Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-17
2001-05-08
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S111000, C548S119000, C548S405000, C548S412000, C548S413000
Reexamination Certificate
active
06229019
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel processes for producing phosphinopyrrolidine compounds which are chiral ligands for catalysts effective in asymmetric synthesis and to novel intermediate compounds which are products in the processes. Said processes enable us to simplify production steps including complicated multi-stages and further to make not only a manufacturing apparatus but also facilities for processes simple.
2. Description of the Related Art
Pantolactone is extensively utilized as a starting material for synthesizing pharmaceuticals, etc. Particularly, D-pantolactone (R-(−)-pantolactone) is well known as an intermediate in the preparation of D-pantothenic acid and pantethine which are useful as vitamins of medical or physiological importance. Since pantolactone has an asymmetric center in its molecule, chemically synthesized pantolactone products usually require optical resolution. In other words, D-pantolactone is prepared via the optical resolution of chemically synthesized D,L-pantolactone. Such a synthesis including the optical resolution is not only complicated and burdensome but also disadvantageous, such as costly. Specifically, the optical resolution has disadvantages in that it requires special agents, etc. and skills of operating it. That is, the process utilizing the optical resolution requires the use of expensive optical resolving agents such as quinine or brucine and further has defects in the recovery of D-pantolactone (it is not easy to recover D-pantolactone), etc. For means for solving these problems, a proposal of synthesizing optically active pantolactone by production processes utilizing an asymmetrically synthesizing reaction has been provided (U.S. Pat. No. 4,879,389).
For the process disclosed in U.S. Pat. No. 4,879,389, it has been reported that optically active pantolactone is prepared enantioselectively in quite excellent yields from an industrial standpoint by asymmetric hydrogenation using the phosphinopyrrolidine compounds; however, the synthesis of the phosphinopyrrolidine compounds, important reagents for the process, requires multi-processes including totally 14 steps, thereby incurring a drawback such as a demand for totally great expenditures. In the prior art process of synthesizing the phosphinopyrrolidine compounds, it is also essential to take a step of converting diphenylphosphino groups into dicyclohexylphosphino groups wherein benzene nuclei in the 4-diphenylphosphino are hydrogenated. The prior art hydrogenation conversion requires reactions at highly elevated temperatures and pressures (e.g., 150° C. and 150 atm), whereby there has been a drawback such as a demand for special facilities. Especially in industrial production, it is not easy to fit manufacturing facilities thereto. Further, such fitting facilities cost very much and are still accompanied with risks upon the manufacturing operation.
The phosphinopyrrolidine compounds are excellent reagents useful in catalytic asymmetric syntheses for not only pantolactone but also a wide variety of optically active compounds. Therefore, if it is feasible to synthesize the phosphinopyrrolidine compounds readily, efficiently, or unexpensively, it may enable us to apply such reagents to a diversity of asymmetric syntheses. Thus, to develop a production technique suited for these purposes is strongly demanded.
SUMMARY OF THE INVENTION
The present inventors have conducted an extensive research on synthesis of phosphinopyrrolidine compounds with aim of developing their simple and efficient production.
As a result, the present inventors have found that the reaction is conducted in the presence of boron compounds while blocking phosphorous atoms, whereby dicyclohexylphosphino groups protected with boron compounds can be efficiently introduced into position 4 of pyrrolidine nuclei, leading to formation of the desired phosphinopyrrolidine compounds useful for chiral ligands of catalysts in asymmetric synthesis, in extremely simple steps even without resort to processes including reduction of phenyl nuclei at highly elevated temperatures and pressures. Thus, the present invention is now provided.
The present invention provides:
(1) a process for producing a compound having the following formula (IV):
wherein R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue, and R
6
is hydrogen or a protecting group for an imino group,
which comprises
(i) reacting a compound having the following formula (I):
wherein R
1
is a protecting group for an imino group, R
2
and R
3
which are identical or different, are independently a protecting group for a hydroxy group, with a metal phosphine compound and a boron compound to form a compound having the following formula (II):
wherein R
1
, R
2
, R
4
and R
5
are as defined above,
(ii) then reacting the resultant compound (II) with a metal dicyclohexylphosphine compound and a boron compound to form a compound having the following formula (III):
wherein R
1
, R
4
and R
5
are as defined above,
(iii) decomplexing the resultant compound (III) for removal of the boron compound completed therewith to form the compound (IV);
(2) a compound of the formula (III) wherein R
1
is a protecting group for an imino group, R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue, or a solvate thereof;
(3) a process for producing a compound of the formula (III) wherein R
1
is a protecting group for an imino group, R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue,
which comprises
(i) reacting a compound of the formula (II) wherein R
2
is a protecting group for a hydroxy group, and R
1
, R
4
and R
5
are as defined above, with a metal dicyclohexylphosphine compound and a boron compound to form the compound (III);
(4) a compound of the formula (II) wherein R
1
is a protecting group for an imino group, R
2
is a protecting group for a hydroxy group, and R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue, or a solvate thereof;
(5) a process for producing a compound of the formula (II) wherein R
1
is a protecting group for an imino group, R
2
is a protecting group for a hydroxy group, and R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue, which comprises
(i) reacting a compound of the formula (I) wherein R
1
is as defined above, R
2
and R
3
which are identical or different, are independently a protecting group for a hydroxy group, with a metal phosphine compound and a boron compound to form the compound (II); and
(6) a process for producing a compound of the formula (IV) wherein R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue, and R
6
is hydrogen or a protecting group for an imino group, which comprises
(i) decomplexing a compound of the formula (III) wherein R
1
is a protecting group for an imino group, and R
4
and R
5
are as defined above, for removal of the boron compound complexed therewith to form the compound (IV).
In another aspect, the present invention provides:
(7) the process according to above (1), which comprises
(i) reacting a compound of the formula (I) wherein R
1
is a group having an intervening carbonyl group or a group having an intervening sulfur atom, and R
2
and R
3
which are identical or different, are independently a group having an intervening sulfur atom, with a metal phosphine compound of the formula: R
4
R
5
PM wherein R
4
and R
5
which are identical or different, are independently an optionally substituted or unsubstituted aromatic hydrocarbon residue wherein substituents on the aromatic hydrocarbon residue include alkyl, alkoxy, mono-, di-, or tri-alky
Achiwa Kazuo
Nakamoto Shin-Ichi
Fuji Yakuhin Kogyo Kabushiki Kaisha
Higel Floyd D.
Wenderoth , Lind & Ponack, L.L.P.
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