA2008 for their preparation. The invention also encompasses a pro cess for converting the novel pregabalin intermediates into (51) Int. Cl. pregabalin, Formula (I): The present invention further pro C07C 237/06 (2006.01) vides a cost effective method for the synthesis of (S)-pregaba C07C 227/30 (2006.01) lin, which involves the recovery of mandelic acid and tartaric C07C 229/12 (2006.01) acid used in the resolution process and recycling them, (52) U.S. Cl. ........................................ 564/197; 562/553 increasing the yields of the final product formed, which sub (58) Field of Classification Search ................... 564/197 See application file for complete search history. stantially reduced the cost of the production. (56) References Cited 28 U.S. PATENT DOCUMENTS 5,599,973 A 2f1997 Silverman et al. lulu NRR 5,637,767 A 6, 1997 Grote et al. 2003/0212290 A1 11, 2003 Burk et al. 29 2007/0197827 A1* 8, 2007 Kansal et al. ..................... 564f1 NH2 O FOREIGN PATENT DOCUMENTS CZ. 297970 B6 5/2007 NRR EP O254685 A2 1, 1988 NH 1. 2 O OTHER PUBLICATIONS CAS Registry No. 766508-49-0, entered STN on Oct. 21, 2004.* Hong-Ju et al. Bioorg. Med. Chem. Lett. 2004, 14, 2537-2541.* lulu, OH English Translation of CZ 297970, translated Mar. 2011.* (S)-PREGABALIN International Search Report, PCT/IN2008/000174, 4 pp., Date of Mailing: Oct. 11, 2010. PCT International Preliminary Reporton Patentability, PCT/IN2008/ 000174, 1 pg., Date of Issuance of Report: Oct. 19, 2010. 19 Claims, 1 Drawing Sheet U.S. Patent May 1, 2012 US 8,168,828 B2 9. - - - - —s s 8 v: v3 &vs was8 3vs was vr8 & 3 & 3 : 3 & 8 s a (Sunoo) ul US 8,168,828 B2 1. 2 PROCESS FOR THE PREPARATION OF GAD (L-glutamic acid decarboxylase). (S)-pregabalin has a PREGABALN dose dependent protective effect on-seizure, and is a CNS active compound. (S)-pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the produc RELATED APPLICATIONS tion of GABA, one Of the brain's major inhibitory neu rotransmitters, which is released at 30 percent of the brains This application is the U.S. National Stage of International synapses. (S)-pregabalin has analgesic, anticonvulsant, and Application No. PCT/IN2008/000174, filed Mar. 24, 2008, anxiolytic activity. (S)-pregabalin is marketed under the trade which designates the U.S., published in English, and claims name LYRICAR). priority under 35 U.S.C. SS 119 or 365(c) to Indian provi 10 sional application no. 1344/CHF/2007, filed Jun. 25, 2007 and Indian patent application No.: 114/CHF/2008, filed on BACKGROUND OF THE INVENTION Jan. 14, 2008. The entire teachings of the above applications are incorporated herein by reference. Several processes were reported for the synthesis of (S)- 15 Pregabalin. One such process is illustrated in drugs of the future, 24 (8), 862-870 (1999), represented as scheme-1. In FIELD OF THE INVENTION which 3-isobutylglutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with The present invention encompasses novel intermediates of refluxing acetic anhydride. The reaction of the anhydride with pregabalin, namely 3-cyano-5-methylhexanamide of general NH-OH produces the glutaric acid mono-amide, compound formula-28 and 3-(aminomethyl)-5 methyl hexanamide of 4, which is resolved with (R)-1-phenylethylamine, yielding general formula-29, and processes for their synthesis. The the (R)-phenyl ethylamine salt of (R)-3-(carbamoylmethyl)- invention also encompasses a process for converting the novel 5-methylhexanoic acid, compound 5. Combining the salt pregabalin intermediates into pregabalin. 25 with an acid liberates the (R)-enantiomer, compound 6. It also encompasses a cost effective and economically use Finally, a Hoffmann's degradation with Br/NaOH provides ful method for the preparation of (S)-pregabalin. (S)-Pre (S)-Pregabalin. A disadvantage of this method is that, it gabalin is chemically known as (S)-(+)-3-(amino methyl)-5- requires separating the two enantiomer thereby resulting in methylhexanoic acid represented as a compound of formula the loss of half of the product, such that the process cost is 1. high. Scheme-1: O OH O O O O O Ac2O 1)NH3(aq). MTBE HO Her -- O reflux 2) HCI O CH3 CH3 NH2 CH3 CH3 CH3 CH3 2 3 4 (R)-(+)- phenylethylamine O GE O OH O O H3N 1) NaOH, Br. O O HN a i 2) HCI St. NH2 CH CH CH Pregabalin (R)-6 5 A few stereo selective processes for the synthesis of (S)- Formula-1 Pregabalin have been disclosed. For example, U.S. Pat. No. 1. NH, 5.599.973 discloses the preparation of (S)-Pregabalin using s Stoichiometric (+)-4-methyl-5-phenyl-2-oxazolidinone as a r chiral auxiliary that may be recycled. In general, however, OH that route is of limited use for scale-up, principally due to the 65 low temperature required for the reactions, the use of pyro Pregabalin is also known as Y-aminobutyric acid or (S)-3- phoric reagent such as butyl lithium, and due to side reactions, isobutyl GABA. (S)-pregabalin has been found to activate which resulted in a low overall yield. US 8,168,828 B2 3 4 Another process is disclosed in U.S. Patent Application In 1989, Silverman reported a convenient synthesis of Publication No. 2003/0212290, which discloses asymmetric 3-alkyl-4-amino acids compounds in Synthesis, Vol. 12, hydrogenation of a cyano-Substituted olefin, compound 7, to 953-954 (1989). Using 2-alkenoic esters as a substrate, a produce a cyano precursor of (S)-3-(amino methyl)-5-methyl series of GABA analogs were produced by Michael addition hexanoic acid, compound 8, as seen in Scheme 2. of nitro methane to C.B-unsaturated compounds, followed by hydrogenation at atmospheric pressure of the nitro compound to amine moiety as depicted in Scheme 4. Scheme-2: CN RR)- N (R,R) 10 Scheme-4: MeDuPHOSRh(COD)" BF4 COR N-" -- O 15 12 OEt He YcoR O ON 13 Subsequent reduction of the nitrile with compound 8 by OR catalytic hydrogenation produces (S)-Pregabalin. The cyano hexenoate starting material, compound 7, is prepared from O HN 2-methyl propanal and acrylonitrile (Yamamoto et al. Bull. 25 Chem. Soc. Jap., 58,3397 (1985)). However, the disclosed 14 method requires carbon monoxide under high pressure, rais ing serious problems in adapting this scheme for production scale processes. Further resolution of compound 14 may be employed to A process published by G. M. Sammis, et al., J. Am. Chem. 30 resolve Pregabalin. This, of course, results in the loss of 50 Soc., 125(15), 4442-43 (2003), takes advantage of the asym percent of the product, a serious disadvantage. However, the metric catalysis of cyanide conjugate addition reactions. The disclosed methodology reveals that the nitro compound can method discloses the application of aluminium salencatalysts serve as an intermediate for the synthesis of 3-alkyl-4-amino to the conjugate addition of hydrogen cyanide to C.B-unsat acids. urated imides as shown in scheme-3. Reportedly, TMSCN is 35 Due to the activity of GABA as an inhibitory neurotrans a useful source of cyanide that can be used in the place of mitter, and its effect on convulsive states and other motor HCN.

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