Synthesis of enantiomerically enriched 4-piperidinylglycine

Details Synthesis of enantiomerically enriched 4-piperidinylglycine Synthesis of enantiomerically enriched 4-piperidinylglycine

2002-03-04

2003-12-30

Desai, Rita (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S246000, C546S248000

Reexamination Certificate

active

06670477

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides a process for making enantiomerically enriched 4-piperidinylglycine.
BACKGROUND OF THE INVENTION
4-Piperidinylglycine is an important amino acid which has been used in synthesizing pharmaceutical ingredients such as matrix metalloproteinase inhibitor and thrombin inhibitor. While racemic piperidinylglycine has been synthesized by hydrogenation of an enamide substrate, enantiomerically enriched piperdinylglycine is much more difficult to synthesize.
U.S. Pat. No. 5,817,822 describes an enantioselective synthesis of (R)-N-t-Boc-4-piperidinylglycine using optically active (R)-4-benzyl-2-oxazolidinone as a chiral auxiliary. (R)-N-t-Boc-4-piperidinylglycine is prepared by an 8-step synthetic sequence utilizing R-(+)-4-benzyl-2-oxazolidinone as a chiral auxiliary and trisyl azide as an electrophile. This method works well for the preparation of small quantities of 4-piperidinylglycine for drug discovery activities, however, for scale up synthesis, this method is economically unsatisfactory due to the many steps involved, and potentially unsafe due to the handling of 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide), which is thermally unstable.
Chiral rhodium catalysts have been used in asymmetric synthesis of heterocyclic amino acids as described by Burk, M. J.; Gross, M. F.; Martinez, J. P. in
J. Am. Chem. Soc.,
117, 9375-9376 (1995); Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. in
Organic Letters,
2, 3421-3423 (2000); Tiffin, P. D.; Jones, S. W.; Palmer, C. F.; Paul, J. M. in
Tetra. Lett.,
40, 1211-1214 (1999).
Therefore, it is desirable to develop a more direct synthesis for 4-piperidinylglycine which does not involve using 2,4,6-triisopropylbenzenesulfonyl azide.
SUMMARY OF THE INVENTION
The invention provides a process for making enantiomerically enriched 4-piperidinylglycine having the formula (I)
said process comprising
(a) combining N-protected glycine ester having the formula (II)
 with 4-piperidone having the formula (III)
 whereby didehydroamino acid ester is formed having the formula (IV);
(b) reducing the didehydroamino acid ester (IV) with hydrogen gas in the presence of a catalyst selected from the group consisting of (R,R)-BPE-Rh having the formula (A1), (S,S)-BPE-Rh having the formula (A2), (R,R)-Me-DuPHOS-Rh having the formula (B1), (S,S)-Me-DuPHOS-Rh having the formula (B2), and combinations thereof;
 whereby a protected chiral compound is formed having the formula (V);
(c) removing the protecting groups of formula (V), whereby the 4-piperidinylglycine having the formula (I) is formed;
wherein R
1
is selected from the group consisting of hydrogen and PO(OM)
2
, wherein M is a phenyl or C
1
-C
8
linear, branched or cyclic alkyl group; R
2
is selected from the group consisting of hydrogen, phenyl and a C
1
-C
8
linear, branched or cyclic alkyl group; R
3
and R
4
are independently selected from the group consisting of hydrogen, phenyl, a C
1
-C
8
linear, branched or cyclic alkyl group, and OR
6
, wherein R
6
is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C
1
-C
8
linear, branched or cyclic alkyl group; R
5
is independently selected from the group consisting of a C
1
-C
8
linear, branched or cyclic alkyl group, a C
1
-C
8
linear, branched or cyclic fluoroalkyl group, and combinations thereof; diene is a counter ligand independently selected from the group consisting of cyclooctadiene (COD) and norbornadiene (NBD); A
−
is an anion wherein A is independently selected from the group consisting of trifluoromethanesulfonate (OTf), tetrafluoroborate (BF
4
), hexafluoroantimonate (SbF
6
) and hexafluorophosphate (PF
6
); X
−
is an anion wherein X is independently a halogen; and “*” designates an asymmetric carbon having (R)- or (S)-configuration.
