Synthesis of nitroalcohol diastereomers

Details Synthesis of nitroalcohol diastereomers Synthesis of nitroalcohol diastereomers

2000-05-19

2002-10-08

Davis, Brian J. (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C564S355000, C562S402000, C562S437000

Reexamination Certificate

active

06462221

ABSTRACT:

BACKGROUND OF THE INVENTION
It is often desirable to obtain a stereochemically pure form of a molecule. For example, pharmaceuticals, which interact with a specific target, are often more potent and/or have less deleterious side effects when they are administered in their stereochemically pure form.
Diastereomers can be synthesized using asymmetric synthetic techniques. However, asymmetric synthesis can require expensive reagents or have other limitation based on the specific molecules (e.g., difficulty in recrystallizing the product).
Another method of obtaining a diastereomerically pure compound is to selectively recrystallize the desired diastereomer or a synthetic precursor, thereof. However, diastereomers, such as 1-nitro-3-substituted-3-amino-2-propanol diastereomer, are difficult, if not impossible, to separate by crystallization. Even where crystallization is possible, it only allows for recovery of one diastereomer without additional processing steps, and recovery of the desired diastereomer is often low and purity is difficult to control.
Diastereomers can be resolved chromatographically. Unfortunately, conventional preparative chromatography requires a large amount of solvent, and can be an impractical way to produce clinical trial quantities of product. In addition, simulated moving bed separations have higher throughput and are more cost efficient than conventional preparative chromatography.
Simulating moving bed chromatography has been applied to the separation of C8 hydrocarbons (see Broughton,
Chem. Eng. Prog
. (1968), 64:60).; the separation of fructose and glucose by adsorption on a zeolite solid phase (see Kieprathipanja, U.S. Pat. No. 5,000,794); and the separation of enantiomers using a chiral solid support (see Gattuso, et al.,
Chemistry Today
(1996), p. 17 and Gattuso, U.S. Pat. No. 5,889,186). However, application of simulated moving bed technology to any specific group of chemical compounds often is unpredictable.
An improved method of making useful diastereomerically pure synthetic intermediates would help meet the demand for stereochemically pure compounds in the pharmaceutical and other industries.
SUMMARY OF THE INVENTION
The present invention relates to a method of preparing a 1-nitro-3-substituted-3-amino-2-propanol diastereomer represented by Structural Formula I:
In Structural Formula I, R is an amine protecting group, and R
1
is an amino acid side-chain, a protected amino acid side-chain, substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl group. Preferably, R
1
is an amino acid side-chain, a protected amino acid side-chain or an aromatic group. More preferably R
1
is an amino acid side-chain or a protected amino acid side-chain. The method involves contacting a 1-nitro-3-substituted-3-amino-2-propanone with a reducing agent to form a mixture of 1-nitro-3-substituted-3-amino-2-propanol diastereomers. The 1-nitro-3-substituted-3-amino-2-propanol diastereomers are then separated by simulated moving bed chromatography to obtain one or more 1-nitro-3-substituted-3-amino-2-propanol diastereomer.
In another embodiment, the method of preparing a 1-nitro-3-substituted-3-amino-2-propanol diastereomer represented by Structural Formula I involves contacting an amino acid having a protected amine group with a carboxylic acid activator to form an activated amino acid. The activated amino acid is contacted with a nitromethane anion solution to form a reaction mixture. An acid is added to the reaction mixture to form a 1-nitro-3-substituted-3-amino-2-propanone. The 1-nitro-3-substituted-3-amino-2-propanone is contacted with a reducing agent to form a mixture of 1-nitro-3-substituted-3-amino-2-propanol diastereomers which are separated by simulated moving bed chromatography to obtain one or more 1-nitro-3-substituted-3-amino-2-propanol diastereomer.
Another embodiment of the invention is a method of preparing a 1-nitro-3-benzyl-3-amino-2-propanol diastereomer represented by Structural Formula II:
In Structural Formula II, R is an amine protecting group. The method involves contacting a phenylalanine that has a protected amine group with a carboxylic acid activator to form an activated phenylalanine. The activated phenylalanine is contacted with a nitromethane anion solution to form a reaction mixture. An acid is added to the reaction mixture to form a 1-nitro-3-benzyl-3-amino-2-propanone. The 1-nitro-3-benzyl-3-amino-2-propanone is contacted with a reducing agent to form a mixture of 1-nitro-3-benzyl-3-amino-2-propanol diastereomers which are separated by simulated moving bed chromatography to obtain one or more 1-nitro-3-benzyl-3-amino-2-propanol diastereomer.
Another embodiment of the invention is a method of preparing a diastereomer of a 3-substituted-3-amino-2-hydroxypropanoic acid salt represented by Structural Formula III:
In Structural Formula III, R
1
is as defined in Structural Formula I. X
−
is Cl
−
, Br
−
, F
−
, I
−
,
−
HSO
4
, or
−
H
2
PO
4
. The method involves contacting a mixture of 1-nitro-3-substituted-3-amino-2-propanol diastereomers with an acid to form a mixture of 3-substituted-3-amino-2-hydroxypropanic acid diastereomeric salts. The 3-substituted-3-amino-2-hydroxypropanic acid diastereomeric salts are then separated by simulated moving bed chromatography to obtain one or more 3-substituted-3-amino-2-hydroxypropanoic diastereomeric salt.
The method of the invention allows one or more 1-nitro-3-substituted-3-amino-2-propanol diastereomer or 3-substituted-3-amino-2-hydroxypropanoic acid salt to be obtained in high diastereomeric excess. The present method avoids the use of costly chiral reagents, and in contrast to the use of chiral reagents or selective recrystallization, more than one diasteromers can be collected in high diastereomeric excess without additional processing steps. In addition, the diastereomers obtained from simulated moving bed separation are more concentrated than those obtained using standard chromatographic techniques.


