Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Reexamination Certificate
1999-04-27
2001-01-09
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
C435S280000, C435S911000
Reexamination Certificate
active
06171832
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the bioconversion of 1,2-indanedione to cis-(1S,2R)-indanediol which is useful as a precursor to (1S)-amino-(2R)-indanol, which in turn can be employed an intermediate in the synthesis of Crixivian® (also referred to an indinavir), a potent HIV protease inhibitor.
BACKGROUND OF THE INVENTION
The present invention is concerned with a process for synthesizing intermediates for compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as Compound J (i.e., indinavir) and other compounds as described in U.S. Pat. No. 5,413,999. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
1(S)-Amino-2(R)-hydroxy indan of the structure
is used to form an amide sidechain group on Compound J, a potent inhibitor of HIV protease, via methods described in U.S. Pat. No. 5,413,999 and in Merck 19464IA, U.S. Ser. No. 08/696,667, filed Aug. 14, 1996, both of which are incorporated herein by reference in their entireties.
Previous attempts at synthesis involve inefficient production of the racemate 1(+/−)amino-2(+/−) hydroxy indan from the racemic indene oxide. Other attempts at synthesis involve bioconversion of indene with a fungal haloperoxidase to give predominantly trans-(2S,1S)-bromoindanol, which is then subjected to various chemical steps to give (1S)-amino-(2R)-indanol. Still other attempts at synthesis relate to chemical synthesis with racemic epoxidation of indene as an intermediate step, followed by resolution with L-tartaric acid. Indene epoxide with a high enantiomeric excess can be obtained from indene via Jacobson's S,S-salen manganese catalyst (Jacobsen et al.,
J. Am. Chem. Soc.,
vol. 113, 7063-7064 (1991)), but upon hydroxylation to open the epoxide ring only a trans-diol is produced.
The chemical synthesis of cis-indanediols via the asymmetric oxidation of indene has been reported, but only in low enantiomeric excess. Tomoka et al.,
Chem. Pharm. Bull.,
vol. 38, 2133-2135 (1990), for example, discloses the formation of 1S,2R-indanediol in 30% enantiomeric excess via oxidation of indene using a stoichiometric amount of an osmium tetroxide-chiral amine complex at −78° C. Resolution of the indanediol product would be required in order to prepare an enantiomeric derivative such as ((S)-amino-(2R)-indanol.
U.S. Ser. No. 08/696,667 discloses an improved synthetic method in which the tartaric acid resolution step is eliminated. The method of U.S. Ser. No. 08/696,667 involves the stereoselective bioconversion of indene to cis-(1S,2R)-indanediol by the action of the enzyme dioxygenase, followed by further chemical treatment of the indanediol (e.g., treatment with a nitrite in the presence of acid in accordance with the Ritter reaction) to give (1S)-amino-(2R)-indanol. Preferred sources for the enzyme dioxygenase disclosed in U.S. Ser. No. 08/696,667 include
Pseudomonas putida
421-5 (ATCC 55687) and Rhodococcus B264-1 (ATCC 55806).
While the route disclosed in USSN 08/696,667 constitutes a practical means for the production of a cis-(1S,2R)-indanediol intermediate, other indene metabolites such as indanone, indenol and keto-hydroxy compounds can form as by-products, which can both limit the yield and complicate the recovery of the desired indanediol product. The maximum isolated yield of cis-(1S,2R)-indanediol in the 08/696,667 process is typically no more than about 20%, which in turn limits the potential yield of the (1S)-amino-(2R)-indanol derivative. There exists the need for bioconversion processes which produce cis-(1S,2R)-indanediol from indene in higher yields and with little or no by-product formation.
SUMMARY OF THE INVENTION
The present invention is a method for preparing cis-(1S-2R)-indanediol via the microbial direduction of 1,2-indanedione. More particularly, the present invention is a process for preparing cis-(1S-2R)-indanediol comprising (A) fermenting a culture medium containing a yeast strain selected from the group consisting of
Trichosporon cutaneum
MY 1506 (ATCC 74440) and mutants thereof and 1,2-indanedione to form cis-(1S,2R)-indanediol; and (B) recovering cis-(1S,2R)-indanediol from the culture medium.
The method of the present invention does not form indanedione, indenol or keto-hydroxy compounds as by-products and can have isolated yields of cis-(1S,2R)-indanediol of 50% or more.
