Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-08-13
2001-06-26
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C435S128000, C435S129000, C560S115000, C564S186000, C564S210000, C564S216000
Reexamination Certificate
active
06252112
ABSTRACT:
The invention relates to a novel process for the preparation of (1S, 4R)- or (1R, 4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol of the formulae
and to a novel process for preparing optically active compounds of the general formulae
(1S, 4R)-4-(2-Amino-6-chloro-9H-purin-9yl)-2-cyclopentene-1-methanol is an important intermediate for preparing 2-aminopurine nucleosides such as, for example, for preparing (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9yl]-2-cyclopentene-1-methanol (WO 95/21 161) or for preparing 1592U89 (J. Org. Chem., 1996, 61, 4192-4193; J. Org. Chem., 1996, 61, 7963-7966).
A process for preparing (1S, 4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol starting from (1S, 4R)-4-amino-2-cyclopentene-1-methanol is described in WO 95/21 161. The disadvantage of this process is that the precursor (1S, 4R)-4-amino-2-cyclopentene-1-methanol can be obtained only via (±)-2-azabicyclo[2.2.1]hept-5-en-3-one substituted by the costly BOC protective group (tert-butyloxycarbonyl protective group) (J. Org. Chem., 1995, 60, 4602-4616).
The object of the invention was to provide a simple, low-cost and more economical process for preparing (1S, 4R)- or (1R, 4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol.
This object has been achieved by the novel process according to claim
1
.
The first stage in the novel process is carried out by acylating (±)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula
to give a (±)-2-azabicyclo[2.2.1]hept-5-en-3-one derivative of the general formula
in which R
1
denotes C
1-4
-alkyl, C
1-4
-alkoxy, aryl or aryloxy.
C
1-4
-Alkyl can be substituted or unsubstituted. Substituted C
1-4
-alkyl means hereinafter C
1-4
-alkyl substituted by a halogen atom. F, Cl, Br or I can be used as halogen atom. Examples of C
1-4
-alkyl are methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, isopropyl, chloromethyl, bromomethyl, dichloromethyl, dibromomethyl. Preferably used as C
1-4
-alkyl is methyl, ethyl, propyl, butyl, isobutyl or chloromethyl.
It is possible to use as C
1-4
-alkoxy, for example, methoxy, ethoxy, propoxy, butoxy, tert-butoxy or isobutoxy. The C
1-4
-alkoxy preferably used is tert-butoxy.
It is possible to use as aryl, for example, phenyl or benzyl, preferably phenyl. Benzyloxy or phenoxy, for example, can be used as aryloxy.
The precursor (±)-2-azabicyclo[2.2.1]hept-5-en-3-one can be prepared as disclosed in EP-A 0 508 352.
The acylation can be carried out with a carbonyl halide of the general formula
or with a carboxylic anhydride of the general formula
in which R
1
has the stated meaning, and X denotes a halogen atom. F, Cl, Br or I can be used as halogen atom. Cl or F is preferably used.
Examples of carbonyl halides are: acetyl chloride, chloroacetyl chloride, butyryl chloride, isobutyryl chloride, phenylacetyl chloride, benzyl chloroformate (Cbz—Cl), propionyl chloride, benzoyl chloride, allyl chloroformate or tert-butyloxycarbonyl fluoride. Examples of carboxylic anhydrides are: di-tert-butyl dicarbonate, butyric anhydride, acetic anhydride or propionic anhydride.
The acylation can be carried out without solvent or with an aprotic solvent.
The acylation is expediently carried out in an aprotic solvent. Examples of suitable aprotic solvents are diisopropyl ether, pyridine, acetonitrile, dimethyl-formamide, triethylamine, tetrahydrofuran, toluene, methylene chloride, N-methylpyrrolidone or mixtures thereof.
The acylation is expediently carried out at a temperature from −80 to 50° C., preferably from 0 to 25° C.
In the second stage of the novel process, the (±)-2-azabicyclo[2.2.1]hept-5-en-3-one derivative of the formula IV is reduced to give a cyclopentene derivative of the general formula
in which R
1
has the stating meaning.
