Organic compounds -- part of the class 532-570 series – Organic compounds – Carbonate esters
Reexamination Certificate
1998-11-24
2004-04-20
Meller, Michael V. (Department: 1654)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbonate esters
Reexamination Certificate
active
06723868
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for the preparation of (1R,4S)- or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formulae
or salts thereof, or the D- or L-hydrogentartrates thereof and also their further conversion to give (1S,4R)- or (1R,4S)-4-(2-amino-6-chloro-9-H-purine-9-yl)-2-cyclopentene. (1R,4S)-1-Amino-4-(hydroxymethyl)-2-cyclopentene of the formula IV is an important intermediate for the preparation of carbocyclic nucleosides such as, for example, Carbovir® (Campbell et al., J. Org. Chem. 1995, 60, 4602-4616).
A process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene is described, for example, by Campbell et al. (ibid) and by Park K. H. & Rapoport H. (J. Org. Chem. 1994, 59, 394-399).
In this process, the starting material is either D-glucono-&dgr;-lactone or D-serine, approximately 15 synthesis stages being required to form (1R,4S)-N-tert-butoxycarbonyl-4-hydroxymethyl-2-cyclopentene, and the protecting group is removed to give (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene.
Both these processes are costly, complex and not practicable industrially. WO 93/17020 describes a process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene, in which (1R,4S)-4-amino-2-cyclopentene-1-carboxylic acid is reduced to the desired product using lithium aluminium hydride.
Disadvantages of this process are firstly that the double bond of the cyclopentene ring is also reduced, the poor handling properties of lithium aluminium hydride and secondly that it is too costly.
Taylor S. J. et al. (Tetrahetron: Asymmetry Vol. 4, No. 6, 1993, 1117-1128) desribe a process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from (±)-2-azabicyclo[2.2.1]hept-5-en-3-one as starting material. In this process, the starting material is converted, using microorganisms of the species
Pseudomonas solanacearum
or
Pseudomonas fluorescens,
into (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one, which is then reacted with di-tert-butyl dicarbonate to give (1R,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]hept-5-en-3-one, and the latter is reduced using sodium borohydride and trifluoroacetic acid to give the desired product.
This process is far too costly.
In addition, Martinez et al. (J. Org. Chem. 1996, 61, 7963-7966) describe a 10-stage synthesis of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from diethyl dialkylmalonate. This process too has the disadvantage that it is complex and not practicable industrially.
It is also known that N-substituted (±)-2-azabicyclo[2.2.1]hept-5-en-3-ones, which carry an electron-withdrawing substituent, can be reduced to the corresponding N-substituted aminoalcohols using a metal hydride (Katagiri et al., Tetrahedron Letters, 1989, 30, 1645-1648; Taylor et al., ibid).
In contrast to this, it is known that unsubstituted (±)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula
is reduced with lithium aluminium hydride to give (±)-2-azabicyclo[2.2.2]octene (Malpass & Tweedle, J. Chem. Soc., Perkin Trans 1, 1977, 874-884), and that the direct reduction of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one to give the corresponding aminoalcohol has to date been impossible (Katagiri et al., ibid; Taylor et al., ibid).
It is also known to resolve racemic 1-amino-4-(hydroxymethyl)-2-cyclopentene using (−)-dibenzoyltartaric acid (U.S. Pat. No. 5,034,394). On the one hand, this reaction has the disadvantage that (−)-dibenzoyltartaric acid is expensive, and, on the other hand, that the separation must take place in the presence of an exactly defined mixture of acetonitrile and ethanol. This solvent mixture cannot be removed and must be fed to the combustion.
SUMMARY OF THE INVENTION
The object of the present invention was to provide a simple, economical and cost-effective process for the preparation of a (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene.
Surprisingly, it has now been found that when (±)-2-azabicyclo[2.2.1]hept-5-en-3-one of the formula
in the form of the racemate or one of its optically active isomers, is reduced with a metal hydride, the aminoalcohol of the formula
in the form of the racemate or one of its optically active isomers is obtained in a simple manner. Preferably, the racemic cis-aminoalcohol is obtained.
