Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1998-06-01
1999-08-03
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
562444, C07C22928
Patent
active
059327588
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is directed to a new process for the production of .beta.-Amino-.alpha.-hydroxy-carboxylic acids and derivatives of the common structure (2R,3S)- or (2S,3R)-N-(X,Y)-3-Amino-2-hydroxy-3-phenyl propionic acid-Z of the formula I ##STR2## wherein X H, (C.sub.1 -C.sub.6) Alkyl, Benzyl, -Phenyl or 4-NO.sub.2 -Benzyl, 4-NO.sub.2 -Benzyl, -Phenyl or Allyl
2. Discussion of the Prior Art
Compounds of Type I are useful intermediates in the total synthesis of Taxol (Paclitaxel), which finds use in the treatment of different types of cancer. A compound (2R, 3S)-Benzoyl-3-amino-2-hydroxy-3-phenylpropionyl-methylester of Formula II falling under Formula I ##STR3## is for example described in Tetrahedron Letters 35, 2845 (1994) as similarly derived from optically active Phenyl glycine and also as a key step in the enzymatic reduction of an .alpha.-Keto ester. A substantial disadvantage of the synthetic method is that the compound of Formula II can only be isolated in 12% yield. Task of the present invention therefore is to provide a process which delivers higher yields and proceeds in an environmentally friendly and economical manner.
SUMMARY OF THE INVENTION
The process in accordance with the invention runs from
a) (S)- or (R)-Phenyl glycine of Formula III ##STR4## as starting material. This is reduced with a Hydride reagent.
Suitable Hydride reagents are Lithium aluminum hydride or Sodium borohydride/Activator.
b) The (S) or (R)-Phenyl glycinol of Formula IV obtained in Step (a) ##STR5## is then
c) converted into N-protected .beta.-Amino alcohol (S)- or (R)-N-(X,Y)-Phenyl-glycinol of general Formula V ##STR6## wherein X H, (C.sub.1 -C.sub.6) Alkyl, Benzyl, -Phenyl or 4-NO.sub.2 -Benzyl, 4-NO.sub.2 -Benzyl.
This temporary blocking of the reactive Amino groups before the subsequent oxidation of the Hydroxyl group is essential to its preservation and proceeds as is described in detail later.
d) By the oxidation of the compound of Formula V a (S)- or (R)-N-(X,Y)-Phenyl glycinal of Formula VI is obtained. ##STR7## the oxidation, wherein X and Y have the above-mentioned values proceeds as will be described in detail below.
Subsequently the compound of Formula VI
e) is converted to (1RS,2S)- or (1RS,2R)-2-(X,Y)-Amino-1-cyano-2-phenylethan-1-ol of Formula VII ##STR8## wherein X and Y have the above-mentioned values. The formation of the nitrile may take place by means of well known procedures.
f) The thus obtained nitrile (Formula VII) is hydrolyzed to the acids VIII+IX or also their addition salts of Formulas X and XI ##STR9## wherein X and Y have the above-given values and W represents HC, HBr or H.sub.2 SO.sub.4. The hydrolysis carried out in the manner set forth in detail below.
g) Subsequently the compounds of Formulae VIII and XI are converted in accordance with usual methods to (2RS,3S)- or (2RS,3R)-3-Amino-2-hydroxy-3-phenyl propionic acid esters of Formula XII ##STR10## wherein Z is (C.sub.1 -C.sub.6) Alkyl, Phenyl, Benzyl, 4-NO.sub.2 -Phenyl, 4-NO.sub.2 -Benzyl or Allyl, and
i) Subsequently the still free nitrogen function of Formula X is protected by likewise known methods ##STR11## wherein Z, X and Y have the above-identified values, or
k) compounds IX and X are converted to the compounds of Formula I in accordance with the procedures of g).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
(S)- or (R)-Phenyl glycinol V are obtained by generally known methods in which the acid function of, for example, (S)-Phenyl glycine III is treated with hydride reagents as in JP-OS-5-221935 such as, for example, Lithium aluminum hydride or sodium borohydride/activator, preferred is the system sodium borohydride/sulfuric acid to reduce it to (S)-Phenyl glycinol IV.
The blocking of the nitrogen function of the .beta.-Amino alcohol (R)- or (S)-Phenyl glycinol V is similarly carried out in a generally known manner (analogous Synth. Commun. 1995, 25, S. 561). Thus for example, the reaction solution of the previous reaction step is reacted at pH 6-12, preferably pH 7-8.
REFERENCES:
Kearns et al. `Application of Yeast-Catalyzed Reductions to Synthesis of (2R, 3S)-Phenylisoserine.` Tetrahedron Letters, vol. 35, No. 18, pp. 2845-2848, 1994.
Drauz Karlheinz
Kottenhahn Matthias
Stingl Klaus
Behr, Esq Omri M.
Davis Brian J.
Degussa - Aktiengesellschaft
Geist Gary
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