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(12) United States Patent (10) Patent No.: US 9,115,175 B2 Phadke Et Al

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(12) United States Patent (10) Patent No.: US 9,115,175 B2 Phadke Et Al US009115175B2 (12) United States Patent (10) Patent No.: US 9,115,175 B2 Phadke et al. (45) Date of Patent: Aug. 25, 2015 (54) PROCESSES FOR PRODUCING SOVAPREVIR Di Marco et al., “Inhibition of the Heapatitis C Virus NS3/4A Protease' The Journal of Biological Chemistry, vol. 275, No. 10, (71) Applicant: Achillion Pharmaceuticals, Inc., New Issue of Mar. 10, 2000, pp. 7152-7157. Haven, CT (US) (Continued) (72) Inventors: Avinash Phadke, Branford, CT (US); Akihiro Hashimoto, Branford, CT (US); Primary Examiner — Thomas S Heard Venkat Gadhachanda, Hamden, CT (74) Attorney, Agent, or Firm — Cantor Colburn LLP (US) (57) ABSTRACT (73) Assignee: ACHILLION PHARMACEUTICALS, The disclosure includes novel processes for producing INC., New Haven, CT (US) Sovaprevir comprising adding (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (21) Appl. No.: 14/211,510 (22) Filed: Mar 14, 2014 (65) Prior Publication Data US 2014/0275480 A1 Sep. 18, 2014 Related U.S. Application Data (60) Provisional application No. 61/784, 182, filed on Mar. 14, 2013. (51) Int. Cl. C07K 5/097 (2006.01) CO7D 40/12 (2006.01) CO7D 207/6 (2006.01) CO7D 40/06 (2006.01) (52) U.S. Cl. CPC ............ C07K5/0821 (2013.01); C07D 207/16 (2013.01); C07D401/06 (2013.01); C07D 401/12 (2013.01) (58) Field of Classification Search None See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 6,872,805 B2 3/2005 Campbell et al. 6,908,901 B2 6/2005 Bailey et al. 6,995,174 B2 2/2006 Wang et al. (Continued) FOREIGN PATENT DOCUMENTS WO 02060926 A2 8, 2002 WO O3O99274 A1 12/2003 (Continued) OTHER PUBLICATIONS Andrews et al., “Pyrrodlidine-5,5-trans-lactams. 2. The Use of X-ray Crystal StructureData in the Optimization of P3 and P4Substituents' Organic Letters, vol. 4. No. 25, (2002), pp. 4479-4482. compound E to F-1 to provide Sovaprevir. The disclosure Arasappan et al., “Hepatitis C Virus NS3-4A Serine Protease Inhibi further includes intermediates useful for producing Sovapre tors: SAR of P2 Moeity with Improved Potency” Bioorganic and vir. The disclosure also include a novel crystalline form of Medicinal Chemistry Letters, 15, (2005), pp. 4180-4184. Sovaprevir, Form F. and a method for preparing spray-dried Barbato et al., “Inhibitor Binding Induces Active Site Stabilization of amorphous Sovaprevir from crystalline Form F. the HCV NS3 Protein Serine Protease Domain'. The EMBO Journal; vol. 19: No. 6; (2000); pp. 1195-1206. 11 Claims, 4 Drawing Sheets US 9,115,175 B2 Page 2 (56) References Cited WO 2007OO9109 A2 1/2007 WO 2007OO9227 A1 1, 2007 U.S. PATENT DOCUMENTS WO 2007O14919 A1 2, 2007 WO 2007 O15824 A2 2, 2007 7,041,698 B2 5/2006 Ripka et al. WO 2007030656 A1 3f2007 7,176,208 B2 2/2007 Nakajima et al. WO 2007044893 A2 4, 2007 2004/0002448 A1 1/2004 Tsantrizos et al. WO 20080085O2 A1 1/2008 2004/00488O2 A1 3/2004 Ripka et al. 2004/OO77551 A1 4/2004 Campbell et al. OTHER PUBLICATIONS 38: A. 1 ES E. al International Search Report of the International Searching Authority 2006, 0046965 A1 3, 2006 Bail et al. for International Application No. PCT/US2007/016018; Interna 2006/O199773 A1 9, 2006 Sausker et al. tional Filing Date: Jul. 13, 2007; Date of Mailing: Dec. 12, 2007, 14 2007/OO 10455 A1 1/2007 Hewawasam et al. pageS. 2007/0093414 A1 4/2007 Carini et al. International Search Report of the International Searching Authority 2007/00998.25 A1 5, 2007 D’Andrea et al. for International Patent Application No. PCT/US2014/028278; Inter 2010/0216725 A1 8, 2010 Phadke et al. national Filing Date: Mar. 14, 2014: Date of Mailing: Nov. 10, 2014: 6 Pages. Liu et al., “Hepatitis C NS3 Protease Inhibition by Peptidyl-a- FOREIGN PATENT DOCUMENTS Ketoamide Inhibitors: Kinetic Mechanism and Structure' Archives of Biochemistry and Biophysics, 421, (2004), pp. 207-216. W. 2 oE 8 A. 1239 Ontoria et al., “The Design and Enzyme-Bound Crystal Structure of WO 2004.072243 A2 8, 2004 Indoline Based Peptidomimetic Inhibitors of Hepatitis C Virus NS3 WO 2004094452 A2 11/2004 Protease” Journal of Med. Chem., 47. (2004), pp. 6443-6446. WO 2004103.996 A1 12/2004 Slater et al., "Pyrrolidine-5,5-Trans-Lactams, 4. Incorporation of al WO 2004.113365 A2 12/2004 P3/P4 Urea Leads to Potent Intracellular Inhibitors of Hepatitis C WO 2005O28501 A1 3, 2005 Virus NS3/4A Protease” Organic Letters, vol. 5, No. 24, (2003), pp. WO 2005037214 A2 4, 2005 4627-4630. WO 2005046712 A1 5, 2005 