Process for substituted 3-hydroxybutyrate esters

Details Process for substituted 3-hydroxybutyrate esters Process for substituted 3-hydroxybutyrate esters

2000-05-02

2001-10-23

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C562S586000, C562S002000

Reexamination Certificate

active

06307094

ABSTRACT:

The present invention relates to a process for the reduction of esters of 4,4,4-trihaloacetoacetic acid and derivatives. The process involves catalytic hydrogenation in the absence of a solvent using a platinum catalyst and is co-catalyzed by the addition of an acid or a base. The resulting product 3-hydroxybutyrate esters are useful as solvents or cleaners, or as fine chemical intermediates to pharmaceuticals, agricultural chemicals, liquid crystals, and dyes.
There are a number of ways of reducing &bgr;-ketoesters which have been disclosed. In addition to hydrogenation, reduction with zinc/acetic acid or with borohydride reagents are known. For the hydrogenation reactions reported in the literature, most use ruthenium, nickel, or baker's yeast as catalyst. All use a solvent. F. G. Kathawala et al. in
Helvetica Chimica Acta
, 69, 803-805 (1986) disclose an example in which 5% platinum on carbon is used as a catalyst for the reduction of various &bgr;-ketoesters using methanol as a solvent. T. Fujima et al. in JP 09268146 A2, Oct. 14, 1997 disclose the hydrogenation of ethyl trifluoroacetoacetate using a nickel catalyst in tetrahydrofuran solvent to provide ethyl 4,4,4-trifluoro-3-hydroxybutyrate in 78% yield. N. Sayo et al. in U.S. 4,933,482, Jun. 12, 1990 disclose the hydrogenation of ethyl trifluoroacetoacetate using a ruthenium catalyst in a polar solvent such as an alcohol or tetrahydrofuran to provide ethyl 4,4,4-trifluoro-3-hydroxybutyrate in 95% yield. None of these references disclose or suggest the process of the present invention in which we have discovered that no solvent is necessary for the catalytic hydrogenation.
The advantages of not using a solvent in the hydrogenation process are:
(1) lower cost preparation of the product because no solvent has to be added,
(2) lower waste disposal costs,
(3) the need for solvent recycle is eliminated,
(4) higher yields of desired product result,
(5) higher process reactor productivity because of reduced volume,
(6) product purification is facilitated since the practitioner needs to only filter away the catalyst to obtain pure product without the need to distill solvent or product,
(7) lower catalysts loads are required for productive hydrogenation, and
(8) the process can be made a continuous process by flowing starting material over a bed of immobilized catalyst.
Accordingly, this invention provides a process for the preparation of a compound of formula (I)
from a compound of formula (II)
without a reaction solvent being present which comprises the steps of
(i) reacting the compound of formula (II) with hydrogen in the presence of a catalytic amount of platinum and a catalytic amount of an acid or base to form the compound of formula (I), and
(ii) separating the compound of formula (I) from the platinum catalyst,
wherein
X is fluoro or chloro,
R is alkyl, haloalkyl, polyhaloalkyl, alkyl substituted with NR
2
R
3
, hydroxy or OR
4
, phenyl or phenyl substituted with one or more groups independently selected from halo, alkyl, hydroxy, alkoxy, haloalkoxy, polyhaloalkoxy, haloalkyl or polyhaloalkyl,
R′ is a hydrogen atom, alkyl, haloalkyl, polyhaloalkyl, alkyl substituted with NR
2
R
3
, hydroxy or OR
4
, phenyl or phenyl substituted with one or more groups independently selected from halo, alkyl, hydroxy, alkoxy, haloalkoxy, polyhaloalkoxy, haloalkyl or polyhaloalkyl, R
2
and R
3
are each independently a hydrogen atom, alkyl, or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, and
R
4
is alkyl, haloalkyl or polyhaloalkyl.
As used herein, the term “alkyl” refers to straight and branched aliphatic hydrocarbon chains, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isoamyl and n-hexyl.
The term “alkoxy” refers to straight and branched aliphatic hydrocarbon chains attached to an oxygen atom, for example, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
