IP Library › Granted Patent US 39,333
Granted Patent E1
US 39,333 · App. 10/705,665 · Granted Oct 10, 2006

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

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Quick Facts
Patent No.
US 39,333
App. No.
10/705,665
Granted
Oct 10, 2006
Kind
E1
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.

Claims (64)

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

wherein R 1 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 R 2 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 R 4 and R 5 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:

CH 3 CO 2 R 1   (I)

wherein R 1 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 R 2 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; R 3 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 R 2 and R 3 may be joined to each other to form a ring, in the presence of a magnesium halide.

2. The process according to claim 1

wherein, referring to the lithium amide, R 4 and R 5 each represents an isopropyl group.

3. The process according to claim 1

wherein, referring to the acetic acid ester, R 1 represents a tert-butyl group.

4. The process according to claim 1 ,

wherein a magnesium halide is added in permitting the lithium amide to act.

5. The process according to claim 4 1

wherein magnesium chloride is used as the magnesium halide.

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

wherein R 1 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 R 2 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):

CH 3 CO 2 R 1   (I)

wherein R 1 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 R 2 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; R 3 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 R 2 and R 3 may be joined to each other to form a ring,

with a Grignard reagent of the, following formula (V):

R 6 —Mg—X  (V)

wherein R 6 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 R 2 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; R 3 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; R 2 and R 3 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 R 4 and R 5 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.

7. The process according to claim 6

wherein, referring to the lithium amide, R 4 and R 5 each is an isopropyl group.

8. The process aces riling to claim 6

wherein, referring to the acetic acid ester, R 1 represents a tert-butyl group.

9. The process according to claim 6 ,

wherein, referring to the Grignard reagent, R 6 represents a tert-butyl group and X represents a chlorine atom.

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

wherein R 1 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 R 2 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 R 4 and R 5 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:

CH 3 CO 2 R 1   (I)

wherein R 1 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 R 2 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; R 3 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; R 2 and R 3 may be joined to each other to form a ring; and X represents a halogen atom.

11. The process according to claim 10

wherein, referring to the lithium amide, R 4 and R 5 each represents an iso propyl group.

12. The process according to claim 10

wherein, referring to the acetic acid ester, R 1 represents a tert-butyl group.

13. The process according to claim 10 ,

wherein, referring to the compound (VI), X represents a chlorine atom.

14. The process according to claim 1

wherein R 3 is a methyl group or an ethyl group.

15. The process according to claim 1

wherein R 2 is a chloromethyl group, a cyanomethyl group or a benzyloxymethyl group.

16. The process according to claim 1

wherein R 2 and R 3 are joined to each other to form a methylene group.

17. The process according to claim 1

wherein the compound (II) or (VI) , the 3 - hydroxypropionic acid derivative of the formula ( II ) or the 5 - hydroxy - 3 - oxopentanoic acid derivative of the formula ( IV ) is optically active.

18. The process according to claim 2

wherein, referring to the acetic acid ester of the formula ( I ), R 1 represents a tert-butyl group.

19. The process according to claim 2

wherein a magnesium halide is added in permitting the lithium amide to act.

20. The process according to claim 3

wherein a magnesium halide is added in permitting the lithium amide to act.

Assignments (1)
CHANGE OF ADDRESS Recorded Jan 15, 2014
From: KANEKA CORPORATION
To: KANEKA CORPORATION
Reel/Frame 032019/0901 →