Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-04-20
2002-09-10
Keys, Rosalynd (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S588000, C568S648000, C568S649000, C556S482000
Reexamination Certificate
active
06448449
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for the preparation of an (R)-1-(aryloxy)propan-2-ol from an (R)-1-aryloxy-2-trialkylsiloxypropane with high regioselectivity and enantioselectivity. More particularly, the present invention relates to a process for the preparation of (R)-1-(2,3-difluoro-6-nitrophenoxy)-propan-2-ol from (R)-1-(2,3-difluoro-6-nitrophenoxy)-2-trimethylsiloxypropane. The (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol is useful as an intermediate in the synthesis of Levofloxacin antibiotic.
2. Description of the Prior Art
U.S. Pat. No. 5,665,890 to Jacobsen et al. describes a stereoselective chemical synthesis by the reaction of a nucleophile and a chiral or prochiral cyclic substrate, such as an epoxide, in the presence of a non-racemic chiral catalyst.
U.S. Pat. No. 5,929,232, also to Jacobsen et al., describes a kinetic resolution of a cyclic substrate, such as an epoxide, in the presence of a non-racemic chiral catalyst.
U.S. Pat. Nos. 5,663,393 and 5,637,739, both to Jacobsen et al., describe catalysts that are useful in the above stereoselective chemical syntheses and kinetic resolution reactions.
The contents of U.S. Pat. Nos. 5,665,890, 5,929,232, 5,663,393 and 5,637,739, all to Jacobsen et al., are incorporated herein by reference in their entirety.
JP 10-77934 to Asahi Glass is directed to the preparation of a 1-aryloxy-2-propanol derivative.
The ring opening of epoxides with phenols has also been mentioned by Annis and Jacobsen,
J. Am. Chem. Soc.,
121, 4147-4154 (1999) and by Ready and Jacobsen,
J. Am. Chem. Soc.,
121, 6086-6087 (1999).
None of the above references disclose the preparation of (R)-1-(aryloxy)-2-trialkylsiloxypropane, such as, (R)-1-(2,3-difluoro-6-nitrophenoxy)-2-trimethylsiloxypropane, and its subsequent conversion to the corresponding (R)-1-(aryloxy)propan-2-ol, such as the (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol, which is useful as an intermediate in the synthesis of Levofloxacin.
Accordingly, the present invention provides processes for the preparation of (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol, which is a useful intermediate in the synthesis of the widely used antibiotic Levofloxacin.
SUMMARY OF THE INVENTION
The present invention includes a process for the preparation of an (R)-1-(aryloxy)propan-2-ol with high regioselectivity and enantioselectivity. The process comprises:
contacting an aryl trialkysilyl ether and (R)-propylene oxide in the presence of a catalyst to produce a regioisomeric mixture of (R)-1-(aryloxy)-2-trialkylsiloxypropane and (S)-2-(aryloxy)-1-trialkylsiloxypropane;
contacting said regioisomeric mixture of said (R)-1-aryloxy-2-trialkylsiloxypropane and said (S)-2-(aryloxy)-1-trialkylsiloxypropane and an alcohol in the presence of an acid at a temperature and for a length of time sufficient to produce a regioisomeric mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)propane-1-ol;
contacting said regioisomeric mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)propane-1-ol and a triarylmethyl halide in the presence of a base at a temperature and for a length of time sufficient to produce a crude mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)-1-triarylmethyloxypropane; and
distilling said crude mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)-1-triarylmethyloxypropane to isolate said (R)-1-(aryloxy)propan-2-ol from said crude mixture.
