Process for synthesizing para-and/or meta-substituted...

Details Process for synthesizing para-and/or meta-substituted... Process for synthesizing para-and/or meta-substituted...

2000-03-31

2001-09-04

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Nitriles

Reexamination Certificate

active

06284912

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel process for synthesizing non-natural amino acids, para- and/or meta-substituted cyanophenylalanine derivatives represented by the following formula (1):
in which
R
1
represents amino-protecting group,
A represents —OR
2
(wherein, R
2
represents hydrogen, lower-alkyl, cycloalkyl or phenyl) or
wherein, R
3
and R4 independently of one another represent hydrogen, lower-alkyl or cycloalkyl, or together with the nitrogen atom to which they are attached represent heterocyclic group),
n represents an integer of 1 or 2, and the —CN group is located at para or meta position, and their isomers. More specifically, the present invention relates to a process for preparing the compound of formula (1) and its stereoisomer, characterized in that a compound represented by the following formula (2):
in which
R represents fluorosulfonyl, trifluoromethanesulfonyl or nonafluorobutanesulfonyl,
R
1
, A and n are defined as previously described, and
the —OR group is located at para or meta position, is reacted with a cyanide in the presence of a nickel catalyst.
BACKGROUND ART
The para- and/or meta-substituted cyanophenylalanine derivatives are important intermediate in medicinal chemistry. Particularly, it acts as a very useful intermediate for preparing the thrombin inhibitor LB30057 which has been recently developed by LG Chemical Ltd. as a selective and orally-administered thrombin inhibitor. Therefore, establishment of the effective manufacturing process thereof is very important for preparing LB30057.
Further, para- and/or meta-substituted cyanophenylalanine derivatives have been used as a key intermediate in the preparation of the existing thrombin inhibitor CRC 220(
Terahedron
, 1995, 51, 12047) and GPIIb/IIIa receptor antagonist(
J. Med. Chem
. 1996, 39, 1372).
For the synthesis of para- and/or meta-substituted cyanophenylalanine derivatives, catalytic asymmetric hydrogenation (
Terahedron
, 1995, 51, 12047), alkylation of the enolate of glycine derivative(
J. Chem. Soc. Perkin Trans
1, 1996, 645 and
J. Am. Chem. Soc
. 1997, 119, 656) have been disclosed. These methods, however, have some drawbacks therewith that adeprotection during the synthesis is not easy and large scale production can hardly be achieved thereby.
The present inventors have already developed a process for preparation of said intermediate based on a cyanation reaction using a palladium catalyst as a result of extensive study. Then, we filed a patent application claiming the invention(Korean Patent Application No. 97-41254).
Under such a technical situation, the present inventors have constantly tried to economically and conveniently prepare the useful medicinal intermediate, compound of formula (1) above. During the tries, unexpectedly, we found that such a purpose can be accomplished by reacting the compound of formula (2) with a cyanide in the presence of a nickel catalyst, and then completed the present invention.
DISCLOSURE OF THE INVENTION
Therefore, it is an object of the present invention to provide a process for preparing the compound of formula (1) with a high yield from the phenylalanine derivative of formula (2) in the presence of an inorganic cyanide salt and a nickel catalyst. The process for preparing the compound of formula (1) from the compound of formula (2) is depicted in the following reaction scheme 1.
in which
R represents fluorosulfonyl, trifluoromethanesulfonyl or nonafluorobutanesulfonyl,
R
1
represents amino-protecting group,
A represents −OR
2
(wherein, R
2
represents hydrogen, lower-alkyl, cycloalkyl or phenyl) or
(wherein, R
3
and R
4
independently of one another represent hydrogen, lower-alkyl or cycloalkyl, or together with the nitrogen atom to which they are attached represent heterocyclic group),
n represents an integer of 1 or 2, and
the —CN(or —OR) group is located at para or meta position.
DETAILED DESCRIPIION OF THE INVENTION
The process summarized in the above reaction scheme 1 are more specifically explained as follows.
