Process for preparing optically active...

Details Process for preparing optically active... Process for preparing optically active...

2001-06-22

2003-02-25

Kumar, Shailendra (Department: 1621)

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Resolution of optical isomers or purification of organic...

C435S068100, C435S195000, C435S227000, C564S133000, C564S443000, C560S129000

Reexamination Certificate

active

06524844

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for preparing enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the general formulae:
in which R
1
is hydrogen, alkyl, aryl or cycloalkyl and R
2
is acyl, and in particular to reacting them further to give the corresponding enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene compounds of the formula IV
BACKGROUND OF THE PRIOR ART
Enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene of the formula IV, such as, for example, (1R,4S)-1-amino-4-(hydroxymethyl)cyclo-pent-2-ene, is an important intermediate in the preparation of carbocyclic nucleosides, such as, for example, carbovir (Campbell et al., J. Org. Chem. 1995, 60, 4602-4616).
Hereinbelow, “enantiomerically enriched” compounds are understood as compounds having an enantiomeric excess (ee) of more than 20%.
A number of processes for preparing (1R,4S)-1-amino-4-(hydroxymethyl)cyclopent-2-ene have been known up until now. WO 97/45529, for example, describes a biotechnological process for preparing (1R,4S)-1-amino-4-(hydroxymethyl)cyclopent-2-ene starting from racemic cis-N-acetyl-1-amino-4-(hydroxymethyl)cyclopent-2-ene using microorganisms which employ the latter as the only carbon source, as the only nitrogen source or as the only carbon and nitrogen source. This process has the disadvantage that it has to be carried out in a fermenter.
OBJECT OF THE INVENTION
It is the object of the present invention to provide an alternative, simple and cost-efficient process for preparing enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the formula I and II and enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene compounds of the formula IV.
According to the invention, the object is achieved by converting a racemic 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivative of the general formula
in which R
1
is hydrogen, an optionally substituted, linear or branched C
1-8
-alkyl radical, aryl radical or cycloalkyl radical using a hydrolase in the presence of an acylating agent into the enantiomerically enriched 1-amino-4-(hydroxymethyl)-cyclopent-2-ene derivatives of the general formulae
in which R
1
is as defined above and R
2
is acyl.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a process for preparing enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the general formulae
wherein R
1
is hydrogen or an optionally substituted C
1-8
- alkyl radical, aryl radical or cycloalkyl radical and R
2
is acyl, and wherein a racemic 1-amino-4-(hydroxymethyl) cyclopent-2-ene derivative of the general formula:
in which R
1
is as defined above is reacted using a hydrolase in the presence of an acylating agent.
Another embodiment of the present invention is directed to a process for preparing enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the general formula
comprising
a) converting a racemic 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivative of the general formula
in which R
1
, as defined in claim
1
; using a hydrolase in the presence of an acylating agent into enantiomerically enriched
wherein R
1
and R
2
, as defined in claim
1
; and
b) chemically hydrolyzing the 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the general formula I into the corresponding enantiomers of the general formula II.
A further embodiment of the present invention is directed to a process for preparing enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene of the formula
comprising:
a) converting a racemic 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivative of the general formula
wherein R
1
, as defined in claim
1
, using a hydrolase in the presence of an acylating agent into enantiomerically enriched
wherein R
1
and R
2