In one embodiment, the step of recovering the cis-(1S,2R)-indanediol comprises separating the cis-(1S,2R)-indanediol from trans-indanediol diastereomer byproducts (i.e., trans-(1S,2S)-indanediol and/or trans-(1R,2R)-indanediol.) In another embodiment of the invention, the recovery step further comprises separating the cis-(1S,2R)-indanediol from its cis-(1R,2S)-indanediol enantiomer, such that the separated cis-(1S,2R) enantiomer formed is essentially free of any stereoisomer.
In a preferred embodiment of the invention, the cis-(1S,2R)-indanediol is formed with an enantiomeric excess of at least about 99%. Enantiomeric excess is the percent excess of one enantiomeric form over the other. Accordingly, the enantiomeric excess of enantiomeric form A over enantiomeric form B is [(A−B)/(A+B)]×100.
In another preferred embodiment of the invention, the yeast strain is
Trichosporon cutaneum
MY 1506 (ATCC 74440).
A further aspect of the present invention is a process for preparing (1S)-amino-(2R)-indanol comprising (A) fermenting a culture medium containing a yeast strain selected from the group consisting of
Trichosporon cutaneum
MY 1506 (ATCC 74440) and mutants thereof and 1,2-indanedione to form cis-(1S,2R)-indanediol; (B) recovering cis-(1S,2R)-indanediol from the culture medium; (C) mixing one equivalent of the recovered cis-(1S,2R)-indanediol with excess acetonitrile and maintaining the mixture at a temperature of from about −40° C. to about 25° C.; and (D) adding to the mixture excess equivalents of strong acid and maintaining the mixture at a temperature of from about −40° C. to about 25° C. to form (1S)-amino-(2R)-indanol.
REFERENCES:
patent: 5413999 (1995-05-01), Vacca et al.
patent: 5605819 (1997-02-01), Chartrain et al.
patent: 5858737 (1999-01-01), Buckland et al.
patent: WO 97/00966 (1997-01-01), None
patent: WO 98/06866 (1998-02-01), None
patent: WO 98/06865 (1998-02-01), None
E. N. Jacobsen et al., “Highly Enantioselective Epoxidation Catalysts Derived from 1,2-Diaminocyclohexane”, J. Amer. Chem. Soc., vol. 113, pp. 7063-7064 (1991).
K. Tomioka et al., “Stereoselective Reactions. XIX. Asymmetric Dihydroxylation of Olefins . . . ”, Chem. Phar. Bull., vol. 38, pp. 2133-2135 (1990).
L. P. Wackett et al., “Benzylic Monooxygenation Catalyzed by Toluene Dioxygenase from Pseudomonas putida”, Biochemistry, vol . 27, pp. 1360-1367 (1988).
J. M. Brand et al., “Stereospecific Hydroxylation of Indan byEscherichia coliContaining the Cloned . . . ”, Appl. Environ. Microbiol., vol. 58, No. 10, pp. 3407-3409 (Oct. 1992).
J. B. Jones, “Enzymes in Organic Synthesis”, Tetrahedron, vol. 42, No. 15, pp. 3351-3403 (1986).
M. D. Lilly, “Advances in Biotransformation Processes”, Chem. Eng. Sci., vol. 49, No. 2, pp. 151-159 (1994).
O. P. Ward et al., “Reductive biotransformations of organic compounds by cells or enzymes of yeast”, Enzyme Microb. Technol., vol. 12, pp. 482-493 (1990).
S. M. Roberts et al., “The Use of Enzymes for the Preparation of Biologically Active Natural Products and Analogues in Optically Active Form”, Current Organic Chem., vol. 1, pp. 1-20 (1997).
M. Chartrain et al., “The Application of Asymmetic Bioreductions of the Production of Chiral Pharmaceutical Drugs”, Enzyme Engineering XIII, Annals of NY Acad. Sciences, vol. 799, pp. 612-619 (1996).
R. Bel-Rhlid et al., “Microbiological Reduction of Carbonyl Groupings: Preparation of Stereoisomeric Acyclic Chiral Alpha Diols”, Bioca
Chartrain Michael M.
Ikemoto Norihiro
King Anthony O.
Merck & Co. , Inc.
Saucier Sandra E.
Walton Kenneth R.
Winokur Melvin
LandOfFree
Process for the preparation cis-(1S,2R)-indanediol by... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation cis-(1S,2R)-indanediol by..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation cis-(1S,2R)-indanediol by... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2553064