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Nited States (12) Patent Application Publication (10) Pub US 2016O137584A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0137584A1 Oniciu et al. (43) Pub. Date: May 19, 2016 (54) PROCESSES AND INTERMEDIATES FOR PREPARING AW-DICARBOXYLIC III ACID-TERMINATED DALKANEETHERS O O (71) Applicant: Gemphire Therapeutics Inc., O Northville, MI (US) RO pi iii. ORI R2 R3 R3 R2 (72) Inventors: Carmen Daniela Oniciu, Toulouse (FR); Otto Joseph Geoffroy, Gainsville, FL (US) compounds of formula (V), (73) Assignee: Gemphire Therapeutics Inc. V (21) Appl. No.: 14/942,765 O O (22) Filed: Nov. 16, 2015 O HO pi iii. OH Related U.S. Application Data R2 R3 R3 R2 (60) Provisional application No. 62/079,894, filed on Nov. 14, 2014. and corresponding salts of formula (IV). Publication Classification (51) Int. C. IV C07C 67/31 (2006.01) O O C07C5L/09 (2006.01) (52) U.S. C. O CPC ................. C07C 67/31 (2013.01); C07C51/09 --~-- n--> (M), (2013.01) (57) ABSTRACT The compounds made by the methods and processes of the The present disclosure provides a process for the preparation invention are particularly useful for administration in humans of compounds of formula (III), and animals. US 2016/O 137584 A1 May 19, 2016 PROCESSES AND INTERMEDIATES FOR PREPARING AW-DICARBOXYLIC ACID-TERMINATED DALKANEETHERS O O O CROSS-REFERENCE TO RELATED RO pi iii. ORI APPLICATION R2 R3 R3 R2 0001. This application claims the benefit of U.S. Provi sional Application Ser. No. 62/079,894, filed Nov. 14, 2014, the disclosure of which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION 0002 C.Co-Dicarboxylic acid-terminated dialkane ethers have activity in lowering several plasma lipids, including Lp(a), triglycerides, VLDL-cholesterol, and LDL-choles terol, both in animals and in humans. See U.S. Pub. No. and corresponding salts of formula (IV): 2010/0256209. The compounds also are known to increase insulin sensitivity. See U.S. Pub. No. 2010/0256209. In par ticular, 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid) (also IV known as 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethyl hexanoic acid), whose USAN name is gemcabene, and its O O calcium salt (gemcabene calcium) have been intensively O studied in multiple clinical trials as a lipid lowering agent for --~- n--> (M), the treatment of patients with low high-density lipoprotein (HDL) and high low density lipoprotein (LDL). See Bays, H. E., et al., Amer. J. Cardiology, 2003, 92,538-543. Gemcabene wherein M' is an alkaline earth metal or alkali metal. has been clinically tested as an anti-hypertensive and anti 0007. The compounds made by the methods and processes of the invention are particularly useful for administration in diabetic agent in addition to the lipid lowering activity. humans and animals. 0003) A synthetic method for the preparation of 6,6'-oxy 0008. One aspect of the invention is a process for prepar bis(2,2-dimethyl-4-hexanoic acid) and other C.()-dicarboxy ing a compound of formula (III): lic acid-terminated dialkane ethers is described by Bisgaier, C. L. et al. in U.S. Pat. No. 5,648,387, which is incorporated herein by reference in its entirety. In addition, preparation and characterization of alcohol and water solvates of 6,6'-oxybis (2,2-dimethyl-4-hexanoic acid) calcium (gemcabene cal cium), for the treatment of dyslipidemia, Vascular disease, and diabetes are disclosed in U.S. Pat. No. 6,861,555, which is incorporated herein by reference in its entirety. Zhang. Yet al. also report a small scale synthesis of C-14- and tritiated wherein: gemcabene congeners in J Label Compa Radiopharm 2007. 0009 R is alkyl; 50, 602-604. 10010 R and Rare each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, 0004. The previously disclosed syntheses raise a number aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and of safety and environmental concerns when replicated on a 0011 in and mare each independently 0-4: scale larger than 1 kg. Thus, a need remains for safe and comprising: environmentally friendly processes for preparing C,c)-dicar 0012 (a) reacting a solution comprising a Substituted boxylic acid-terminated dialkane ethers on a large scale. acetic acid ester of formula (I): SUMMARY OF THE INVENTION 0005. These and other needs are met by the current disclo Sure, which provides general and industrially-scalable meth ods for the preparation of C.O)-dicarboxylic acid-terminated dialkane ethers and salts thereof. 0006. The present disclosure provides a process for the preparation of compounds of formula (III), US 2016/O 137584 A1 May 19, 2016 0013 with a deprotonating reagent to produce an inter mediate of formula (Ia): II 1\-h-N-6)-1N Ia M2 No 0024 wherein X is halo: R2 afor to produce a compound of formula (III). 