Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-10-09
2004-09-21
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S468000, C564S488000, C564S490000, C558S392000, C558S393000
Reexamination Certificate
active
06794542
ABSTRACT:
The invention relates to a process for the preparation of a diastereomerically enriched compound having formula 1
where
R
1
is a substituted or unsubstituted phenyl group,
R
2
, R
3
and R
4
each differ from one another and R
2
and R
3
represent H, a substituted or unsubstituted (cyclo)alkyl group, (cyclo)alkenyl group, aryl group, cyclic or acyclic heteroalkyl group or heteroaryl group with one or more N, O or S atoms, or (CH
2
)
n
—COR
6
, where n=0, 1, 2 . . . 6 and R
6
=OH, a substituted or unsubstituted alkyl group, aryl group, alkoxy group or amino group and
R
4
=CN, H or a substituted or unsubstituted allyl group and
R
5
is H or alkyl with 1-6 C atoms, in which an enantiomerically enriched phenylglycine amide having formula 2
where R
1
and R
5
have the aforementioned meanings, is, with the aid of a compound having formula 3
R
2
—C(O)—R
3
(3)
where R
2
and R
3
have the aforementioned meanings, converted into the corresponding Schiff base or the tautomeric enamine, and the Schiff base obtained is subsequently converted into the diastereomerically enriched compound having formula 1 with the aid of a cyanide source, for instance HCN or an alkali cyanide, a reducing agent (for example H
2
) or an allyl organometallic compound (as shown in
FIG. 1
, wherein R represents a substituted or an unsubstituted allyl group).
In this process an enantiomerically enriched phenylglycine amide is used as a chiral auxiliary in diastereoselective reaction concepts. The literature refers to a number of examples of processes in which chiral auxiliaries are used, for example enantiomerically enriched &agr;-phenylglycinol or enantiomerically enriched &agr;-methylbenzyl amine.
A drawback of the known chiral auxiliaries is that they are very costly and thus less suitable for commercial use, as the chiral auxiliaries are consumed during the process.
The applicant has now found that phenylglycine amides according to formula (2), for example phenylglycine amide, p-hydroxyphenylglycine amide or &agr;-methylphenylglycine amide, are particularly suitable for use as chiral auxiliaries in the preparation of enantiomerically enriched compounds, in particular &agr;-amino acids, &bgr;-amino acids, or derivatives thereof and amines (e.g. as represented in
FIGS. 2
,
3
and
4
). This is the more surprising since phenylglycine amides are known to be susceptible to racemisation. Phenylglycine amides, for example phenylglycine amide or &agr;-methyl phenylglycine amide are available on large scale.
Another major advantage of the invention is that, in most cases, the phenylglycine amide derivatives formed in the process of the invention result in crystalline products. This means that compounds that are not completely diastereomerically pure can be purified to diastereomerically pure compounds via a simple crystallisation step. This is in contrast with the hitherto commonly used chiral auxiliaries. These often yield oils, and, therefore, cannot be diastereomerically enriched by crystallization. Consequently, these oils (derivatised or non-derivatised) are for instance separated by means of for example (chiral) chromatography.
Suitable compounds having formula (3) are for example aldehydes, ketones, ketoacids, ketoesters, ketoamides and glyoxylic acid (derivatives), in particular pivaldehyde, methyl isopropyl ketone, acetophenone, isobutyraldehyde, pyruvic acid, trimethylpyruvic acid and ethyl acetoacetate.
Diastereomerically enriched compounds that can particularly well be prepared with the process of the invention are for example compounds according to formula 1 where R
4
=CN. It has also been found that either of the two diastereomers may crystallise preferentially, while the other one remains in solution and epimerises in situ. This means that, under the chosen conditions, regardless of the intrinsic diastereomeric excess, complete conversion into one diastereomer may occur (the intrinsic diastereomeric excess is obtained via asymmetric induction by the chiral auxiliary under homogeneous conditions).
