Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-06-08
2002-08-20
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S128000, C560S169000, C549S436000, C549S546000, C549S315000
Reexamination Certificate
active
06437171
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention concerns a new multi-step process for preparing 1,2-diamino compounds from 1,2-epoxides, in particular 1,2-diamino compounds useful as inhibitors of viral or bacterial neuraminidases, a new step of that multi-step process for preparing 2-aminoalcohols from 1,2-epoxides, a new step for the transformation of a 2-aminoalcohol into a 1,2-diamino compound as well as specific intermediates useful in that multi-step process.
PCT Patent Publication No. 96/26933 describes a large class of compounds useful as inhibitors of viral or bacterial neuraminidases and their preparation. These compounds comprise a six membered partially unsaturated carbocyclic or heterocyclic ring system, which can be substituted by several different substituents.
PCT Patent Publication No. 98/07685 discloses various methods for preparing compounds of the above class which are cyclohexene carboxylate derivatives. A particularly interesting compound is (3R,4R,5S)-5-amino-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-ene-carboxylic acid ethyl ester (C. U. Kim et al., J. Am.Chem. Soc., 1997, 119, 681-690). A method of preparation of that 1,2-diamino compound in 10 steps starting from shikimic acid, or in 12 steps starting from quinic acid, is described by J. C. Rohloff et al., J. Org. Chem.,1998, 63, 4545-4550. The 10 step method involves a final 4-step reaction sequence from the 1,2-epoxide (1S,5R,6R)-5-(1-ethyl-propoxy)-7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester via three potentially highly toxic and explosive azide intermediates. Dedicated know-how and expensive equipment are required to perform such a process. In a technical process it is preferable to avoid use of azide reagents and azide intermediates.
The problem to be solved by the present invention therefore was to find an azide-free process for preparing 1,2-diamino compounds from 1,2-epoxides.
That problem has been solved by the invention as described below and as defined in the appended claims.
SUMMARY OF THE INVENTION
The invention provides a process for preparing 1,2-diamino compounds of formula
and pharmaceutically acceptable addition salts thereof wherein,
R
1
, R
1′
, R
2
and R
2′
, independently of each other, are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, or aryl-lower alkynyl, or
R
1
and R
2
, R
1
and R
2′
, R
1′
and R
2
or R
1′
and R
2′
taken together with the two carbon atoms to which they are bound, are a carbocyclic or heterocyclic ring system, or
R
1
and R
1′
or R
2
and R
2′
taken together with the carbon atom to which they are bound, are a carbocyclic or heterocyclic ring system,
with the proviso that at least one of R
1
, R
1′
, R
2
and R
2′
is not H, and
R
3
and R
4
, independently from each other, are H or a substituent of an amino group, with the proviso that not both R
3
and R
4
, are H,
which process is characterized in that it comprises the steps of
a) reacting a 1,2-epoxide of formula
wherein R
1
, R
1′
, R
2
and R
2′
are as above with an amine of formula R
5
NHR
6
wherein R
5
and R
6
, independently of each other, are H, or a substituent of an amino group, with the proviso that not both R
5
and R
6
are H to form a 2-aminoalcohol of formula
wherein R
1
, R
1′
, R
2
, R
2′
, R
5
and R
6
are as above
b) converting the 2-aminoalcohol of formula (III) into a 2-aminoalcohol of formula
wherein R
1
, R
1′
, R
2
and R
2′
are as above,
c) transforming the 2-aminoalcohol of formula (IV) into a 1,2-diamino compound of formula
wherein R
1
, R
1′
, R
2
, R
2′
, R
5
and R
6
are as above
d) acylating the free amino group in position 1 of the 1,2-diamino compound of formula (V) to form an acylated 1,2-diamino compound of formula
wherein R
1
, R
1′
, R
2
R
2′
, R
3
, R
4
, R
5
and R
6
are as above and finally
e) deprotecting the amino group in position 2 of formula (VI) to form the 1,2-diamino compound of formula (I).