The term “haloalkyl” refers to a straight or branched aliphatic hydrocarbon chain substituted with a fluoro, chloro or bromo, for example chloromethyl, 2-fluoroethyl and 4-bromobutyl.
The term “polyhaloalkyl” refers to a straight or branched aliphatic hydrocarbon chain multiply substituted with a fluoro or chloro, for example difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroethyl and trichloromethyl.
The term “haloalkoxy” refers to a straight or branched aliphatic hydrocarbon chain, attached to an oxygen atom, substituted with a fluoro, chloro or bromo, for example fluoromethoxy, 2-chloroethoxy and 4-bromobutoxy.
The term “polyhaloalkoxy” refers to a straight or branched aliphatic hydrocarbon chain, attached to an oxygen atom, multiply substituted with a fluoro or chloro, for example difluoromethoxy, trifluoromethoxy, 1,1,2,2,2-pentafluoroethoxy and trichloromethoxy.
In a preferred process of this invention,
X is fluoro or chloro,
R is (C
1
-C
4
)alkyl, halo(C
1
-C
4
)alkyl, polyhalo(C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl substituted with NR
2
R
3
, hydroxy or OR
4
, phenyl or phenyl substituted with one or more groups independently selected from halo, (C
1
-C
2
)alkyl, hydroxy, (C
1
-C
2
) alkoxy, halo (C
1
-C
2
) alkoxy, polyhalo (C
1
-C
2
) alkoxy, halo(C
1
-C
2
)alkyl or polyhalo(C
1
-C
2
)alkyl,
R′ is a hydrogen atom, (C
1
-C
4
)alkyl, halo(C
1
-C
4
)alkyl, polyhalo(C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl substituted with NR
2
R
3
, hydroxy or OR
4
, phenyl or phenyl substituted with one or more groups independently selected from halo, (C
1
-C
2
)alkyl, hydroxy, (C
1
-C
2
)alkoxy, h halo(C
1
-C
2
)alkyl or polyhalo(C
1
-C
2
)alkyl,
R
2
and R
3
are each independently a hydrogen atom, (C
1
-C
2
)alkyl, or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, and
R
4
is (C
1
-C
2
)alkyl, halo(C
1
-C
2
)alkyl or polyhalo(C
1
-C
2
)alkyl.
In a more preferred process of this invention,
X is fluoro,
R is (C
1
-C
3
)alkyl, polyhalo(C
1
-C
2
)alkyl or (C
1
-C
2
)alkyl substituted with OR
4
,
R′ is a hydrogen atom, (C
1
-C
2
)alkyl, polyhalo(C
1
-C
2
)alkyl, (C
1
-C
2
)alkyl substituted with NR
2
R
3
, hydroxy or OR
4
,
R
2
and R
3
are each independently a hydrogen atom, (C
1
-C
2
)alkyl, or together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, and
R
4
is (C
1
-C
2
)alkyl or polyhalo(C
1
-C
2
)alkyl.
In an even more preferred process of this invention, R is methyl or ethyl and R′ is a hydrogen atom, (C
1
-C
2
)alkyl or polyhalo(C1-C
2
)alkyl.
In a most preferred process of this invention, R is ethyl and R′ is a hydrogen atom.
The catalytic amount of platinum can be any form of platinum with a high surface area. Such catalysts may take the form of platinum on a carbon support, preferably 5% by weight of platinum on carbon (5% Pt/C), platinum on an alumina support, platinum on a silica support, platinum on a ceramic support, platinum(IV) oxide (PtO
2
) or a fluidized bed. The catalyst load can range from 0.001 to 10%, preferably from 0.001 to 0.1%, more preferably from 0.001 to 0.05% and even more preferably from 0.01 to 0.05%. The catalyst load is measured as the weight of platinum relative to the weight of 4,4,4-trihaloacetoacetate starting material. Other metals have been explored as catalysts, including Raney nickel, palladium on carbon, and ruthenium on carbon. Only very low yields of a 4,4,4-trihalo-3-hydroxybutyrate ester product were obtained (0-25%)
The hydrogen pressure can range from 1 to 100 bars, preferably from 2 to 5 bars. The reduction reaction temperature can range from ambient to 150° C., preferably from ambient to 80° C., more preferably from 30 to 60° C. Reaction times are dependent on the reactor design, reaction temperature, hydrogen pressure, etc. but are usually from 1 to 24 hours, preferably from 2 to 10 hours. Good agitation of the reaction mixture leads to shorter reaction times.
A base or acid is added as a co-catalyst. Loading of the co-catalyst can be from 0.1 to 10% by weight relative to the weight of trihaloacetoacetate starting mate

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