Process for the synthesis of 1,3-diols

Details Process for the synthesis of 1,3-diols Process for the synthesis of 1,3-diols

2002-06-11

2003-07-22

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S376100, C548S377100, C548S469000

Reexamination Certificate

active

06596879

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing cis-1,3-diols. More particularly, the present invention relates to the use and subsequent recovery and reuse of a trialkylborane or dialkylalkoxyborane or a mixture of a trialkylborane and a dialkylalkoxyborane in the reduction of a beta-hydroxy ketone to obtain a cis-1,3-diol. Additionally, the present invention relates to the use of a synergistic combination of a trialkylborane and a dialkylalkoxyborane in the reduction of a beta-hydroxy ketone to obtain a cis-1,3-diol.
The use of trialkylboranes or dialkylalkoxyboranes in the stereoselective reduction of 1,3-keto alcohols to the corresponding syn-1,3-diols has been widely described in the literature. This method has given high stereoselectivity without using extraordinarily difficult conditions (Brower P. L., Butler D. E., Deering C. F., Le T. V., Millar A., Nanninga T. N., and Roth B.,
Tetrahedron Lett.,
1992;33:2279; Narasaka K., and Pai F. C.,
Tetrahedron,
1984;40:2233; Chen K. M., Hardtmann G. E., Prasad K., Repic O., and Shapiro M. J.,
Tetrahedron Lett.,
1987;28:155; Chen K. M., Gunderson K. G., Hardtmann G. E., Prasad K., Repic O., and Shapiro M. J.,
Chem. Lett.,
1987:1923). There seems to be general acceptance of the formation of a borate ester from either the trialkyl or dialkylalkoxyboranes which is said to form a cyclic chelate (Narasaka K. and Pai F. C.,
Tetrahedron,
1984;40:2233; Chen K. M., Hardtmann G. E., Prasad K., Repic O., and Shapiro M. J.,
Tetrahedron Lett.,
1987;28:155; Chen K. M., Gunderson K. G., Hardtmann G. E., Prasad K., Repic O., and Shapiro M. J.,
Chem. Lett.,
1987:1923; see for example Paterson I., Cumming J. G., and Smith J. D.,
Tetrahedron Lett.,
1994;35:3405). Axial delivery of a hydride to the complex then leads predominately to the syn-product which can be hydrolyzed to the diol. The diols are valued as intermediates for the preparation of, for example, HMG-CoA reductase inhibitors which are useful hypolipidemic and hypocholesterolemic agents. This is a widely used method of preparation of such agents (U.S. Pat. Nos. 4,645,854, 5,354,772, 5,155,251, and 4,970,313).
Many procedures in the literature, describe the work-up of the reaction with hydrogen peroxide (U.S. Pat. No. 4,645,854 and 4,970,313). This results in the destruction of active alkylborane species. Some procedures describe the repeated distillation with methanol and an acid (U.S. Pat. No. 5,354,772 and 5,155,251). This also dilutes and eventually destroys the active alkylborane species. We have surprisingly and unexpectedly found that by performing the reduction and workup with a minimal amount of acid, and keeping the distillate streams separated, that the initial distillate can be recovered and reused to obtain very good selectivity in subsequent reductions.
Thus, the present process offers significant advantages over the prior art processes. For example, the cost of additional alkylborane is eliminated for each batch in which the distillate stream is recycled. Additionally, since alkylboranes are hazardous, they must be destroyed prior to being disposed. The present process minimizes this expensive and time-consuming procedure. Moreover, it is especially surprising that very good selectivity in the reductions is obtained using recovered alkylboranes.
Finally, we have also surprisingly and unexpectedly found that a combination of a trialkylborane and a dialkylalkoxyborane is synergistic in selectively reducing a beta-hydroxy ketone to obtain a cis-1,3-diol.
SUMMARY OF THE INVENTION
Accordingly, a first aspect of the present invention is a process for the preparation of a compound of Formula I
wherein R is alkyl,
NC—CH
2
—,
PG—O—CH
2
— wherein PG is a protecting group,
