Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-02-09
2002-05-21
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S881000
Reexamination Certificate
active
06392103
ABSTRACT:
TECHNICAL FIELD AND PRIOR ART
The present invention relates to the field of organic synthesis. More specifically, it concerns a process for the asymmetric reduction of prochiral ketones to chiral alcohols using as reducing agent a silane agent, preferably polymethylhydro-siloxane (PMHS), and zinc, cobalt or cadmium compounds, together with ligands selected from the group comprising chiral amines, imines, alcohols and amino alcohols.
The enantioselective reduction of ketones to alcohols is a field in which there is considerable scientific activity in view of the potential industrial importance of this reaction. The production of chiral alcohols is of great importance, particularly in the fine chemicals industry, for example in the pharmaceuticals industry, the perfumes and flavourings industry, and the agrochemicals industry, and for the production of insecticides. Research workers are endeavouring to find processes which produce high yields and enantiomeric excesses but which still use metal catalysts and ligands which are readily available at reasonable prices; the same criteria also apply to reducing agents.
In this context, reference should be made to the publications of Buchwald et al, in particular to U.S. Pat. No. 5,227,538, which describes the enantioselective reduction of ketones using silanes in the presence of catalysts selected from the metal compounds in groups 3, 4, 5 and 6 of the periodic table, and from lanthanides and actinides, and, more particularly, from titanium derivatives, the said catalysts being used in the presence of chiral additives such as amines, diamines and diols. These systems are generally not very active and produce moderate enantiomeric excesses, generally below 40%.
In J. Am. Chem. Soc., 1994, 116, 11667, Carter, Schiott, Gutierrez and Buchwald also described the enantioselective reduction of ketones using PMHS in the presence of chiral titanocenes activated by butyllithium, but these systems have the disadvantage of being very expensive and of requiring relatively large quantities of catalyst, namely, of the order of 5%, based on the substrate.
In the context of the present invention, reference is also made to the applicant's international patent application WO 96/12694, which describes the reduction of aldehydes, ketones, esters and lactones using a reducing system comprising a silane derivative and a metal hydride formed from a metal salt or complex and a reducing agent. It is possible to use not only zinc salts but also cadmium, manganese and iron salts as precursors for the production of the metal hydride. According to a preferred embodiment, polymethylhydrosiloxane (PMHS) is used as the silane derivative. This process is not, however, suitable for the production of chiral alcohols.
DESCRIPTION OF THE INVENTION
We have now discovered that it is possible to prepare chiral secondary alcohols of considerable optical purity economically by reducing prochiral ketones using a silane derivative, preferably PMHS, in the presence of zinc, cobalt or cadmium derivatives complexed by chiral ligands such as amino alcohols, alcohols, amines or imines.
The process comprises the following steps:
a) the reaction of a prochiral ketone with an effective amount of a silane agent in the presence of a catalyst derived from a zinc, cobalt or cadmium precursor compound and from a chiral ligand selected from the group consisting of chiral amines, imines, alcohols and amino alcohols;
b) the hydrolysis of the siloxane obtained using an appropriate agent;
c) the separation and purification of the optically active alcohol formed.
The process is characterised, in particular, in that small quantities of the zinc, cobalt or cadmium precursor compound and of ligand can be used. Furthermore, these reactants and catalysts are not expensive and do not require special handling precautions, particularly in terms of protection from moisture and air.
Without wishing to prejudge the reaction mechanism of the process of the invention, it seems likely that the reaction characterising this process can be illustrated by the following diagram, which relates to a preferred embodiment:
The silane agent used can be a dialkylsilane, a trialkoxysilane, an alkylchlorosilane or a phenylsilane. Dimethylsilane, diethylsilane, trimethoxysilane or triethoxysilane can be cited as examples. According to a preferred embodiment the silane agent used is PMHS or polymethylhydrosiloxane, which has proved to be very effective and is commercially available. Furthermore, unlike other silanes, in a disproportionation reaction PMHS does not form gaseous silanes such as SiH
4
, a pyrophoric and tear gas which requires special precautions.
Silane agents, which act as the reducing agent in the invention, are used in an effective amount to ensure complete conversion. In general, the amount of silane agent used will be at least the stoichiometric quantity and, according to a preferred embodiment of the invention, the amount of silane agent used will be a slight excess of the order of approximately 10 to 40%, based on the stoichiometric quantity. The reduction reaction according to the invention naturally likewise takes place when the silane agent is used in sub-stoichiometric quantities, but this results in a decrease in conversion. In this case, therefore, the term “effective amount” means an amount of silane agent sufficient to induce reduction of the substrate in an industrially effective manner.
The catalyst according to the invention can be produced in situ in the reaction medium or can be prepared separately. In either case, the catalyst is obtained from a metal precursor compound and a chiral ligand selected from the group comprising amines, imines, amino alcohols and alcohols.
The metal precursor compound used can be zinc, cobalt or cadmium derivatives. The preferred metal compounds of the present invention are zinc compounds, by virtue of their efficacy, ease of handling and non-toxicity.
In an embodiment of the invention, the precursor used is a compound which is prepared in situ from a salt or complex of one of the metals referred to above and from a reducing agent. This embodiment will be used mainly when the metal precursors used are unstable or sensitive, for example, forms which cannot be handled without decomposition taking place. For example, metal hydrides can be prepared by reacting a salt or complex of any respective metal with a reducing agent such as BH
3
or a metal borohydride of the formula M
+
BH
4
−
(M=Li, Na or K) or M(BH
4
)
2
(M=Mg, Ca or Zn), an alkylborane MR
n
BH
(4−n)
(n=1 to 3, M=alkali metal), an alkoxyborane (RO)
n
BH
(4−n)
M (n=1 to 3, M=alkali metal) or an aluminium hydride such as AlH
3
, AlH
n
R
3−n
, MAlH
4
, MAlH
n
R
4−n
or MAlH
n
(OR)
4−n
(M=Li, Na or K, n=1 to 3). In the formulae given above, R is an alkyl, cycloalkyl, alkoxy, aryl, aryloxy, alkoxyalkyl, alkoxyaryl, aralkoxy, aralkoyl or alkylaryl group comprising from 1 to 20 carbon atoms. R is preferably a C
1
to C
4
allyl group. It is also possible to prepare organometallic derivatives by reacting a salt or complex of one of the metals referred to above with an organolithium compound of the formula LiR, an organoaluminium compound of the formula AlR
3
or an organomagnesium compound of the formula RMgX (X=Cl, Br or I), R having the meaning defined above. Specific examples include NaBH
4
, LiAlH
4
or NaAlH
2
(OCH
2
CH
2
OCH
3
)
2
(Vitride®). Reducing agents other than those mentioned above can be used in accordance with common knowledge in the field.
Virtually any salt or complex of the chosen metal can be used in the reaction with the reducing agent to produce the precursor of the active catalyst. In this context, these may include but are not restricted to zinc, cobalt or cadmium halides (fluorides, chlorides, bromides and iodides), carbonates, cyanides, isocyanates, sulphates, phosphates, nitrates, carboxylates (acetates, propionates, 2-ethyl hexanoates, stearates and naphthenates) or alkoxid
Barts Samuel
Firmenich SA
Price Elvis O.
Winston & Strawn
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