DETAILED DESCRIPTION
As the person skilled in the art is aware, the aminoalcohol of the formula I can be converted using an acid into the corresponding salts, such as, for example, into hydrohalide salts. Suitable hydrohalide salts are hydrobromides and hydrochlorides.
The starting material, the (±)-2-azabicyclo[2.2.1]hept-5-en-3-one can be prepared according to EP-A 0 508 352.
Metal hydrides which may be used are alkali metal or alkaline earth metal hydrides and also binary or complex metal hydrides of the boron or aluminium group, such as alkali metal and alkaline earth metal borohydrides, alkali metal and alkaline earth metal aluminium hydrides. Suitable alkali metal or alkaline earth metal hydrides are LiH, NaH, KH, BeH
2
, MgH
2
or CaH
2
.
Binary alkali metal or alkaline earth metal borohydrides which may be used are NaBH
4
, LiBH
4
, KBH
4
, NaAlH
4
, LiAlH
4
, KAlH
4
, Mg(BH
4
)
2
, Ca(BH
4
)
2
, Mg(AlH
4
)
2
and Ca(AlH
4
)
2
. Complex metal hydrides of the boron or aluminium group may have the general formula M
1
M
2
H
n
L
m
, in which n is an integer from 1 to 4, and m is an integer from 4 to 4 minus the corresponding number n, M
1
is an alkali metal atom, M
2
is boron or aluminium, and L is C
1-4
-alkyl, C
1-4
-alkenyl, C
1-4
-alkoxy, CN or an amine, or the complex metal hydrides may have the general formula M
2
H
O
L
p
, in which M
2
is as defined above and O is an integer from 0 to 3, and p is an integer from 3 to 3 minus the corresponding number p. Possible M
1
M
2
H
n
L
m
compounds are LiBH(C
2
H
5
)
3
, LiBH
x
(OCH
3
)
4-1
, LiAlH(OC(CH
3
)
3
)
3
, NaAlH
2
(OC
2
H
4
OCH
3
)
2
, NaAlH
2
(C
2
H
5
)
2
or NaBH
3
CN. Preferably, the reduction is carried out using a metal borohydride. As an expert in the art is aware, the metal hydrides mentioned such as, for example, LiBH
4
, can also be produced “in situ”. Common preparation methods for LiBH
4
are, for example, the reaction of an alkali metal borohydride with a lithium halide (H. C. Brown et al., Inorg. Chem. 20, 1981, 4456-4457), the reaction of LiH with B
2
O
3
in the presence of hydrogen and a hydrogenation catalyst (EP-A 0 512 895), the reaction of LiH with (H
5
C
2
)OBF
3
(DE-A 94 77 02) and that of LiH with B(OCH
3
)
3
(U.S. Pat. No. 2,534,533).
The metal hydrides are expediently used in a molar ratio of from 1 to 5 per mole of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one.
The metal hydrides, in particular NaBH
4
, are preferably used with lithium salt additives. Lithium salts which may be used are LiCl, LiF, LiBr, LiI, Li
2
SO
4
, LiHSO
4
, Li
2
CO
3
, Li(OCH
3
) and LiCO
3
.
The reduction is expediently carried out in an inert-gas atmosphere, such as, for example, in an argon or nitrogen atmosphere.
The reduction can be carried out at a temperature of from −20 to 200° C., preferably at a temperature of from 60 to 150° C.
Suitable solvents are aprotic or protic organic solvents. Suitable aprotic organic solvents may be ethers or glycol ethers, such as, for example, diethyl ether, dibutyl ether, ethyl methyl ether, diisopropyl ether, tert-butyl methyl ether, anisole, dioxane, tetrahydrofuran, monoglyme, diglyme and formaldehyde dimethylacetal. Suitable protic organic solvents are C
1-6
-alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, pentanol, tert-amyl alcohol or hexanol and also mixtures of these with water. Suitable protic organic solvents are also mixtures of one of said ethers, glycol ether with water or with one of said alcohols, such as a mixture of a C
1-6
-alcohol with an ether or glycol ether, in particular a mixture of methanol, ethanol or water
Berchtold Katja
Bernegger-Egli Christine
Breitbach Holger
Brieden Walter
Petersen Michael
Darby & Darby
Lonza AG
Meller Michael V.
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