REFERENCES:
patent: 5000794 (1991-03-01), Kulprathipanja
patent: 5475138 (1995-12-01), Pal et al.
patent: 5889186 (1999-03-01), Gattuso
patent: WO 96/01788 (1996-01-01), None
patent: WO 97/45185 (1997-12-01), None
Database CAPLUS on STN, Acc. No. 1997:259211, Francotte et al., ‘Applications of simulated moving bed chromatography to the separation of the enantiomers of chiral drugs.’ J. Chromatotgr., A, (1997), 769(1), pp. 101-107 (abstract).*
Database CAPLUS on STN, Acc. No. 1999:164888, Mazzotti et al., ‘Separation of fine chemicals by continuous SMB chromatography.’ Funda. Adsorpt., [conf.], 6th (1998), pp. 377-382 (abstract).*
Adachi, S., “Simulated moving-bed chromatography for continuous separation of two components ants application to bioreactors,”Jour. of Chromatography A658:271-282 (1994).
Pais, L.S. et al., “Separation of 1,1′-bi-2-naphthol enantiomers by continuous chromatography in simulated moving bed,”Chemical Engineering Science, 52(2) :245-257 (1997).
Nagamatsu, Shinji et al., “Optical resolution of a pharmaceutical intermediate by Simulated Moving Bed,”Chiral Europa(1996).
Gattuso, M.J. et al., “Simulated Moving Bed Technology—The Preparation of Single Enantiomer Drugs,”Chemistry Today, (1996, Nov./Dec.).
Strube, J. et al, “Comparison of Batch Elution and Continuous Simulated Moving Bed Chromatography,”Organic Process Research and Development2:305-319 (1998).
Hiroshi, Harada, “3-Amino-2-Hdyroxy-1-Nitrobutane Derivative and Production of Alpha-Hdyroxy-Beta-Amino Acid,”Patent Abstracts of Japan, vol. 014, No. 236 (c-0720) (1990).

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