Venkatraman, et al., “Discovery of (1R,55)-N-3-Amino-1- WO 2005051410 A1 6, 2005 (cyclobutylmethyl)-2,3-dioxopropyl-32(S)-(1,1-dimethyl WO 2005054430 A2 6, 2005 lethyl)aminocarbonyl amino-3,3-dimethyl-1-oxobutyl-6,6- WO 2005070955 A1 8, 2005 dimethyl-3-azabicyclo[3.1.0 hexan-2(S)-carboxamide (SCH WO 2005073216 A1 8, 2005 50304), a Selective, Potent, Orally Bioavailable Hepatitis C Virus WO 2005090383 A2 9, 2005 NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treat WO 2005095.403 A2 10, 2005 ment of Hepatitis C Infection”. J. Med. Chem. 2006, 49: pp. 6074 WO 2006OO77OO A1 1, 2006 6086. WO 2006007708 A1 1, 2006 Written Opinion of the International Searching Authority for Inter WO 2006.033878 A1 3, 2006 national Application No. PCT/US2007/016018; International Filing WO 2006086.381 A2 8, 2006 Date: Jul. 13, 2007, Date of Mailing: Dec. 12, 2007, 8 Pages. WO 2006096652 A2 9, 2006 Written Opinion of the International Searching Authority for Inter WO 2005.007681 A2 1, 2007 national Patent Application No. PCT/US2014/028278; International WO 2007OO5838 A2 1, 2007 Filing Date: Mar. 14, 2014: Date of Mailing: Nov. 10, 2014;9 Pages. U.S. Patent Aug. 25, 2015 Sheet 1 of 4 US 9,115,175 B2 FIG. 1 U.S. Patent Aug. 25, 2015 Sheet 2 of 4 US 9,115,175 B2 ::: U.S. Patent Aug. 25, 2015 Sheet 3 of 4 US 9,115,175 B2 FIG. 3 -4 r------------ O 50 100 150 200 250 Temperature (C) U.S. Patent Aug. 25, 2015 Sheet 4 of 4 US 9,115,175 B2 F.G. 4 00 90 80 i 70 60 50 O 50 100 50 200 250 300 350 Temperature (C) US 9,115,175 B2 1. 2 PROCESSES FOR PRODUCING SOVAPREVIR FIG.3 is a graph of heat flow (Watts per gram, W/g) versus temperature (C.) showing the results of differential scanning CROSS REFERENCE TO RELATED calorimetry analysis of the Form F polymorph, Sample size APPLICATION 0.990 mg. Additional experimental details for the DSC analy 5 sis are provided in Example 9. This application claims priority from U.S. Provisional Application No. 61/784,182, filed Mar. 14, 2013, which is FIG. 4 is a graph of weight (percent) versus temperature ( hereby incorporated by reference in its entirety. C.) showing the results of thermogravimetric analysis of the Form F polymorph. The analysis was performed on a 3.4990 BACKGROUND mg sample. Analysis was performed using a TA Instruments 10 2950 thermogrametric analyzer. Data were collected by heat Sovaprevir is a hepatitis C virus NS3 protease inhibitor, ing under nitrogen at a rate of 10° C./min to a maximum effective for treating HCV infection in humans. temperature of 350° C. Sovaprevir can be prepared by the method presented in U.S. Pat. No. 7,906,619, Example 1. DETAILED DESCRIPTION 15 Starting materials for Sovaprevir production are prepared by methods known in the art. For example Compound A (tert-butyl ((1R)-1-(cyclopropylsulfonyl)carbamoyl)-2-vi nylcyclopropyl)carbamate) is prepared by the method dis cussed in WO 2006/122188, page 34, Scheme III and pages 77-78. This procedure is illustrated in Scheme I. Scheme 1 25 30 Coupling agent, Base He Sovaprevir O 35 D -Ni, SUMMARY The disclosure provides methods of preparing Sovaprevir. These methods are designated Methods 1 and 2 in the EXAMPLES section of the application. A number of the steps 40 in the methods are unique as are the overall methods for preparing Sovaprevir. The disclosure provides the steps occurring after the synthesis of Compound 13 in Synthetic Method 1 to form Sovaprevir. The disclosure also provides the addition of Compound F-1 to Compound E to form 45 Sovaprevir. The formation of the product in Scheme IX, Method 2. (Compound IX) is provided, as is the formation of Sovaprevir from the steps occurring after the formation of the Compound B ((S)-4-(tert-butoxy)-2-(tert-butyl)-4-oxobu Scheme IX product. tanoic acid) is prepared by the method discussed in Evans et. The disclosure also provides intermediates useful for pre 50 al. J. Org. Chem. 1999, 64, 6411-6417. The synthesis of paring Sovaprevir and close analogues of Sovaprevir. Particu Compound B is shown in Scheme II. larly the disclosure provides, as useful intermediates, at least Compounds 13, 14, 15, C, C-1, and D in Method 1, the compounds of Schemes IX, X, and XI, F, F-1 (the first com Scheme II pound of Scheme XIII in Method 2), and F-2. The disclosure provides a crystalline polymorph, Form F. 55 O The disclosure further provides a bioavailable amorphous form of Sovaprevir and a method for making the amorphous p-( form. NH Base BRIEF DESCRIPTION OF THE DRAWINGS 60 FIG.1. Amino acids residues P1", P1, P2, P2 Top, P3, and P4 as present in Sovaprevir.
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