Process for the preparation of chiral lactones

Details Process for the preparation of chiral lactones Process for the preparation of chiral lactones

2000-10-20

2001-08-21

Trinh, Ba K. (Department: 1612)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S226000, C548S316100, C548S517000, C548S545000

Reexamination Certificate

active

06277997

ABSTRACT:

The present invention is concerned with a novel process for the manufacture of intermediates which are useful in the synthesis of pharmacologically active compounds. The invention also relates to the novel intermediates obtained in said process which are useful in the synthesis of pharmacologically active compounds.
DESCRIPTION OF THE INVENTION
In one aspect, the invention is concerned with a process for the manufacture of a lactone having the formula I
wherein
R
1
signifies lower alkyl or lower cycloalkyl and
R
2
represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO
2
as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl.
In accordance with the invention compounds of formula (I) can be manufactured by hydrogenating asymmetrically a compound of formula (II)
wherein R
1
and R
2
have the meaning as given before, in the presence of an optically active metal diphosphine complex.
As used in this specification, the term “lower alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like.
The term “lower cycloalkyl” means a cycloalkyl group containing 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Examples of N-heterocyclic rings denoted by R
2
are rings of the formula:
wherein
R
4
and R
5
each represent hydrogen or together represent an additional bond or the remainder of a fused benzene ring;
R
6
represents hydrogen or lower alkyl;
X represents —CO—, —CH
2
—, —CH(lower alkyl)—,—C(lower alkyl)
2
—, —NH—, —N(lower alkyl)— or —O—; and
R
7
and R
8
each represent hydrogen or lower alkyl.
Examples of such rings are 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidino, phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl, 3,4,4-trimethyl-2.5-dioxo-imidazolidin-1-yl, 2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl and 2,6-dioxopiperidino.
Preferred rings are those of formula (a), (b) or (c) with formula (b) being most preferred. Within formula (b) a preferred substituent is 3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl.
A preferred group within R
1
is lower cycloalkyl with cyclopentyl being most preferred.
Although the formulas presented herein show the respective compounds in their absolute stereochemistry, the invention embraces not only the depicted stereoisomers of a compound of formula (I), but also the corresponding enantiomers. The same applies to the products which can be made out of these compounds.
In one embodiment the asymmetric hydrogenation can be carried out using complexes of optically active, preferably atropisomeric, diphosphine ligands with a metal of Group VIII of the periodic system, especially rhodium, as the catalyst. Complexes which can be used as catalysts in the process of the present invention are
[Rh(Y)(Ln)]
+
A
−
  (III)
wherein
L signifies a neutral ligand
A signifies an anion of an oxygen or complex acid
n signifies 0, 1 or 2
Y signifies an optically active, preferably atropisomeric diphosphine ligand.
The term “neutral ligand” signifies in the scope of the present invention readily exchangeable ligands such as olefins, e.g. ethylene, propylene, cyclooctene, 1,5-hexadiene, 1,5-cyclooctadiene and the like, nitriles such as acetonitrile and benzonitrile or also the solvent which is used. Where more than one such ligand is present, they can be the same or different from each other.
The term “oxygen acid” signifies in the scope of the present invention acids from the group H
2
SO
4
, HClO
4
, HBrO
4
, HIO
4
, HNO
3
, H
3
PO
4
, CF
3
SO
3
H or C
6
H
5
SO
3