The aminonitrile obtained may subsequently be converted, in any one of various manners known for aminonitriles (FIG.
2
), into amino acids, amino acid amides and amino acid esters, for example through acidic hydrolysis, basic hydrolysis, enzymatic hydrolysis or through metal-catalysed hydrolysis. A suitable embodiment is for example treatment with a strong acid at elevated temperature to form the corresponding diacid, which subsequently, after hydrogenolysis according to a known method (for example with the aid of H
2
and a Pd/C or Pd(OH)
2
catalyst), yields the corresponding amino acid.
The aminonitrile obtained may also be converted into the corresponding diamide, for example by treating it with a strong acid, which diamide subsequently, after hydrogenolysis of the auxiliary group, yields the corresponding amino acid amide. If desired, the amino acid amide may be converted, in a known manner (for example with a strong acid), into the corresponding amino acid.
Another conversion comprises for example treating the aminonitrile obtained with a strong acid in alcohols (for example with methanol) to form the corresponding monoester or diester, which subsequently, after hydrogenolysis of the auxiliary group, yields the corresponding amino acid ester. If desired, the amino acid ester may be converted by means of a known method (for example using a strong acid) into the corresponding amino acid.
Other compounds that can particularly well be prepared using the process of the invention are for example enantiomerically enriched amines. These amines can be prepared for instance through reduction of the Schiff base followed by hydrogenolysis according to a known method, for example with the aid of H
2
and a Pd/C or a Pd(OH)
2
catalyst (FIG.
3
).
Reduction of the Schiff base can be effected for example with the aid of NaBH
4
, LiAIH
4
or derivatives thereof (e.g. alkoxy derivatives such as NaBH(OAc)
3
), with hydrogenation catalysts, for example Pd, Pt or Raney-Ni in combination with H
2
or under transfer-hydrogenation conditions. Especially Raney-Ni or Pd was found to be a suitable catalyst for hydrogenation reactions leading to high diastereoselectivities.
Amines and &bgr;-amino acid derivatives (e.g. as represented in FIGS.
3
and
4
), too, may be particularly well prepared through selective addition to the Schiff base of allyl organometallic compounds. Particularly suitable allyl organometal compounds were found to be for example Zn or Mg, preferably Zn, derivatives. After addition of a substituted or unsubstituted allyl organometal compound to the Schiff base, the allyl compound obtained can for example be converted into a &bgr;-amino acid or a derivate thereof. A suitable embodiment is for example conversion of the double bond according to known oxidative methods, for example by catalytic oxidation, stoichiometric oxidizing agents or via ozonolysis, followed by oxidative treatment and subsequent hydrogenolysis into the corresponding &bgr;-amino acid (FIG.
4
), or &bgr;-amino acid ester.
Particularly suitable appeared to be the conversion via ozonolysis in the presence of a base, for instance NaOH, and an alcohol, for example methanol, of the double bond into a &bgr;-amino acid ester derivative via a method as described in J. Org. Chem., 1993, 58, 3675-3680, and the subsequent hydrogenolysis into the corresponding &bgr;-amino acid ester.
Furthermore it has been found that the allyl compound obtained can be converted in a 3-amino alcohol derivative, for instance by ozonolysis followed by reductive work up, for instance using NaBH
4
. Subsequently the 3-amino alcohol can be liberated by hydrogenolysis.
Amines can be obtained through reduction of the substituted or unsubstituted allyl group followed by hydrogenolysis (
FIG. 3
, wherein R represents a substituted or unsubstituted allyl group and R
4
1
represents the hydrogenated form of R).
The compounds having formula 1, where R
1
, R
2
, R
3
, R
4
, R
5
, are as previously defined, and the compounds with formu
Boesten Wilhelmus Hubertus Joseph
Broxterman Quirinus Bernardus
Kaptein Bernardus
Lange De Ben
Moody Harold Monro
DSM N.V.
Kumar Shailendra
Morrison & Foerster / LLP
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