0025. In other aspects, the compound of formula (III) is R3 hydrolyzed to produce a compound of formula (V). (0014 wherein M is Lior Zn; and 0015 (b) reacting the intermediate of formula (Ia) with a solution comprising a C.O)-halo-terminated dialkane ether of formula (II): O HO pi iii. OH II 1\-6)N-1'N-6-1N 0026. In some aspects, the compound of formula (V) is 0016 wherein X is a halogen; 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid). In other aspects, to produce a compound of formula (III). the salt of formula (IV) is the calcium salt of 6,6'-oxy-bis(2. 0017. A further aspect of the invention is the process for 2-dimethyl-4-hexanoic acid). preparing a compound of formula (III): 0027. In some aspects, the compound of formula (III) is a compound of formula (48). 48 O O R2No iii. O n----- R21 wherein: R22 R23 R22 R23 0018) R' is alkyl: 0019 RandR are eachindependently RandR are each 0028. In some aspects, the compound of formula (V) is a independently alkyl, cycloalkyl, cycloalkylalkyl, heterocy compound of formula (49). cloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and 49 0020 in and mare each independently 0-4: comprising: O O O 0021 (a) reacting a solution comprising an O-bromo HO iii. iii. OH acetic acid ester of formula (IX): R22 R23 R22 R23 IX O 0029. In some aspects, the salts of formula (IV) are salts of Br formula (50). ORI 50 O O 0022 with a metal, until the metal is essentially dis solved; - X^-n- On-n-rx's (M), 0023 (b) reacting the solution of step (a) with a solution R22 R23 R22 R23 comprising a C.O)-halo-terminated dialkane ether of for mula (II): US 2016/O 137584 A1 May 19, 2016 0030. A further aspect discloses a process for preparing a the compound of formula (50) is the calcium salt of 6,6'-oxy compound of formula (48): bis(2,2-dimethyl-4-hexanoic acid). 0042. In a further aspect, a compound of formula (48): 48 O O R N----- R21 R22 R23 R22 R23 R22 R23 wherein: 0031) R' is alkyl; 0043 wherein: 0032 R and R are each independently alkyl, 0044) R' is alkyl: cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy 0045 R’ and R are each independently alkyl, cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; cycloalkyl, cycloalkylalkyl, heterocycloalkyl, hetero and cycloalkylalkyl, arylalkyl, heteroaryl, or heteroaryla 0033 m is 0-4: lkyl; and comprising: 0046 m is 0-4: 0034 (a) reacting a first solution of a compound of 0047 comprising: formula (46): 0.048 (a) reacting a solution of a cyclic lactone of for mula (41): 46 O 41 HO R21 iii. O1 R22 R23 0035 with a halogen source to produce an intermediate of formula (47): 0049 with a deprotonating reagent to produce an inter mediate of formula (41a): 47 O X2 R21 41a. iii. O1 R22 R23 0036) wherein X* is F, Cl, or I and where R is alkyl: 0037 (b) reacting a second solution of the compound of formula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48). 0038. In some embodiments, step (a) is in the presence of 0050 wherein M is Lior Zn; triphenylphosphine. 0051 (b) reacting the intermediate of formula (41a) 0039. In one embodiment, the first compound of formula with a solution of an alkylhalide of formula (42): (46) and the second compound of formula (46) have identical R22X22 42 substituents R', R’ and R', and m is the same. In another embodiment, they are different. 0.052 wherein X* is halo: 0040. In other aspects, the compound of formula (48) is 0.053 to produce a compound of formula (43): hydrolyzed to produce a compound of formula (49). 43 O R22 O )m R22 R23 R22 R23 0.054 (c) reacting the solution of a compound of for 0041. In some aspects, the compound of formula (49) is mula (43) with a deprotonating reagent to produce an 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid). In other aspects, intermediate of formula (43a): US 2016/O 137584 A1 May 19, 2016 48 43a MNo O O R2 O R21 R22 O S. kn- N----- R22 R23 R22 R23 )m 0.063 (h) reacting the solution of a compound of for mula (48) with dilute acid to form (49). 0055 wherein M is Li or Zn; 0056 (d) reacting the intermediate of formula (43a) 49 with a solution of an alkylhalide of formula (44): O O R23X23 44 O HO iii. iii. OH 0057 wherein X* is halo: R22 R23 R22 R23 0.058 to produce a compound of formula (45): 0064. A further aspect is a process for preparing a com pound of formula (45): 45 O 45 O 23 O 23 O )m )m 0059 (e) reacting the solution of a compound of for wherein: mula (45) with potassium tert-butoxide to produce an 0065 R’ and R are each independently alkyl, intermediate of formula (46): cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and 0066 m is 0-4: 46 comprising: 0067 (a) reacting a solution of a cyclic lactone of for HO R21 mula (41): R22 R23 41 O 0060 (f) reacting the solution of a compound of for O mula (46) with a halogen source in the presence of triphenylphosphine to produce an intermediate of for mula (47): )m 0068 with a deprotonating reagent to produce an inter 47 mediate of formula (41a): 41a.
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