The reduction is expediently carried out with an alkali metal borohydride or alkaline earth metal borohydride, with an alkali metal aluminium hydride or alkaline earth metal aluminium hydride or with Vitride (sodium bis(2-methoxyethoxy)aluminium hydride). Sodium or potassium aluminium hydride can be used as alkali metal aluminium hydride. Sodium or potassium borohydride can be used as alkali metal borohydride. Calcium borohydride can be used as alkaline earth metal borohydride. Aluminium nitride for example can be used as nitride.
The reduction is expediently carried out in a protic solvent. Protic solvents which can be used are lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, isobutanol or water, or a mixture of the said alcohols and water.
The reduction is expediently carried out at a temperature from −40 to 40° C., preferably from 0 to 20° C.
The third stage in the novel process, the conversion of the cyclopentene derivative of the general formula V into the (1R, 4S)- or (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formulae
is carried out either by means of microorganisms or of an enzyme having N-acetylamino-alcohol hydrolase activity or by means of penicillin G acylases. This biotransformation converts the acylated (1S, 4R)- or (1R, 4S)-amino alcohol derivative to result in the (1R, 4S) or (1S, 4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene (formula VI, VII).
All microorganisms which utilize a cyclopentene derivative of the general formula V as sole nitrogen source, as sole carbon source or as sole carbon and nitrogen source are suitable for the biotransformation. The microorganisms can be isolated from soil samples, sludge or waste water with the assistance of conventional microbiological techniques. The microorganisms are isolated by culturing them in a nutrient medium containing a cyclopentene derivative of the general formula
in which R
1
has the stated meaning,
as sole carbon and nitrogen source
as sole nitrogen source with a suitable carbon source a
as sole carbon source with a suitable nitrogen source,
in a conventional way.
Examples of suitable cyclopentene derivatives of the general formula V are: N-acetyl-, N-propionyl-, N-isobutyryl-, N-tert-butoxycarbonyl-(N-BOC), N-butyryl- or N-phenylacetyl-1-amino-4-hydroxymethyl-2-cyclopentene.
The microorganisms can use as suitable nitrogen source, for example, ammonium, nitrates, amino acids or ureas as substrate for growth. The microorganisms can use as suitable carbon source, for example, sugars, sugar alcohols, C
2
-C
4
-carboxylic acids or amino acids as substrate for growth. Hexoses such as glucose or pentoses can be used as sugars. Glycerol, for example, can be used as sugar alcohol. Acetic acid or propionic acid can be used, for example, as C
2
-C
4
-carboxylic acids. Leucine, alanine, asparagine can be used, for example, as amino acids.
The selection medium and culture medium which can be used are those conventional among those skilled in the art, such as, for example, the one described in Table 1 or a complete medium (medium containing yeast extract) such as, for example, nutrient yeast broth (NYB), preferably using the one described in Table 1.
During the culturing and selection, the active enzymes of the microorganisms are expediently induced. The cyclopentene derivatives of the general formula V can be used as enzyme inducer.
The culturing and selection normally takes place at a temperature from 20° C. to 40° C., preferably from 30° C. to 38° C. and at a pH between pH 5.5 and pH 8, preferably between pH 6.8 and pH 7.8.
The biotransformation is expediently carried out with microorganisms which utilize the (1R, 4S) isomer of the cyclopentene derivative as sole carbon source, as sole carbon and nitrogen source or as sole nitrogen source.
The biotransformation is preferably carried out by means of microorganisms of the genus Alcaligenes/Bordetella, Rhodococcus, Arthrobacter, Alcaligenes, Agrobacterium/Rhizobium, Bacillus, Pseudomonas or Gordona, in particular of the species Alcaligenes/Bordetella FB 188 (DSM 11172),
Rhodococcus erythropolis
CB 101 (DSM 10686),
Arthrobacter sp.
HSZ5 (DSM 10328),
Rhodococcus sp.
FB
Bernegger Christine
Birch Olwen Mary
Bossard Pierre
Brieden Walter
Brux Frank
Baker & Botts L.L.P.
Lonza A.G.
Raymond Richard L.
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