H. The term “complex acid” signifies in the scope of the present invention halogen complexes with the elements boron, phosphorus, arsenic, antimony or bismuth. HClO
4
, CF
3
SO
3
H, HPF
6
, HBF
4
, HB(Ph)
4
, HB(3,5-(CF
3
)
2
-C
6
H
3
)
4
, HSbF
6
and HAsF
6
are preferred representatives with HSbF
6
and HBF
4
being most preferred.
Suitable chiral ligands Y in the chiral diphosphin-complexes, which can exist in the (R) or (S) form, can be selected from the group consisting of:
MeOBIPHEP:
(6,6′-Dimethoxybiphenyl-2,2′-diyl)bis-
(diphenylphosphine)
BIPHEMP:
(6,6′-Dimethylbiphenyl-2,2′-diyl)bis-
(diphenylphosphine)
BINAP:
[(1,1′-Binaphthyl)-2,2′diyl]bis(di-
phenylphosphine)
2-Furyl-MeOBIPHEP
(6,6′-Dimethoxybiphenyl-2,2′-di-
yl)bis(di-2-furylphosphine)
2-Naphthyl-MeOBIPHEP:
(6,6′-Dimethoxybiphenyl-2,2′-di-
yl)bis(di-2-naphthylphosphine)
TriMeOBIPHEP:
(4,4′,5,5′,6,6′-Hexamethoxybi-
phenyl-2,2′-diyl)bis(diphenylphosphine)
(3,5-Me,4-MeO)-MeOBIPHEP:
(6,6′-Dimethoxybiphenyl-2,2′-di-
yl)bis[bis(3,5-dimethyl-4-methox-
y-phenyl)phosphine]
Me-DuPHOS:
1,2-Bis(2,5-dimethylphospholano)ben-
zol
3,5-iPr-MeOBIPHEP:
(6,6′-Dimethoxybiphenyl-2,2′-di-
yl)bis[bis(3,5-diiso-propylphenyl)phos-
phine]
PPF-P(tBu)
2
:
1-[2-(Diphenylphosphino)ferrocen-
yl]ethyl-di-tert.-butyl-phosphine
pCF
3
-PPF-PPh
2
:
1-[2-(Di-(4-trifluoromethyl)phenyl)
phosphino)ferrocenyl]ethyl-di-phen-
yl-phosphine
3,5-tBu
2
-MeOBrPHEP:
P,P-Bis-(3,5-di-tert-butyl-phen-
yl)-P′P-40 -diphenyl-(6,6′-
dimethoxybiphenyl-2,2′-diyl)di-
phosphine
(3,4,5-MeO)-MeOBIPHEP:
(6,6′-Dimethoxybiphenyl-2,2′-di-
yl)bis(di-3,4,5-
trimethoxyphenyl)phosphine)
These ligands are known and/or can be prepared according to the Examples or methods as described in EP O 398 132 A2 and WO-92/16535 (MeOBIPHEP; TriMeOBIPHEP, 3,5-iPr-MeOBIOPHEP, 3,5-tBu
2
-MeOBIPHEP, (3,4,5-MeO)-MeOBIPHEP, (3,5-Me, 4-MeO)-MeOBIPHEP, 2-Naphtyl-MeOBIPHEP), EP O 104 375 A1 (BIPHEMP), EP O 580 331 A1 (BINAP), WO 92/16536 (2-Furyl-MeOBIPHEP), U.S. Pat. No. 5,171,892 (Me-DuPHOS), EP O 564 406 A1 (PPF-P(tBu)
2
), and EP O 646 590 A1 (pCF
3
-PPF-PPh
2
).
The preferred optically active rhodium complexes (III) can be synthesized or prepared in situ from the components in the absence or in the presence of the compounds of formula II to be hydrogenated. The optically active rhodium diphosphine complexes are either known or can be produced in a manner known per se, e.g. by reacting an optically active atropisomeric diphosphine ligand Y described above with a compound which can yield rhodiumn in a suitable inert organic or aqueous solvent. As suitable compounds which yield rhodium there can be mentioned, for example, organic rhodium complexes with ethylene, propylene and the like and with dienes, e.g. (Z,Z)-1,5-cyclooctadiene, 1,5-hexadiene and bicyclo[2.2.1]hepta-2,5-diene, which form readily soluble complexes with rhodium. Preferred compounds which yield rhodium are e.g. di-&mgr;-chloro-bis [&eegr;
4
-(Z,Z)-1,5-cyclooctadiene]dirhodium(I), di-&mgr;-chloro-bis[&eegr;
4
-norbornadiene] dirhodium(l), di-&mgr;-trifluoroacetato-bis[&eegr;
4
-(Z,Z)-1,5-cyclooctadiene] dirhodium(I), bis[&eegr;
4
-(Z,Z)-1,5-cyclooctadiene]rhodium(I) tetrafluoroborate, bis[&eegr;
4
-(Z,Z)-1,5-cyclooctadiene]rhodium(I) perchlorate and bis[&eegr;
4
-(Z,Z)-1,5-cyclooctadiene]rhodium(I) hexafluoroantimonate. Other metal catalysts with e.g. iridium can be prepared in the same manner.
The ratio of rhodium to Ligand Y in the complexes of formula (III) conveniently lies between about 0.5 and about 2 mol, preferably at about 1 mol, of rhodium per mol of ligand. The substrate/catalyst ration (S/C; mol/mol) conveniently lies between about 20 and about 20000, preferably between about 100 and about 5000.
In the method of the present invention [Rh(1,5-Cyclooctadiene)((R)-3,5-iPr-MeOBIPHEP)]

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