Process and intermediates for preparation of substituted...

Details Process and intermediates for preparation of substituted... Process and intermediates for preparation of substituted...

1999-07-13

2001-07-31

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06268499

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to a intermediates useful in a process for the preparation of substituted piperidine-epoxides. More particularly, the invention relates to the preparation of compounds of the formula 1
and salts thereof, wherein
A
is arylene;
R
1
is -C*R
3
R
4
R
5
;
R
2
is -O-alkyl, -O-cycloalkyl, -O-alkenyl, -O-aryl, -O-aralkyl,
-O-aralkoxyalkyl, -O-alkylsulfonyl, -O-arylsulfonyl, chlorine,
bromine or iodine;
R
3
is hydrogen;
R
4
is aryl;
R
5
is alkyl, cycloalkyl, aryl, alkoxyalkyl or hydroxyalkyl;
and C*
is an asymmetric carbon atom.
The invention also relates to compounds of formula 1, which are useful as chiral building blocks in the preparation of renin inhibitors, especially trisubstituted renin inhibitors as is disclosed in WO 97/09311 e.g. (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl [-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine.
BACKGROUND OF THE INVENTION
The syntheses of optically active renin inhibitors via resolution of racemates as disclosed in WO 97/09311 results in a considerable loss of product. The present invention provides a novel process which avoids the disadvantages of this process.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, compounds of formula 1 above and their salts can be prepared by a process comprising:
a) epoxidation of a compound of formula 2 or a salt thereof
wherein
R
1
, R
2
and A are defined as above.
In another embodiment of the present invention, step a) above may be optionally followed by isolation of the desired stereoisomer.
The term “alkyl” means alone or in combination a branched or unbranched alkyl group containing 1 to 8 carbon atoms, preferred 1 to 6 carbon atoms. Examples for branched or unbranched C
1
-C
8
alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls, the isomeric octyls and preferred ethyl, n-propyl, and isopropyl and particularly preferred methyl.
The term “cycloalkyl” means alone or in combination a cycloalkyl cycle with 3 to 8 carbon atoms and preferred a cycloalkyl cycle with 3 to 6 carbon atoms. Examples for C
3
-C
8
cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl and cycloheptyl.
The term “alkenyl” means alkenyl groups of 2 to 8 carbon atoms. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-ethyl-2-butenyl, and the like. Preferred is allyl.
The term “aryl” means alone or in combination a phenyl or a naphthyl group which can be substituted by one or several substituents chosen from alkyl, cycloalkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, hydroxy, amino, nitro, trifluoromethyl and the like. Examples for aryl are phenyl, tolyl, methoxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, trifluoromethylphenyl, 1-naphthyl and 2-naphthyl.
The term “arylene” means alone or in combination a phenylene or a naphthylene group which optionally can be substituted by one or several substituents chosen from alkyl, cycloalkyl, halogen, nitro, alkoxy, hydroxy, amino, preferably alkyl, halogen and nitro. Examples for arylene are ortho-phenylene, meta-phenylene, para-phenylene, the tolylenes, methoxyphenylenes, fluorophenylenes, chlorophenylenes and naphthylenes. Preferred are phenylene, wherein the substituents of the phenylene which are defined by formula 1 are placed ortho, meta or preferred para to one another and wherein one or several additional substituents chosen from alkyl, halogen and nitro can be present at the arylene cyclus. Especially preferred substituents are methyl, chloro and nitro. Particularly preferred is unsubstituted phenylene and especially unsubstituted para phenylene.
The term “alkoxy” means alone or in combination the group
13
O-alkyl, wherein alkyl is defined as before. Examples are ethoxy, n-propyloxy, and iso-propyloxy. Preferred is methoxy.
The term “alkoxyalkyl” means alone or in combination an alkyl group, wherein a hydrogen is substituted by an alkoxy group. Examples are methoxymethyl, ethoxymethyl and 2-methoxyethyl. Particularly preferred is methoxymethyl.
The term “hydroxyalkyl” means alone or in combination an alkyl group, wherein a hydrogen is substituted by an hydroxy group. Examples are hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl. Preferred is hydroxymethyl.
The term “aralkyl” means alone or in combination an alkyl group, wherein a hydrogen is substituted by an aryl group. A preferred example is benzyl.
The term “aralkoxyalkyl” means alone or in combination an alkyl group, wherein a hydrogen is substituted by an alkoxy group in which a hydrogen is substituted by an aryl group. A preferred example for aralkoxyalkyl is 3-(2-methoxy-benzyloxy)-propyl.
The term “alkylsulfonyl” means alone or in combination a sulfonyl group which is substituted by an alkyl group. The alkyl group can be substituted by halogen. Preferred examples are methylsulfonyl and trifluoromethylsulfonyl.
The term “arylsulfonyl” means alone or in combination a sulfonyl group which is substituted by an aryl group. Preferred is the tosyl group.
The term “salts” means compounds which are formed by reaction of compounds of formula 1 with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. The term salts includes solvates and particularly hydrates of such salts.
The term “halogen” means fluorine, chlorine, bromine, iodine, preferably chlorine and bromine. Most preferred is chlorine.
The term “anion” means an atom, a group of atoms or a molecule with negative charge. This charge can be a single or a multiple charge. Examples of anions are the halogen anions, SO
4
2−
, PO
4
3−
. Particularly preferred is the Cl
−
anion.
The term “asymmetric carbon atom (C*)” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog-Convention, the asymmetric carbon atom have “R ” or “S ” configuration. A preferred example for an asymmetric carbon atom (C*) is shown in the formula
wherein the asymmetric carbon atom C* is of the R configuration.
The term “—O—” in groups such as —O-alkyl, —O-cycloalkyl, —O-alkenyl, —O-aryl, —O-benzyl, —O-aralkoxyalkyl, —O-alkylsulfonyl, —O-arylsulfonyl, means an oxygen with a free valence. For example —O-alkyl means alkoxy and —O-cycloalkyl means cycloalkoxy.
In a preferred embodiment, the above process is used to prepare compounds of the formula 1 wherein R
5
is alkyl or cycloalkyl and R
1
, R
2
and A are defined as above.
Also preferred is a process according to the present invention, wherein R
4
is unsubstituted phenyl or substituted phenyl and, wherein the substituents of phenyl are independently selected from one or more of alkyl, halogen or nitro, preferably methyl or chloro. In a particularly preferred embodiment of the above process R
4
is unsubstituted phenyl and R
1
, R
2
and A are as defined above.
Particularly preferred is the above process above, wherein R
4
is phenyl, particularly unsubstituted phenyl, and R
5
is methyl and R
1
, R
2
and A are as otherwise defined above.
In another preferred embodiment of the present invention, A is substituted or unsubstituted ortho, meta or para phenylene. When substituted, the substituents on the phenylene are placed ortho, meta or para to one another. The para position is preferred. The substituted phenylene has one to four substituents chosen from alkyl, halogen and nitro. Most preferably, A is unsubstituted phenylene, and in particular unsubstituted para phenylene.
In another preferre

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