US2010036130A1PendingUtilityA1
Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
Est. expiryDec 7, 2027(~1.4 yrs left)· nominal 20-yr term from priority
Inventors:David Andrew Siesel
C07D 317/60C07D 213/74C07D 213/73C07D 405/12
70
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Claims
Abstract
The present invention relates to a process of providing the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in substantially free form (Compound 1).
Claims
exact text as granted — not AI-modified1 - 70 . (canceled)
71 . A process for preparing a compound of formula 7a:
wherein,
A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;
R J is hydrogen or C 1-6 aliphatic;
m is an integer from 0 to 3 inclusive;
n is an integer from 1 to 4 inclusive; and
X is a halide or OH;
comprising the steps of
ic) reducing Compound 10a in a fourth organic solvent:
wherein,
A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
R 1 is independently selected from —R J , —OR J , —N(R J ) 2 , —NO 2 , halogen, —CN, —C 1-4 haloalkyl, —C 1-4 haloalkoxy, —C(O)N(R J ) 2 , —NR J C(O)R J , —SOR J , —SO 2 R J , —SO 2 N(R J ) 2 , —NR J SO 2 R J , —COR J , —CO 2 R J , —NR J SO 2 N(R J ) 2 , —COCOR J ;
R J is hydrogen or C 1-6 aliphatic;
R K is C 1-6 aliphatic; and
m is an integer from 0 to 3 inclusive,
with a reducing agent to produce Compound 11a:
wherein, ring A, R 1 , and m are as defined in Compound 10a above;
iic) reacting Compound 11a with a first halogenating agent in a fifth organic solvent to produce Compound 12a:
wherein, ring A, R 1 , and m are as defined in Compound 10a above, and Hal is a halide;
iiic) reacting Compound 12a with a cyanide to produce Compound 13a:
wherein, ring A, R 1 , and m are as defined in Compound 10a above;
ivc) reacting Compound 13a with a compound of formula 13aa in the presence of a third base:
wherein,
Hal is a halide; and
q is an integer from 0 to 3 inclusive; to produce a compound of formula 14a:
wherein,
r is an integer from 1 to 4 inclusive; and
ring A, R 1 , and m are as defined in Compound 10a above;
vc) sequentially reacting Compound 14a with a hydroxide base and second acid to form Compound 15a, which is compound 7a when X═OH:
wherein, r, ring A, R 1 , and m are as defined in Compound 14a above; and
vc) reacting Compound 15a with a second halogenating agent in a sixth organic solvent to form Compound 16a, which is compound 7a when X=halide:
wherein,
Hal is halide; and
r, ring A, R 1 , and m are as defined in Compound 14a above.
72 . The process of claim 71 , wherein the fourth organic solvent is an aprotic solvent.
73 . The process of claim 71 , wherein the fourth organic solvent is toluene.
74 . The process of claim 71 , wherein the reducing agent is a hydride.
75 . The process of claim 71 , wherein the reducing agent is sodium bis(2-methoxyethoxy)aluminum hydride.
76 . The process of claim 71 , wherein the reducing reaction is run at between 15° C. and 40° C.
77 . The process of claim 71 , wherein the fifth organic solvent is an aprotic solvent.
78 . The process of claim 71 , wherein the fifth organic solvent is methyl t-butyl ether.
79 . The process of claim 71 , wherein the first halogenating agent is thionyl chloride.
80 . The process of claim 71 , wherein the reaction of Compound 11a with a first halogenating reaction is run at between 15° C. and 30° C.
81 . The process of claim 71 , wherein the cyanide is sodium cyanide.
82 . The process of claim 71 , wherein the reaction of Compound 12a with a cyanide is run at between 30° C. and 40° C.
83 . The process of claim 71 , wherein the third base is an inorganic base.
84 . The process of claim 71 , wherein the third base is potassium hydroxide.
85 . The process of claim 71 , wherein Compound 13aa is 1-bromo-2-chloroethane.
86 . The process of claim 71 , wherein the reaction of Compound 13a with a compound of formula 13aa is run at between 50° C. and 90° C.
87 . The process of claim 71 , wherein the hydroxide base is sodium hydroxide.
88 . The process of claim 71 , wherein the second acid is an inorganic acid.
89 . The process of claim 71 , wherein the second acid is hydrochloric acid.
90 . The process of claim 71 , wherein the sequential reaction of Compound 14a with a hydroxide base and second acid is run at between 70° C. and 90° C.
91 . The process of claim 71 , wherein the sixth organic solvent is an aprotic solvent.
92 . The process of claim 71 , wherein the sixth organic solvent is toluene.
93 . The process of claim 71 , wherein the second halogenating agent is thionyl chloride.
94 . The process of claim 71 , wherein the reaction of Compound 15a with a second halogenating agent is run at between 40° C. and 80° C.
95 . (canceled)
96 . (canceled)
97 . The process of claim 71 , wherein R K is methyl.
98 - 106 . (canceled)Join the waitlist — get patent alerts
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