PROCESSES AND INTERMEDIATES FOR PREPARING alpha,omega-DICARBOXYLIC ACID-TERMINATED DIALKANE ETHERS
The present disclosure provides a process for the preparation of compounds of formula (III), compounds of formula (V), and corresponding salts of formula (IV). The compounds made by the methods and processes of the invention are particularly useful for administration in humans and animals.
1 .- 24 . (canceled)
25 . A process for making a compound of formula (48):
wherein:
R 21 is alkyl;
each R 22 and R 23 is independently alkyl; and
each m is independently 0, 1, 2, 3, or 4;
comprising:
(a) allowing a compound of formula (46):
to react with a Br, Cl, or I source to provide a compound of formula (47):
wherein X 24 is Br, Cl, or I; and
(b) allowing a compound of formula (46) to react with the compound of formula (47) in the presence of base to provide the compound of formula (48).
26 . The process of claim 25 , further comprising allowing a compound of formula (45):
to react with potassium tert-butoxide to provide a compound of formula (46) wherein R 21 is tert-butyl.
27 . The process of claim 26 , further comprising allowing a compound of formula (43a):
wherein M 23 is Li or Zn;
to react with an alkyl halide of formula (44):
R 23 —X 23 44
wherein X 23 is Br, Cl, or I;
to provide the compound of formula (45).
28 . The process of claim 27 , further comprising allowing a compound of formula (43):
to react with a lithium or zinc deprotonating reagent to provide the compound of formula (43a).
29 . The process of claim 28 , further comprising allowing a compound of formula (41a):
wherein M 22 is Li or Zn;
to react with an alkyl halide of formula (42):
R 22 —X 22 42
wherein X 22 is Br, Cl, or I;
to provide the compound of formula (43).
30 . The process of claim 29 , further comprising allowing a compound of formula (41):
to react with a lithium or zinc deprotonating reagent to provide the compound of formula (41a).
31 . A process for making a compound of formula (49)
comprising:
(a) performing the process of claim 25 ;
(b) hydrolyzing the compound of formula (48) in the presence of an alkali metal salt, alkali metal base, alkali metal oxide, alkaline earth metal salt, alkaline earth metal base or alkaline earth metal oxide; and
(c) acidifying the product of step (b) to provide the compound of formula (49).
32 . A process for making a compound of formula (49)
comprising:
(a) performing the process of claim 25 where R 21 is tert-butyl and
(b) allowing the compound of formula (48) to react with trifluoroacetic acid to provide the compound of formula (49).
33 . The process of claim 31 or 32 , wherein the compound of formula (49) is
34 . A process for making a compound of formula (50):
wherein M 1 is Ca 2+ and x is 1;
comprising:
(a) performing the process of claim 31 ; and
(b) allowing the compound of formula (49) to react with CaO or Ca(OH) 2 to provide the compound of formula (50).
35 . A process for making a compound of formula (50):
wherein M 1 is Ca 2+ and x is 1;
comprising:
(a) performing the process of claim 32 ; and
(b) allowing the compound of formula (49) to react with CaO or Ca(OH) 2 to provide the compound of formula (50).
36 . The process of claim 34 , wherein each R 22 is methyl, each R 23 is methyl and each m is 1.
37 . The process of claim 35 , wherein each R 22 is methyl, each R 23 is methyl and each m is 1.
38 . The process of claim 36 , wherein the compound of formula (49) reacts with CaO or Ca(OH) 2 in absolute ethanol at reflux and provides compound (4)
as an ethanolic mixture.
39 . The process of claim 37 , wherein the compound of formula (49) reacts with CaO Ca(OH) 2 in absolute ethanol at reflux and provides compound (4)
as an ethanolic mixture.
40 . The process of claim 38 , further comprising:
allowing the ethanolic mixture to cool to room temperature;
diluting the ethanolic mixture with methyl t-butyl ether;
allowing compound (4) to precipitate from the ethanolic mixture; and
filtering compound (4) from the ethanolic mixture to provide a filtered compound (4).
41 . The process of claim 39 , further comprising:
allowing the ethanolic mixture to cool to room temperature;
diluting the ethanolic mixture with methyl t-butyl ether;
allowing compound (4) to precipitate from the ethanolic mixture; and
filtering compound (4) from the ethanolic mixture to provide a filtered compound (4).
42 . A process for making a hydrate of compound (4), comprising:
performing the process of claim 40 ;
drying the filtered compound (4); and
hydrating the filtered compound (4) to provide the hydrate of compound (4).
43 . A process for making a hydrate of compound (4), comprising:
performing the process of claim 41 ;
drying the filtered compound (4); and
hydrating the filtered compound (4) to provide the hydrate of compound (4).
44 . The process of claim 42 , wherein the hydrating is performed at 100° C.
45 . The process of claim 43 , wherein the hydrating is performed at 100° C.
46 . A process for making a compound of formula (50):
wherein M 1 is an alkaline earth metal and x is 1 or M 1 is an alkali metal and x is 2;
comprising:
(a) performing the process of claim 25 ; and
(b) hydrolyzing the compound of formula (48) in the presence of
(i) an alkaline earth metal salt, alkaline earth metal base or alkaline earth metal oxide to provide the compound of formula (50), wherein M 1 is an alkaline earth metal and x is 1, or
(ii) an alkali metal salt, alkali metal base or alkali metal oxide to provide the compound of formula (50), wherein M 1 is an alkali metal and x is 2.
47 . The process of claim 46 , wherein M 1 is Ca 2+ and x is 1, or M 1 is K + and x is 2; and
comprising hydrolyzing the compound of formula (48) in the presence of
(a) potassium hydroxide to provide the compound of formula (50) wherein M 1 is K + and x is 2, or
(b) calcium hydroxide or calcium oxide to provide the compound of formula (50) wherein M 1 is Ca 2+ and x is 1.