which comprises:
Step (a) treating a compound of Formula II
wherein R and R
1
are as defined above with a trialkylborane or dialkylalkoxyborane or a mixture of a trialkylborane and a dialkylalkoxyborane in a solvent;
Step (b) adding an alkali metal hydride at about −110° C. to about −50° C.;
Step (c) concentrating the reaction by distillation to afford a compound of Formula I and a distillate containing alkylborane species; and
Step (d) treating additional compound of Formula II or III with the distillate from Step (c) containing recovered alkylborane species and repeating Steps (b) and (c) as desired to afford additional compound of Formula I.
A second aspect of the present invention is a process for the preparation of a compound of Formula I
wherein R is alkyl,
NC—CH
2
—,
PG—O—CH
2
— wherein PG is a protecting group,
which comprises:
Step (a) treating a compound of Formula II
wherein R and R
1
are as defined above with a synergistic combination of a trialkylborane and a dialkylalkoxyborane in a solvent; and
Step (b) adding an alkali metal hydride at about −110° C. to about −50° C. to afford a compound of Formula I.
A third aspect of the present invention is a synergistic combination comprising a trialkylborane and a dialkylalkoxyborane.
DETAILED DESCRIPTION OF THE INVENTION
In this invention the term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary-butyl, isobutyl, tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
“PG” means a protecting group used for protecting an alcohol moiety such as, for example, benzyl and the like. Additional examples of protecting groups for an alcohol moiety are disclosed at Chapter 2 in Greene T. W., “Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc., 1981.
“Alkali metal” is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
“Alkaline-earth metal” is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, and the like.
“Alkali metal hydride” includes, for example, sodium borohydride, zinc borohydride, lithium borohydride, lithium aluminum hydride, and the like.
“Alkylborane species” means a mono, di- or trialkylborane where the mono or dialkylborane is further substituted by hydrido or alkoxy as defined hereinafter or a dimeric alkylborane species.
“Alkoxy” means O-alkyl as defined above for alkyl.
As previously described, the compounds of Formula I are either useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) or are useful as intermediates to prepare HMG CoA reductase inhibitors.
Thus, the present process can be used to prepare various HMG CoA reductase inhibitors containing a cis-1,3-diol moiety. For example, atorvastatin disclosed and described in U.S. Pat. Nos. 4,681,893 and 5,273,995; fluvastatin disclosed and described in U.S. Pat. No. 5,354,772; bervastatin disclosed and described in U.S. Pat. No. 5,082,859; cerivastatin disclosed and described in U.S. Pat. No. 5,177,080; NK-LO4 disclosed and described in U.S. Pat. No. 5,011,930; dalvastatin disclosed and described in U.S. Pat. No. 4,863,957; glenvastatin disclosed and described in U.S. Pat. No. 4,925,852; erythro-7-[5-(2,2-dimethylbutyryloxymethyl)-4-(4-fluorophenyl)-2,6-diisopropylpyridin-3-yl]-3,5-dihydroxy-6(E)-heptenoic methyl ester disclosed and described in U.S. Pat. Nos. 5,006,530, 5,169,857, and 5,401,746; 7,7′-[2-(dimethylamino)-4-(4-fluorophenyl)-6-isopropylpyridine-3,5-diyl]bis [erythro-(E)-3,5-dihydroxy-6-heptenoic acid methyl ester disclosed and discribed in U.S. Pat. No. 5,145,857; 7-[6-cyclopropyl-4-(4-fluorophenyl)-2-(4-methoxyphenyl)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid sodium salt disclosed and described in U.S. Pat. No. 5,026,708; (E)-7-[4-(4-fluorophenyl)-2-isopropylquinolin-3-yl]-3,5-dihydroxy-6-heptenoic acid &dgr;-lactone disclosed and described in U.S. Pat. Nos. 5,011,930, 5,102,888, and 5,185,328; trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-6,6-dimethyl-4-(N-phenyl-carbamoyloxy)-1-cyclohexenyl]vinyl]-4-hydroxytetrahy

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