The present invention further includes a process for the preparation of an (R)-1-(aryloxy)propan-2-ol with high regioselectivity and enantioselectivity, said process comprising the steps of:
contacting an aryl trialkysilyl ether and (R)-propylene oxide in the presence of a catalyst to produce a regioisomeric mixture of (R)-1-(aryloxy)-2-trialkylsiloxypropane and (S)-2-(aryloxy)-1-trialkylsiloxypropane;
contacting said regioisomeric mixture of said (R)-1-aryloxy-2-trialkylsiloxypropane and said (S)-2-(aryloxy)-1-trialkylsiloxypropane and an alcohol in the presence of an acid at a temperature and for a length of time sufficient to produce a regioisomeric mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)propane-1-ol;
contacting said regioisomeric mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)propane-1-ol and a sulfonating agent selected from the group consisting of: trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride and a mixture thereof, in the presence of a base at a temperature and for a length of time sufficient to produce a crude mixture of (R)-1-(aryloxy)propan-2-ol and an (S)-2-(aryloxy)-1-trifluoromethansulfonyloxypropane; and
distilling said crude mixture of (R)-1-(aryloxy)propan-2-ol and (S)-2-(aryloxy)-1-trifluoromethansulfonyloxypropane to isolate said (R)-1-(aryloxy)propan-2-ol from said crude mixture.
The present invention also includes a process for the preparation of an (R)-1-aryloxy-2-trialkylsiloxypropane with high regioselectivity and enantioselectivity. The process comprises: contacting an aryl trialkysilyl ether and (R)-propylene oxide in the presence of a catalyst selected from the group consisting of: a racemic and non-racemic catalyst, to produce a regioisomeric mixture of (R)-1-(aryloxy)-2-trialkylsiloxypropane and (S)-2-(aryloxy)-1-TRIALKYLSILOXYPROPANE.
The present invention also includes a regioisomeric mixture which is prepared by a process, which comprises: contacting an aryl trialkysilyl ether and (R)-propylene oxide in the presence of a catalyst to produce a regioisomeric mixture of (R)-1-(aryloxy)-2-trialkylsiloxypropane and (S)-2-(aryloxy)-1-TRIALKYLSILOXY-PROPANE.
The present invention further includes a kinetic resolution process for the preparation of an (R)-1-aryloxy-2-trialkylsiloxypropane with high regioselectivity and enantioselectivity. This process comprises the step of: contacting an aryl trialkysilyl ether and racemic propylene oxide in the presence of a non-racemic catalyst to produce a regioisomeric mixture of (R)-1-(aryloxy)-2-trialkylsiloxy-propane and (S)-2-(aryloxy)-1-trialkylsiloxypropane.
The present invention still further includes a regioisomeric mixture prepared by a kinetic resolution process comprising the step of: contacting an aryl trialkysilyl ether and racemic propylene oxide in the presence of a non-racemic catalyst to produce a regioisomeric mixture of (R)-1-(aryloxy)-2-trialkylsiloxypropane and (S)-2-(aryloxy)-1-trialkylsiloxy-propane.
Protection of the aromatic hydroxy compound reactant and the intermediate alcohol derivatives with a trialkylsilyl group prevents side reactions, such as, the “Smiles Rearrangement,” which could lead to equilibration of the regioisomeric products thereby causing erosion of the enantiomeric excess as well as loss of yield of the desired regioisomer.
DETAILED DESCRIPTION
The Levofloxacin intermediate is an optically active compound having an asymmetric carbon C* at C-2. This intermediate can be prepared from the reaction of a substituted phenol (ArOH) with propylene oxide in the presence of a metal complex catalyst, under conditions that produce a product with an enantiomeric excess of the desired enantiomer, as shown below:
The antibiotic compound Levofloxacin possesses one center of asymmetry. Currently, this center is installed by the incorporation of (R)-propylene glycol through a circuitous, multi-step route involving several protection/deprotection steps of the 1,2-diol hydroxyls. Regioselective alkylation of the free primary alcohol with 2,3,4-trifluoronitrobenzene followed by a final deprotection step leads to (R)-1-(2,3-difluoro-6-nitrophenoxy)propan-2-ol, which is then converted to Levofloxacin by conventional means.
A more straightforward route to the desired intermediate is the direct ring opening of (R)-propylene oxide with 2,3-difluoro-6-nitrophenol. Ring openings of this type have been demonstrated to be catalyzed by chiral Co(salen) complexes. Among the problems associated with this route include the fact that the Co(salen) catalyst does not open the epoxide with 100% regioselectivity, leading to two possible regioisomeric products
Keys Rosalynd
Ohlandt Greeley Ruggiero & Perle L.L.P.
Rhodia ChiRex, Inc.
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