US2008167480A1PendingUtilityA1
Processes for preparing pyrroles
Est. expiryOct 28, 2023(expired)· nominal 20-yr term from priority
Inventors:Michael Wallace
C07D 207/416A61P 31/16C07D 207/34A61P 43/00
59
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Claims
Abstract
The present invention relates to an improved synthesis of pyrrole capping group precursors.
Claims
exact text as granted — not AI-modified1 . A process for preparing a compound of formula I-a:
comprising:
combining an aqueous solution of the compound of formula IV-a:
wherein R 3 is C 1-12 aliphatic, C 3-12 alkyl-cycloaliphatic, C 3-12 alkyl-aryl, C 3-12 alkyl-heteroaryl, or C 3-12 alkyl-cycloaliphatic;
with a compound of formula V-a
wherein R 1 and R 2 are each independently C 1-6 aliphatic;
in the presence of zinc, water, and optionally an additional suitable solvent to form a compound of formula VI
2 . A process for preparing a compound of formula VI-a:
comprising, combining an aqueous solution of compound of formula IV-a:
wherein R 3 is C 1-12 aliphatic, C 3-12 alkyl-cycloaliphatic, C 3-12 alkyl-aryl, C 3-12 alkyl-heteroaryl, or C 3-12 alkyl-cycloaliphatic;
with a compound of formula V-a
wherein R 1 and R 2 are each independently C 1-6 aliphatic in the presence of zinc and a suitable solvent to form the compound of formula VI.
3 . A process for preparing a compound of formula I-a:
comprising,
D) combining an aqueous solution of the compound of formula IV-a:
wherein R 3 is C 1-12 aliphatic, C 3-12 alkyl-cycloaliphatic, C 3-12 alkyl-aryl, C 3-12 alkyl-heteroaryl, or C 3-12 alkyl-cycloaliphatic;
with a compound of formula V-a
wherein R 1 and R 2 are each independently C 1-6 aliphatic;
in the presence of zinc and a solvent comprising of water and optionally another suitable solvent to form the compound of formula VI:
E) Acylating the compound of formula VI with a suitable acylating agent to form the compound of formula VII:
F) Hydrolyzing the compound of formula VII under suitable hydrolysis conditions to form the compound of formula I:
4 . The process according to any one of claims 1 - 2 further comprising reacting the compound of formula VI under suitable acylation conditions to provide a compound of formula IX
5 . The process according to claim 4 wherein the compound of formula VI is reacted with R 5 —X or R 5 C(═O)—O—C(═O)R 5 to form the compound of formula IX wherein
X is a suitable leaving group; R 5 is C 1-12 aliphatic, aryl, heteroaryl, C 1-12 aliphatic-cycloaliphatic, C 1-12 aliphatic-aryl, C 1-12 aliphatic-heteroaryl, or C 1-12 aliphatic-cycloaliphatic.
6 . The process according to claim 5 , wherein the acylation conditions comprise:
heating the compound with AlCl 3 and R 5 C(═O)—O—C(═O)R 5 to form the compound of formula IX.
7 . The process according to claim 6 , wherein the acylation conditions comprise:
heating the compound with AlCl 3 and Ac 2 O in refluxing dichloromethane to form the compound of formula IX wherein R 5 is methyl.
8 . The process according to claim 7 further comprising reacting the compound of formula IX under suitable hydrolysis conditions to provide a compound of formula I.
9 . The process according to claim 8 wherein the hydrolysis conditions comprise:
a suitable base, a suitable solvent, and a reaction temperature between 20-100° C.
10 . The process according to claim 9 wherein the base is M(OH) n , wherein M is a metal selected from lithium, sodium, potassium, cesium, magnesium, and calcium and n is 1-2.
11 . The process according to claim 10 wherein the solvent is an alcoholic solvent.
12 . The process according to claim 11 wherein the base is KOH, the solvent is EtOH, and the temperature is that of refluxing ethanol.
13 . The process according to any one of claims 1 - 12 wherein the compound of formula IV, the compound of formula V, and a suitable acid are reacted in water and a suitable volume of an organic solvent to keep the reaction mixture in solution.
14 . The process according to any one of claims 1 - 13 wherein the compound of formula IV, the compound of formula V, and acetic acid are reacted in a suitable volume of water and dioxane to maintain the internal temperature of the reaction between about 50° C. to about 80° C.
15 . The process according to any one of claims 1 - 14 wherein the compound of formula IV, the compound of formula V, water, dioxane, and acetic acid are stirred at about 50° C. to about 65° C.
16 . The process according to claim 15 wherein the reaction mixture is stirred at about 58° C. to about 60° C.
17 . The process according to any one of claims 1 - 16 further comprising the step of adding zinc.
18 . The process according to claim 17 further comprising stirring the mixture at about 75° C. to about 85° C.
19 . The process according to claim 18 wherein the mixture is stirred at about 80° C. to about 85° C.
20 . The process according to claim 19 wherein the mixture is stirred at about 80° C. to about 82° C.
21 . The process according to any one of claims 1 - 20 wherein the zinc is added portionwise.
22 . The process according to any one of claims 1 - 21 wherein each R 3 is independently C 1-6 alkyl.
23 . The process according to claim 22 wherein each R 3 is independently C 1-3 alkyl.
24 . The process according to claim 23 wherein each R 3 is independently methyl.
25 . The process according to any one of claims 1 - 24 wherein each R 2 and R 3 is independently methyl and R 1 is ethyl.
26 . The process according to any one of claims 1 - 21 , wherein R 5 is C 1-6 alkyl.
27 . The process according to claim 26 wherein R 5 is methyl.
28 . The process according to any one of claims 1 - 27 wherein each R 3 and R 5 is independently methyl.
29 . The process according to claim 28 wherein each R 2 , R 3 , and R 5 is independently methyl and R 1 is ethyl.Cited by (0)
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