48 . A process for making a compound of formula (49):
wherein:
each R 22 and R 23 is independently alkyl; and
each m is independently 0, 1, 2, 3, or 4;
comprising:
(a) allowing a compound of formula (41):
to react with a lithium or zinc deprotonating reagent to provide a compound of formula (41a):
wherein M 22 is Li or Zn;
(b) reacting the compound of formula (41a) with an alkyl halide of formula (42):
R 22 —X 22 42
wherein X 22 is Br, Cl, or I;
to provide a compound of formula (43):
(c) allowing the compound of formula (43) to react with a lithium or zinc deprotonating reagent to provide a compound of formula (43a):
wherein M 23 is Li or Zn;
(d) allowing the compound of formula (43a) to react with an alkyl halide of formula (44):
R 23 —X 23 44
wherein X 23 is Br, Cl, or I;
to provide a compound of formula (45):
(e) allowing the compound of formula (45) to react with potassium tert-butoxide to provide a compound of formula (46):
where R 21 is tert-butyl;
(f) allowing the compound of formula (46) to react with a Br, Cl, or I source to provide a compound of formula (47):
wherein X 24 is Br, Cl, or I;
(g) allowing the compound of formula (46) to react with the compound of formula (47) in the presence of base to provide a compound of formula (48):
(h) allowing the compound of formula (48) to react with trifluoroacetic acid to provide the compound of formula (49)
49 . The process of claim 48 , wherein the compound of formula (49) is:
50 . A process for making a compound of formula (50):
wherein M 1 is an alkaline earth metal and x is 1 or M 1 is an alkali metal and x is 2;
comprising:
(a) performing the process of claim 31 ;
(b) allowing the compound of formula (49) to react with an aqueous solution of hydroxide or oxide of an alkali metal or earth alkaline metal in water-miscible solvent; and
(c) precipitating the compound of formula (50).
51 . A process for making a compound of formula (50):
wherein M 1 is an alkaline earth metal and x is 1 or M 1 is an alkali metal and x is 2;
comprising:
(a) performing the process of claim 32 ;
(b) allowing the compound of formula (49) to react with an aqueous solution of hydroxide or oxide of an alkali metal or earth alkaline metal in water-miscible solvent; and
(c) precipitating the compound of formula (50).
52 . A process for making a compound of formula (45):
wherein:
R 22 and R 23 are each independently alkyl; and
m is 0, 1, 2, 3, or 4;
comprising:
(a) allowing a compound of formula (41):
to react with a lithium or zinc deprotonating reagent to produce a compound of formula (41a):
wherein M 22 is Li or Zn;
(b) reacting the compound of formula (41a) with an alkyl halide of formula (42):
R 22 —X 22 42
wherein X 22 is Br, Cl, or I;
to provide a compound of formula (43):
(c) allowing the compound of formula (43) to react with a lithium or zinc deprotonating reagent to provide a compound of formula (43a):
wherein M 23 is Li or Zn; and
(d) allowing the compound of formula (43a) with an alkyl halide of formula (44):
R 23 —X 23 44
wherein X 23 is Br, Cl, or I;
to provide the compound of formula (45).
53 . A process for making a compound of formula (IV):
wherein:
M 1 is an alkaline earth metal and x is 1 or M 1 is an alkali metal and x is 2;
each R 2 and R 3 is independently alkyl; and
n and m are independently 0, 1, 2, 3, or 4;
comprising:
allowing a compound of formula (III)
wherein each R 1 is independently alkyl,
to react with an aqueous solution of an alkali metal hydroxide, alkali metal oxide, alkaline earth metal hydroxide or alkaline earth metal oxide in a water-miscible solvent to provide the compound of formula (IV).
54 . The process of claim 53 , further comprising precipitating the compound of formula (IV) from an organic solvent.
55 . The process of claim 53 , wherein the water-miscible solvent is DMF, DMSO, acetone, methanol, isopropyl alcohol, or ethanol.
56 . The process of claim 53 , wherein the water miscible solvent is DMSO.
57 . The process of claim 53 , wherein:
each R 2 and R 3 is methyl;
m and n are 1;
M 1 is Ca 2+ ; and
x is 1.
58 . A process for making compound (4)
comprising
allowing a compound of formula (III)
wherein each R 1 is independently alkyl and each R 2 and R 3 is methyl,
to react with an aqueous solution of CaO or Ca(OH) 2 in water-miscible solvent to provide compound (4).
59 . The process of claim 25 , further comprising debenzylating tert-butyl 6-benzyloxy-2,2-dimethylhexanoate to provide the compound of formula (46)
wherein
R 21 is tert-butyl,
each R 22 and R 23 is independently methyl, and
m is 1.
60 . The process of claim 59 , wherein the debenzylating is performed in the presence of palladium on carbon.
61 . The process of claim 59 , further comprising allowing tert-butyl isobutyrate to react with benzyl 4-bromobutyl ether in the presence of base to provide the tert-butyl 6-benzyloxy-2,2-dimethylhexanoate.
62 . The process of claim 59 , further comprising allowing 6-benzyloxy-2,2-dimethylhexanoic acid to react with tert-butyl-dicyclohexyl isourea to provide the tert-butyl 6-benzyloxy-2,2-dimethylhexanoate.
63 . The process of claim 62 , further comprising allowing ethyl 6-benzyloxy-2,2-dimethylhexanoate to hydrolyze in the presence of base to provide 6-benzyloxy-2,2-dimethylhexanoic acid.