US RE39,333 E1 · Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives

Abstract

This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low-temperature reactor. Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C. This invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid, a useful pharmaceutical intermediate, easily from a readily available, inexpensive starting material without using any extraordinary production equipment such as a very-low temperature reactor. Thus, this invention provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises permitting a lithium amide to act upon a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative at not below −20° C. Further, this invention also provides a process for producing a 5-hydroxy-3-oxopentanoic acid which comprises treating a mixture of an acetic acid ester and a 3-hydroxypropionic acid derivative with a Grignard reagent to prepare a mixture of a compound and an acetic acid ester of the above formula (I), and permitting a lithium amide to act upon the mixture at a temperature not below −20° C.

Claims20

Dependent claims

A process for producing a 5-hydroxy-3-oxopentanoic acid derivative of the following formula (IV):

wherein R1 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 1:2 carbon atoms;
and R2 represents any of hydrogen, an alky, group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxy group and an alkoxycarbonyl group,
which comprises permitting adding a lithium amide of the following formula (III):
wherein R4 and R5 may be the same or different and each represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms and a silyl group,
to act upon a mixture of an acetic acid ester of the following formula (I) and a 3-hydroxypropionic acid derivative of the following formula (II) at a temperature not below −20° C. to conduct reaction:
CH3CO2R1 (I)
wherein R1 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl croup of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms:
wherein R2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group;
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
and R2 and R3 may be joined to each other to form a ring, in the presence of a magnesium halide.

7 more elements

A process for producing a 5-hydroxy-3-oxopentanoic acid derivative of the following formula (IV):

wherein R1 represents any off an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
and R2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group,
which comprises treating a mixture of an acetic acid ester of the following formula (I) and a 3-hydroxypropionic acid derivative of the following formula (II):
CH3CO2R1 (I)
wherein R1 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms:
wherein R2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group;
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
and R2 and R3 may be joined to each other to form a ring,
with a Grignard reagent of the, following formula (V):
R6—Mg—X (V)
wherein R6 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
and X represents halogen,
to prepare a mixture of a compound off the following formula (VI) and an acetic acid ester of the above formula (I):
wherein R2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon t atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group;
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
R2 and R3 may be joined to each other to form a ring;
and X represents a halogen atom,
and permitting adding a lithium amide of the following formula (III):
wherein R4 and R5 may be the same or different and each represents any of an alkyl group of 1to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms and a silyl group
to act upon the mixture at a temperature not below −20° C. to conduct reaction.

17 more elements

A process for producing a 5-hydroxy-3-oxopentanoic acid derivative of the following formula (IV):

wherein R1 represent any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
and R2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group,
which comprises permitting adding a lithium amide of the following formula (III):
wherein R4 and R5 may be the same or different and each represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms and a silyl group,
to act upon a mixture of an acetic acid ester of the following formula (I) and a compound of the following formula (VI) at a temperature not below −20° C. to conduct reaction:
CH3CO2R1 (I)
wherein R1 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms:
wherein R2 represents any of hydrogen, an alkyl group of 1 to 12 carbon atoms which may (have a substituent, an alkenyl group of 2 to 12 carbon atoms which may have a substituent, an aryl group of 6 to 12 carbon atoms which may have a substituent, an aralkyl group of 7 to 12 carbon atoms which may have a substituent, a cyano group, a carboxyl group and an alkoxycarbonyl group;
R3 represents any of an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms and an aralkyl group of 7 to 12 carbon atoms;
R2 and R3 may be joined to each other to form a ring;
and X represents a halogen atom.

8 more elements

Dependencies are inferred from the claim text.

Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives

Life of this patent

Process for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives

Life of this patent

Abstract

Claims20