, as defined in claim
1
; and
b) chemically hydrolyzing the 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the general formulae I and II
into the corresponding enantiomerically enriched 1-amino-4-(hydroxymethyl)cyclopent-2-ene isomers of the formula IV.
The starting materials, the racemic 1-amino-4-(hydroxymethyl)cyclopent-2-ene derivatives of the general formula III, can be prepared starting from (±)-2-azabicyclo[2.2.1]hept-5-ene-3-one, in accordance with WO 97/45529. Preference is given to using the cis-racemic starting materials.
The term alkyl, as used in this context, includes both linear and branched alkyl. Alkyl can be substituted or unsubstituted. C
1-8
-alkyl is in particular methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers or octyl and its isomers. Substituted C
1-8
-alkyl is understood as C
1-8
-alkyl which is substituted by one or more halogen atoms, by OR
3
or by NR
3
R
4
, R
3
and R
4
being identical or different and being hydrogen or branched or linear C
1-8
-alkyl, aryl or cycloalkyl. The halogen atom used may be F, Cl, Br or I. Examples of NR
3
R
4
s are methylamino, N-methyl-N-ethylamino, 1-piperidinyl or aminomethyl. Examples of OR
3
s are methoxy, methoxymethyl, ethoxy, propoxy and phenoxy.
Aryl is preferably understood as benzyl or phenyl, substituted or unsubstituted. Substituted aryl is understood hereinbelow as aryl which is substituted by one or more halogen atoms C
1-4
-alkyl groups, C
1-4
-alkoxy groups, amino, cyano or nitro groups. The substituted benzyl used is preferably chloro- or bromobenzyl, and the substituted phenyl used is preferably bromo- or chlorophenyl. Cycloalkyl is advantageously substituted or unsubstituted C
3-7
-cycloalkyl, for example cyclopropyl, cyclopentyl or cyclohexyl. Examples of suitable substituents are those mentioned for aryl.
Acyl corresponds to the acid component of the acylating agent used.
Acyl is preferably C
1-6
-alkanoyl, unsubstituted or substituted by one or more halogen atoms, C
1-4
-alkoxy, aryl, hydroxy, amino, cyano, nitro, and/or COOR, where R is C
1-4
-alkyl. Examples of unsubstituted or substituted acyl radicals are acetyl, propionyl, butyryl, chloroacetyl, bromoacetyl, dichloroacetyl, cyanoacetyl, methoxycarbonyl, ethoxycarbonyl, methoxyethanoyl, hydroxybutyroyl, hydroxyhexanoyl, phenylcarbonyl, chlorophenylcarbonyl and benzylcarbonyl.
Suitable acylating agents are, in general, carboxylic acid derivatives, such as carboxamides, carboxylic anhydrides or carboxylic esters.
The carboxylic esters used may be alkoxycarboxylic esters, such as ethyl methoxyacetate, or propyl methoxyacetate, C
1-6
-carboxylic esters, such as butyl acetate, ethyl butyrate, phenyl butyrate, trichloroethyl butyrate, ethyl hexanoate, vinyl butyrate, glycerol esters, such as tributyrin (glyceryl tributyrate), glycol esters, such as glycol dibutyrate, diethyl diglycolate, or dicarboxylic esters, such as vinyl succinate, cyano-substituted esters, such as cyanoacetic esters, or cyclic carboxylic esters, such as butyrolactone, caprolactone.
The carboxamides used may be the amides which correspond to the abovementioned esters.
The carboxylic anhydrides used may be simple, mixed or cyclic anhydrides, such as butyric anhydride, acetyl benzoate, succinic anhydride.
The hydrolases used may be lipases, esterases or proteases. Suitable for use as lipase are customary lipases, such as, for example, Novo-Lipase SP523 from
Aspergillus oryzae
(Novozym 398), Novo-Lipase SP524 from
Aspergillus oryzae
(Lipase=Palatase 20000L from Novo), Novo-Lipase SP525 from
Candida antarctica
(Lipase B Novozym 435, immobilized), Novo-Lipase SP526 from
Candida antarctica
(Lipase A=Novozym 735, immobilized), Lipase kits from Fluka (1 & 2), Amano P Lipase, lipase from Pseudomonas sp., lipase from
Candida cylindracea
, lipase from
Candida lipolytica
, lipase from
Mucor miehei,
lipase M from
Mucor javanicus
(Amano), lipase from
Aspergillus niger,
lipase from
Bacillus thermocatenulatus
, lipase from
Candida antarctica,
Lipase AH (Amano; immobilized), Lipase P (Nagase), Lipase AY from
Candida rugosa
, Lipase

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