US2013131356A1PendingUtilityA1
Preparation of protected alpha-keto beta-amino esters and amides
Est. expiryJul 3, 2028(~1.9 yrs left)· nominal 20-yr term from priority
Inventors:William A. NugentAdam LookerRaymond E. ForslundTheodore A. MartinotCristian HarrisonSheree Ibrahim
A61P 31/14A61P 7/04C07D 339/06A61P 25/28A61K 31/385
47
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Claims
Abstract
The invention provides β-sulfonamide α-keto esters and amides in which the α-keto is protected as a 1,3-dithiolane derivative. Also provided are methods for preparing such esters and amides and for incorporating them into peptides.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for preparing a β-sulfonamide α-keto ester of Formula (S,S s )-I or (R,R s )-I:
wherein:
each of R 1 and R 3 independently is alkyl or aryl; and
R 2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom, comprising the step of:
mixing a sulfinimine of Formula (S s )-II or (R s )-II:
with a dithiolane carboxylate ester of Formula III:
in the presence of a base of sufficient strength to deprotonate the dithiolane hydrogen of Formula III, wherein R 1 and R 2 in Formula II and R 3 in Formula III are as defined above, to give a β-sulfonamide α-keto ester of Formula (S,S s )-I or (R,R s )-I.
2 . The method of claim 1 , wherein at least 95% of the β-sulfonamide α-keto ester is a single (R,R s ) or (S,S s ) enantiomer.
3 . The method of claim 2 , wherein the at least 99% of the β-sulfonamide α-keto ester is a single (R,R s ) or (S,S s ) enantiomer.
4 . The method of claim 1 , wherein the reaction between compounds of Formula II and Formula III is carried out in a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, dioxane, and mixtures thereof.
5 . The method of claim 1 , wherein the reaction between compounds of Formula II and Formula III is in the presence of a base containing lithium, potassium, or sodium.
6 . The method of claim 5 , wherein the base is lithium hexamethyldisilamide, hexynyllithium, lithium diisoproplyamide, sodium hexamethyldisilamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, sodium bis(trimethylsilyl)amide, potassium hexamethyldisilamide, potassium tert-butoxide, potassium hydride, or potassium tert-amyloxide.
7 . The method of claim 5 , wherein the base is lithium diisoproplyamide, hexynyl lithium, sodium bis(trimethylsilyl)amide, or lithium bis(trimethylsilyl)amide.
8 . The method of claim 1 , wherein R 1 is optionally substituted phenyl.
9 . The method of claim 8 , wherein R 1 is methylphenyl.
10 . The method of claim 9 , wherein R 1 is p-methylphenyl.
11 . The method of claim 1 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.
12 . The method of claim 1 , wherein R 2 is alkyl, (cycloalkyl)alkyl, or aryl.
13 . The method of claim 12 , wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, (cyclopropyl)methyl, or naphthyl.
14 . The method of claim 1 , wherein R 3 is alkyl.
15 . The method of claim 14 , wherein R 3 is methyl, ethyl, propyl, isopropyl, or tert-butyl.
16 . The method of claim 1 , wherein each of R 1 and R 3 independently is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl; and R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, (cyclopropyl)methyl, or naphthyl.
17 . A method for preparing a β-sulfinamide α-keto amide of Formula (S,S s )-IV or (R,R s )-IV:
wherein:
R 1 is alkyl or aryl;
R 2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom; and
R 4 is hydrogen, alkyl, cycloalkyl, or aryl;
Comprising the step of:
mixing the compound of Formula (S,S s )-I or (R,R s )-I:
with an amine of the formula R 4 NH 2 to give a product of Formula (S,S s )-IV or (R,R s )-IV,
wherein R 1 , R 2 , and R 4 are as defined above, and R 3 in the compound of Formula (S,S s )-I or (R,R s )-I is alkyl or aryl.
18 . The method of claim 17 , wherein at least 95% of the product is a single (R,R s ) or (S,S s ) enantiomer.
19 . The method of claim 18 , wherein the at least 99% of the product is a single (R,R s ) or (S,S s )enantiomer.
20 . The method of claim 19 , wherein the reaction between the compound of Formula (I) and the amine is in an alcohol.
21 . The method of claim 20 , wherein the alcohol is ethanol or methanol.
22 . The method of claim 19 , wherein R 1 is optionally substituted phenyl.
23 . The method of claim 22 , wherein R 1 is methylphenyl.
24 . The method of claim 23 , wherein R 1 is p-methylphenyl.
25 . The method of claim 19 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.
26 . The method of claim 19 , wherein R 2 is alkyl, (cycloalkyl)alkyl, or aryl.
27 . The method of claim 26 , wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, (cyclopropyl)methyl, or naphthyl.
28 . The method of claim 19 , wherein R 4 is alkyl or cycloalkyl.
29 . The method of claim 28 , wherein R 4 is methyl, ethyl, or cyclopropyl.
30 . A method for preparing a β-sulfonamide α-keto amide of Formula (S,S s )-IV or (R,R s )-IV:
wherein:
R 1 is alkyl or aryl;
R 2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom; and
R 4 is hydrogen, alkyl, cycloalkyl, or aryl;
Comprising the steps of:
a) mixing the compound of Formula (S,S s )-I or (R,R s )-I:
wherein R 3 is alkyl or aryl, with an aqueous base solution optionally in the presence of a co-solvent;
b) neutralizing the solution to provide a carboxylic acid of Formula (S,S s )-V or (R,R s )-V:
and
c) mixing the carboxylic acid of Formula (S,S s )-V or (R,R s )-V with an amine R 4 NH 2 , wherein R 4 is as defined above, to provide a product of Formula (S,S s )-IV or (R,R s )-IV.