Through the present specification, the starting and object compounds wherein A is restricted to —OR
2
are cited by adding “—A” to the compound number.
In the definitions for the substituents of the compound of fonnula (1), the term “amino-protecting group” means the conventionally used one in the field of organic synthesis, which includes carbonyl groups such as fluorenylmethyloxycarbonyl, phthalyl, t-butoxycarbonyl, benzyloxycarbonyl, etc., or aromatic- or heteroaromatic sulfonyl groups such as toluenesulfonyl, benzenesulfonyl, naphthalenesulfonyl, benzothiazole-2-sulfonyl, 5-methyl-1,3,4-thiadiazole-2-sulfonyl, etc.; the term “lower-alkyl” means a saturated and straight-chain or branched hydrocarbon radical having 1 to 4 carbon atoms, which includes methyl, ethyl, isopropyl, n-butyl, isobutyl and t-butyl; the term “cycloalkyl” means cyclic alkyl having 3 to 8 carbon atoms, which includes cyclopentyl; and the term “heterocyclic group” means 5- or 6-membered saturated or unsaturated ring containing one or two nitrogen atom(s) which may be substituted, the representative example of which is 4-methylsulfonyl-piperazine.
The compound of formula (1) can exist as a pure stereoisomer such as enantiomer of R or S, and therefore, without a specific mention hereinafter, the present invention is understood to include each of these stereoisomers and their mixtures.
The nickel catalyst used in the process according to the present invention is produced by reducing a nickel divalent compound with a reducing agent The nickel divalent compound which can be used for this purpose includes Ni(PPh
3
)
2
Cl
2
, Ni(PPh
3
)
2
Br
2
, NiBr
2
, NiCl
2
, Ni(acac)
2
, Ni(OAc)
2
(wherein, Ph means phenyl, ac or Ac means acetate), etc. These compounds are reduced with zinc, n-BuLi or DIBAL(diisobutylaluminum-chloride) in the reaction solution in the presence of triphenylphosphine or its derivative to produce a Ni compound having 0 valence[Ni(0)] which actually acts as the nickel catalyst in the process according to the present invention. As far as the catalyst thus obtained functions in the desired manner, there are no restriction on the kind of catalyst compound or reducing agent. This reaction has been used for converting trifluoromethanesulfonyl group in a simple benzene compound into cyano group(
Chem. Lett
. 1989, 1957), which, however, has never been applied to the more complicated compounds.
It is preferable to use the catalyst in an amount of 1-20 mol % with respect to the compound of formula (2) since using the excess reagent of more than 20 mol % is uneconomic.
The reducing agent zinc, n-BuLi or DIBAL is suitably used in an amount of 1 equivalent with respect to the nickel divalent compound. However, there is no influence on the reaction when the reducing agent is used in excess. Triphenylphosphine or its derivative which acts as a ligand is used in an amount of 1 to 5 equivalents with respect to the nickel compound because the stabilization of Ni(0) catalyst can be achieved in said range and the reaction can hardly be completed due to the decomposition of the catalyst when the ligand is used in an amount of less than 1 equivalent.
Whatever cyanides generate cyanide ion into the reaction medium can be used in the present invention. Preferably, one or more selected from the group consisting of KCN, NaCN and Zn(CN
2
is used. In the case of KCN and NaCN, the cyanide is preferably used in an amount of 1to 2.5 times molar amount with respect to the compound of formula (2), and in the case of Zn(CN)
2
, it is preferably used in an amount of 0.5 to 1.5 times molar amount to the compound (2). When the cyanide is used in an amount of more than the respective upper limit, it may react with Ni(0) catalyst to cause the reduction of catalyst activity.
The reaction is carried out at temperatures ranging from 40 to 80° C., and one or more selected from the group consisting of acetonitrile, tetrahydrofuran(THF), dimethylformarnide(DMF), dimethylsulfoxide(DMSO) and N-methylpyrrolidone(NMP) are used as the solvent. T

Affiliated with

Also associated with

Rating

Process for synthesizing para-and/or meta-substituted... 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 synthesizing para-and/or meta-substituted..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for synthesizing para-and/or meta-substituted... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2548713