The process of the invention yields an enantiomerically enriched 4-piperidineglycine in excellent yield. As used herein, “enantiomerically enriched” 4-piperidinylglycine means at least 60% enantiomeric excess, preferably at least 80% entantiomeric excess, most preferably at least 98% enantiomeric excess, of 4-piperidinylglycine.
DESCRIPTION OF THE INVENTION
The process of the invention is used to prepare 4-piperidinylglycine having the formula (I)
wherein X
−
is an anion wherein X is independently a halogen; and “*” designates an asymmetric carbon having (R)- or (S)-configuration. Preferably the halogen is chlorine. The process involves at least three steps. In the first step, Step (a), N-protected glycine ester having the formula (II)
 is combined with 4-piperidone having the formula (III)
 to form didehydroamino acid ester having the formula (IV);
wherein R
1
is selected from the group consisting of hydrogen and PO(OM)
2
, wherein M is a phenyl or C
1
-C
8
linear, branched or cyclic alkyl group. Preferably, R
1
is PO(OCH
3
)
2
. R
2
is selected from the group consisting of hydrogen, phenyl and a C
1
-C
8
linear, branched or cyclic alkyl group. Preferably R
2
is methyl. R
3
and R
4
are independently selected from the group consisting of hydrogen, phenyl, a C
1
-C
8
linear, branched or cyclic alkyl group, and OR
6
, wherein R
6
is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C
1
-C
8
linear, branched or cyclic alkyl group. Preferably, R
3
is OCH
2
Ph. Preferably, R
4
is OC(CH
3
)
3
. X
−
is an anion wherein X is independently a halogen; and “*” designates an asymmetric carbon having (R)- or (S)-configuration.
In the second step, Step (b), the didehydroamino acid ester (IV) is reduced with hydrogen gas. The reduction takes place in the presence of a rhodium catalyst. The selection of rhodium catalyst is critical to the enantioselective process of the invention. The rhodium catalyst may be present as (R,R) or (S,S) which is used to prepare either the enantiomerically enriched (R)-4-piperdinylglycine or (S)-4-piperdinylglycine, respectively. The rhodium catalyst is selected from the group consisting of (R,R)-BPE-Rh having the formula (A1), (S,S)-BPE-Rh having the formula (A2), (R,R)-DuPHOS-Rh having the formula (B 1), (S,S)-DuPHOS-Rh having the formula (B2), wherein R
5
is independently selected from the group consisting of a C
1
-C
8
linear, branched or cyclic alkyl group, a C
1
-C
8
linear, branched or cyclic fluoroalkyl group, and combinations thereof, diene is a counter ligand independently selected from the group consisting of cyclooctadiene (COD) and norbornadiene (NBD). A
−
is an anion wherein A is independently selected from the group consisting of trifluoromethanesulfonate (OTf), tetrafluoroborate (BF
4
), hexafluoroantimonate (SbF
6
) and hexafluorophosphate (PF
6
). The rhodium catalysts' [(Me-BPE)-Rh-(COD)]OTf and [(Me-DuPHOS)-Rh-(COD)]OTf are commercially available from Strem Chemicals Inc. A combination of catalysts may also be used.
Preferably, the rhodium catalyst is selected from [((R,R)-Me-BPE-Rh-(COD)]OTf, [((S,S)-Me-BPE-Rh-(COD)]OTf, [((R,R)-Me-DuPHOS-Rh-(COD)]OTf, or [((S,S)-Me-DuPHOS-Rh-(COD)]OTf having the respective formulas T1, T2, T3, T4,
The reduction in Step (b) is preferably conducted at a temperature of from about 0° C. to about 60°, more preferably, 20° C. to 28° C.; and under gaseous hydrogen pressure of from about 1 atm to about 200 atm, more preferably, 50 atm to 100 atm.
The reduction in Step (b) results in the formation of a protected compound having the formula (V) which contains an asymmetric carbon as designated by a “*” sign,
In the compound of formula (V), R
2
is selected from the group consisting of hydrogen, phenyl and a C
1
-C
8
linear, branched or cyclic alkyl group. Preferably R
2
is methyl. R
3
and R
4
are independently selected from the group consisting of hydrogen, phenyl, a C
1
-C
8
linear, branched or cyclic alkyl group, and OR
6
, wherein R
6
is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C
1
-C
8
linear, branched o

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