Processes for production of intermediates for 2-alkyl cephem compounds

Patent metadata

Field	Value
Publication number	US-9527866-B2
Application number	US-201314439113-A
Country	US
Kind code	B2
Filing date	Oct 29, 2013
Priority date	Oct 29, 2012
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

The invention relates to processes for the production of intermediates for preparing 2-alkyl cephem compounds useful as antimicrobial drugs. The invention provides a process which comprises oxidating a compound of the formula (I) or a salt thereof to give a compound of the formula (II) or a salt thereof wherein each symbol is as defined in the specification.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (XVI) or a salt thereof,

wherein,
R 5 is hydrogen;
Y is halogen;
L is lower alkylene or lower alkenylene;
P 1 is acyl, phthalimide, optionally substituted aralkanoyl, optionally substituted aralkyl, optionally substituted arylimino, optionally substituted lower alkylimino, or tri-lower alkylsilyl;
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups; and
the wavy line means that the bond is in cis or trans configuration, or a mixture thereof;
provided that -L-Y is not —CH 2 —O—C(═O)—CH 3 ,
which comprises:
reacting aldehyde, amino acid and a compound of formula (XV) or a salt thereof,

wherein, each symbol is as defined above,
to give the compound of the formula (XVI) or a salt thereof.

2. A process for preparing a compound of formula (II) or a salt thereof,

wherein,
R 5A is lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene;
P 1 is acyl, phthalimide, optionally substituted aralkanoyl, optionally substituted aralkyl, optionally substituted arylimino, optionally substituted lower alkylimino, or tri-lower alkylsilyl; and
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups,
which comprises:
reduction of a compound of formula (XVI)′ or a salt thereof,

wherein,
R 5 is hydrogen or lower alkyl; and
the wavy line means that the bond is in cis or trans configuration, or a mixture thereof,
provided that -L-Y is not —CH 2 —O—C(═O)—CH 3 ; and
the other symbols are as defined above,
to give the compound of the formula (II) or a salt thereof.

3. A process for preparing a compound of formula (III) or a salt thereof,

wherein,
R 5A is lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene;
P 1 is acyl, phthalimide, optionally substituted aralkanoyl, optionally substituted aralkyl, optionally substituted arylimino, optionally substituted lower alkylimino, or tri-lower alkylsilyl; and
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups,

which comprises:
reduction of a compound of formula (II) or a salt thereof,

wherein each symbol is as defined above,
to give the compound of the formula (III) or a salt thereof.

4. The process for preparing a compound of the formula (III) or a salt thereof according to claim 3 , wherein the compound of the formula (II) or a salt thereof is obtained by a process comprising:
reduction of a compound of formula (XVI)′ or a salt thereof,

wherein,
R 5 is hydrogen or lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene;
P 1 is acyl, phthalimide, optionally substituted aralkanoyl, optionally substituted aralkyl, optionally substituted arylimino, optionally substituted lower alkylimino, or tri-lower alkylsilyl;
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups; and
the wavy line means that the bond is in cis or trans configuration, or a mixture thereof, provided that -L-Y is not —CH 2 —O—C(═O)—CH 3 ,
to give the compound of the formula (II) or a salt thereof.

5. The process for preparing a compound of the formula (II) or a salt thereof according to claim 2 , from the compound of the formula (XVI)′:

wherein each symbol is as defined above,
or a salt thereof obtained by a process, which comprises:
reacting aldehyde, amino acid and a compound of formula (XV) or a salt thereof,

wherein, each symbol is as defined above,
to give the compound of the formula (XVI)′ or a salt thereof.

6. The process of claim 2 , wherein R 5A is methyl.

7. The process of claim 6 , wherein L is —CH 2 —.

8. The process of claim 7 , wherein P 1 is acyl.

9. The process of claim 7 , wherein P 2 is optionally substituted aralkyl.

10. A process for preparing a compound of formula (VII) or a salt thereof,

wherein,
R 5A is lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene; and
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups,
which comprises:
deprotection of the compound of the formula (III) or a salt thereof obtained by the process according to claim 3 , to give the compound of the formula (VII) or a salt thereof.

11. A compound of formula (II) or a salt thereof,

wherein
R 5A is lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene;
P 1 is acyl, phthalimide, optionally substituted aralkanoyl, optionally substituted aralkyl, optionally substituted arylimino, optionally substituted lower alkylimino, or tri-lower alkylsilyl; and
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups.

12. A compound of the formula (III) or a salt thereof,

wherein
R 5A is lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene;
P 1 is acyl, phthalimide, optionally substituted aralkanoyl, optionally substituted aralkyl, optionally substituted arylimino, optionally substituted lower alkylimino, or tri-lower alkylsilyl; and
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups.

13. A compound of the formula (VII) or a salt thereof,

wherein
R 5A is lower alkyl;
Y is halogen;
L is lower alkylene or lower alkenylene; and
P 2 is lower alkyl, alkylcarbonyloxymethyl in which the alkyl group is lower alkyl, optionally substituted aralkyl, or silyl groups.

14. A compound of the formula (XVI) or a salt thereof,

Assignees

• Shionogi & Co

Inventors

• Yokoo Katsuki
• Hisakawa Shinya
• Yamawaki Kenji
• Aoki Toshiaki
• Yokota Yutaka
• Takeo Masatoshi
• Asai Mikito

Classifications

• C07D501/16 Primary

  with a double bond between positions 2 and 3 · CPC title

• C07D501/18

  7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D501/59

  with hetero atoms directly attached in position 3 · CPC title

• C07D501/24 Primary

  with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3 · CPC title