31 . The method of claim 30 , wherein at least 95% of the product is a single (S,S s ) or (R,R s ) enantiomer.
32 . The method of claim 31 , wherein at least 99% of the product is a single (S,S s ) or (R,R s ) enantiomer.
33 . A method for preparing a β-sulfonamide α-keto amide of Formula (S,S s )-IV or (R,R s )-IV,
wherein:
R 1 is alkyl or aryl;
R 2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom; and
R 4 is hydrogen, alkyl, cycloalkyl, or aryl;
comprising the steps of:
a) mixing a sulfinimine of Formula (S s )-II or (R s )-II:
with a dithiolane carboxylate ester of Formula III:
in the presence of a base of sufficient strength to deprotonate the dithiolane hydrogen of Formula III, wherein R 1 and R 2 in Formula II and R 3 in Formula III are as defined above, to give a β-sulfonamide α-keto ester of Formula (S,S s )-I or (R,R s )-I:
and
b) mixing the compound of Formula (S,S s )-I or (R,R s )-I with an amine of the formula R 4 NH 2 to give a product of Formula (S,S s )-IV or (R,R s )-IV:
wherein R 1 , R 2 , and R 4 are as defined above, and R 3 in the compound of Formula (S,S s )-I or (R,R s )-I is alkyl or aryl; or
mixing the compound of Formula (S,S s )-I or (R,R s )-I with an aqueous base solution optionally in the presence of a co-solvent; neutralizing the solution to provide a carboxylic acid of Formula (S,S s )-V or (R,R s )-V; and mixing
the carboxylic acid of Formula (S,S s )-V or (R,R s )-V with an amine R 4 NH 2 , wherein R 4 is as defined above, to provide a product of Formula (S,S s )-IV or (R,R s )-IV.
34 . A process for coupling an amide of Formula (S,S s )-IV or (R,R s )-IV to a peptide containing a carboxylic acid terminus (HOOC-Pep.)
wherein:
the α-keto group is protected as a 1,3-dithiolane derivative;
R 1 is alkyl or aryl;
R 2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom; and
R 4 is hydrogen, alkyl, cycloalkyl, or aryl,
Comprising the steps of:
a) mixing a solution of the amide (S,S s )-IV or (R,R s )-IV with a mineral acid to provide a compound of Formula (S)-VI or (R)-VI:
wherein R 1 is as defined above;
b) mixing the compound of Formula (S)-VI or (R)-VI with the carboxylic acid terminus of the peptide optionally in the presence of a coupling agent to give a compound of Formula (S)-VII or (R)-VII:
and
c) removing the 1,3-dithiolane protecting group in the compound of Formula (S)-VII or (R)-VII in the presence of an oxidant to provide a peptide of Formula (S)-VIII or (R)-VIII:
containing a β-amino α-keto amide functionality.
35 . The method of claim 34 , wherein the β-sulfonamide α-keto amide of Formula (S,S s )-IV or (R,R s )-IV is prepared by a method comprising the steps of:
a) mixing a sulfinimine of Formula (S s )-II or (R s )-II:
with a dithiolane carboxylate ester of Formula III:
in the presence of a base of sufficient strength to deprotonate the dithiolane hydrogen of Formula III, wherein R 1 and R 2 in Formula II and R 3 in Formula III are as defined above, to give a β-sulfonamide α-keto ester of Formula (S,S s )-I or (R,R s )-I:
and
b) mixing the β-sulfonamide α-keto ester of Formula (S,S s )-I or (R,R s )-I with an amine of the formula R 4 NH 2 , wherein R 4 is as defined above, to give a product of Formula (S,S s )-IV or (R,R s )-IV; or
mixing the β-sulfonamide α-keto ester of Formula (S,S s )-I or (R,R s )-I with an aqueous base solution optionally in the presence of a co-solvent; neutralizing the solution to provide a carboxylic acid of Formula (S,S s )-V or (R,R s )-V:
and mixing the carboxylic acid of Formula (S,S s )-V or (R,R s )-V with an amine R 4 NH 2 to provide a product of Formula (S,S s )-IV or (R,R s )-IV.
36 . A compound of Formula I, Formula IV, or Formula VI:
wherein:
each of R 1 and R 3 independently is alkyl or aryl;
R 2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl; and
R 4 is hydrogen, alkyl, cycloalkyl, or aryl.
37 . The compound of claim 36 , wherein R 1 is optionally substituted phenyl.
38 . The compound of claim 37 , wherein R 1 is methylphenyl.
39 . The compound of claim 38 , wherein R 1 is p-methylphenyl.
40 . The compound of claim 36 , wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.
41 . The compound of claim 40 , wherein R 2 is alkyl, (cycloalkyl)alkyl, or aryl.
42 . The compound of claim 41 , wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, (cyclopropyl)methyl, or naphthyl.
43 . The compound of claim 36 , wherein R 3 is alkyl.
44 . The compound of claim 43 , wherein R 3 is methyl, ethyl, propyl, isopropyl, tert-butyl.
45 . The compound of claim 36 , wherein R 4 is alkyl or cycloalkyl.
46 . The compound of claim 45 , wherein R 4 is methyl, ethyl, or cyclopropyl.
47 . The compound of claim 36 , wherein the compound is
48 . The compound of claim 36 , wherein the compound isJoin the waitlist — get patent alerts
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