If desired, the resulting 1,2-diamino compound of formula (I) can be further transformed into a pharmaceutically acceptable addition salt.
DETAILED DESCRIPTION OF THE INVENTION
The term “alkyl” means a straight chain or branched saturated alkyl group with 1-20, preferably 1-12, C-atoms, which can carry one or more substituents.
The term “alkenyl” means a straight chain or branched alkenyl group with 2-20, preferably 2-12, C-atoms, which can carry one or more substituents.
The term “alkynyl” means a straight chain or branched alkynyl group with 2-20, preferably 2-12, C-atoms, which can carry one or more substituents.
The term “cycloalkyl” signifies a saturated, cyclic hydrocarbon group with 3-12, preferably 5-7, C-atoms, which can carry one or more substituents.
The term “aryl” denotes a mono-nuclear or di-nuclear aromatic group which can carry one or more substituents, such as, for example, phenyl, substituted phenyl, naphthyl, or substituted naphthyl.
The term “heterocyclyl” means a saturated or unsaturated monocyclic or bicyclic group with 1 or 2 nitrogen, sulfur and/or oxygen atoms such as, for example pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, isobenzofuranyl, furanyl, tetrahydrofuranyl, thiofuranyl, dihydrothiofuranyl, benzo[b]dihydrofuranyl, tetrahydrothiofuranyl, thioxanyl, dioxanyl, dithianyl, chromanyl, isochromanyl, dithiolanyl, pyridyl, pyperidyl, imidazolidinyl, pyrrolidinyl, quinolyl or isoquinolyl, which can carry one or more substituents.
The term “carbocyclic ring system” means a cyclic alkyl group with 3-12, preferably 5-7, C-atoms, which can include one or two carbon-carbon double bonds, and which can carry one or more substituents, such as for example cyclopentene, substituted cyclopentene, cyclohexene, substituted cyclohexene, cycloheptene, or substituted cycloheptene.
The term “heterocyclic ring system” means a monocyclic or bicyclic group with 1 or 2 nitrogen, sulfur and/or oxygen atoms, which can include one or two double bonds and carry one or more substituents, as exemplified above under the term “heterocyclyl”, for example tetrahydropyran, dihydropyran, substituted dihydropyran, tetrahydrofuran, isobenzotetrahydrofuran, thioxan, 1,4-dioxane, dithian, dithiolan, piperidine, or piperazine.
Suitable substituents on the above groups are those which are inert in the reactions involved.
Examples of suitable substituents on such alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, aryl, or aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, are lower alkyl, lower alkoxy, lower alkyl carboxylate, carboxylic acid, carboxamide, N-(mono/di-lower alkyl)-carboxamide.
Examples of suitable substituents on such a carbocyclic or heterocyclic ring system are alkyl of 1 to 12 C-atoms, alkenyl of 2 to 12 C-atoms, alkynyl of 2 to 12 C-atoms, alkoxy of 1 to 12 C-atoms, alkyl of 1 to 12 C-atoms-carboxylate, carboxylic acid, carboxamide, N-(mono/di-alkyl of 1 to 12 C-atoms)-carboxamide. Preferred substituents are lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, carboxylic acid, lower alkyl carboxylate, carboxamide, N-(mono/di-lower alkyl)-carboxamide.
The term “lower” here denotes a group with 1-6, preferably 1-4, C-atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl and its isomers and hexyl and its isomers. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, sec.-butoxy, tert.-butoxy and 1-ethyl-propoxy. Examples of lower alkyl carboxylates are methyl carboxylate, ethyl carboxylate, propyl carboxylate, isopropyl carboxylate and butyl carboxylate. Examples
Karpf Martin
Trussardi Rene
Gitomer Ralph
Hoffman-La Roche Inc.
Johnston George W.
Khare Devesh
Tramaloni Dennis P.
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