Synthesis of (R) and (S)-aminocarnitine, (R) and...

Details Synthesis of (R) and (S)-aminocarnitine, (R) and... Synthesis of (R) and (S)-aminocarnitine, (R) and...

2003-02-25

2004-11-23

Zucker, Paul A. (Department: 1621)

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

Organic compounds

Carboxylic acids and salts thereof

C562S567000

Reexamination Certificate

active

06822115

ABSTRACT:

The invention described herein relates to a process for the production of (R) and (S)-aminocarnitine and its derivatives starting from D- and L-aspartic acid. The same process can be applied to produce other related compounds such as (R) and (S)-4-phosponium-3-amino-butanoate and its derivatives or (R) and (S) 3,4-diamino butanoic acid dihydrochloride.
Aminocarnitine is a substance endowed with interesting pharmaceutical properties and its N-derivatives arouse a similar degree of interest. For example, D. L. Jenkins and W. O. Griffith have described the antiketogenic and hypoglycaemic effects of the N-acetylates in the racemic form. U.S. Pat. No. 4,521,432 (Takeda) describes the possible applications of (−)-N-acetyl-aminocarnitine, inner salt, in the treatment of the complications of diabetes. Similar activity has been described for (+)-aminocarnitine, chloride hydrochloride. It would therefore be of interest to have processes for the preparations of the enantiomorph, which match up to the criteria of economic convenience on an industrial scale.
R(+)-aminocarnitine is obtained via hydrolysis of R-(−)-N-acetylcarnitine, the latter being isolated by the cultivation of micro-organisms of the genera
Emericella
or
Aspergillus
, or, alternatively, via a complex chemical process described in the Takeda patent cited above.
Other methods of chemical synthesis are known, all rather complex, such as, for example, the one described by Shinagawa, J. Med. Chem., 30; 1458 (1987), who uses diazomethane, which is known to be hazardous. In any event, this method is not of industrial interest, in that it was conceived in order to ascertain the absolute configuration of the single enantiomorph.
The single enantiomorphs can also be obtained by resolution of the racemic mixture of (±)-N-acetylaminocarnitine, as described in EP 0 287 523.
Alternatively, R(+)- and S(−)-aminocarnitine chloride can be obtained by resolution on silica gel chromatography or fractional crystallisation of the respective N-&agr;-methylbenzyl, benzylester chlorides, as described in Italian patent 1,231,751. This process, which involves subsequent debenzylation is laborious and not very suitable for industrial-scale production.
A method is also known using chiral carnitine as a starting product (
Journal of Organic Chemistry
, 1995, 60, 8318-8319; (Sigma-Tau) EP 636603, 1995). This method uses reagents such as methane-sulphonic anhydride and sodium azide and solvents such as anhydrous dimethylsulphoxide, and involves a catalytic reduction step.
A process has now been found for the preparation of single enantiomorphs starting from D-aspartic acid and L-aspartic acid, respectively, with an overall yield of at least 38% in 6 to 7 steps, but without it being necessary to purify the intermediates. In pratice, the process according to the invention described herein is realised via direct hydrolysis of the chiral aminocarnitine ester in an acidic milieu to yield a chiral aminocarnitine inner salt without purifying the intermediate products. The enantiomeric purity of the aminocarnitine thus obtained is >99%.
The same synthetic process can be performed to prepare new compounds such as (R) and (S) 4-phosphonium-3-aminobutanoate (hereinafter referred as phosphonium aminocarnitine) and a chiral synthon as (R) and (S) 3,4-diaminobutanoic acid dihydrochloride.
4-phosphonium-3-aminobutanoate is potentially useful as CPT inhibitor with antiketogenic and hypoglycemic effects and as intemediate for the synthesis of pharmacologically active compounds.
Thus, an object of the invention described herein is a process for the preparation of (R) and (S)-aminocarnitine, (R) and (S) phosphonium aminocarnitine and of a number of their N-substituted derivatives, and a process for the preparation of (R) and (S) 3,4-diaminobutanoic acid dihydrochloride (
Synlett
1990, 543-544
; Synth. Comm
. 1992, 22(6), 883-891). In particular, the invention described herein provides a process which also enables aminocarnitine, phosphonium aminocarnitine and 3,4-diaminobutanoic acid derivatives to be obtained which are useful for the preparation of medicaments for the treatment of diseases associated with hyperactivity of carnitine palmitoyltransferase.
These derivatives are described in Italian patent application MI98A001075, filed on 15 May 1998, and in international patent application PCT/IT99/00126, filed on 11 May 1999, both of which in the name of the applicant and incorporated herein for reference purposes.
The process according to the invention described herein allows the preparation of compounds with the following formula:
in which
W is Q(CH
3
)
3
where Q is N or P
or
W is NH
3
Y is hydrogen or one of the following groups:
—R
1
,
—COR
1
,
—CSR
1
,
—COOR
1
,
—CSOR
1
,
—CONHR
1
,
—CSNHR
1
,
—SOR
1
,
—SO
2
R
1
,
—SONHR
1
,
—SO
2
NHR
1
,
where
R
1
is a straight or branched, saturated or unsaturated alkyl containing from 1 to 20 carbon atoms, optionally substituted with an A
1
group, where A
1
is selected from the group consisting of halogen, C
6
-C
14
aryl or heteroaryl, aryloxy or heteroaryloxy, which can optionally be substituted with straight or branched, saturated or unsaturated lower alkyl or alkoxy, containing from 1 to 20 carbon atoms, halogens;
said process comprises the following steps:
a) conversion of D-aspartic or L-aspartic acid to N—Y substituted D-aspartic or L-aspartic acid;
b) conversion of the N—Y substituted D-aspartic or L-aspartic acid to the respective anhydride;
c) reduction of the anhydride obtained in step b) to the corresponding 3-(NH—Y)-lactone;
d) opening of the lactone obtained in step c) to yield the corresponding D- or L-3-(NH—Y)-amino-4-hydroxybutyric acid;
e) transformation of the 4-hydroxy group of the D- or L-3-(NH—Y)-amino-4-hydroxybutyric acid into a leaving group;
f) substitution of the end group in position 4 of the D- or L-3-(NH—Y)-aminobutyric acid with a trimethylammonium group or with a trimethylphosphonium group
g) hydrolysis of the ester group; and, if so desired,
h) restoration of the amino group.
The usefulness of this new synthesis route for optically pure aminocarnitine, as compared to the method involving the use of chiral carnitine as the starting product (
Journal of Organic Chemistry
, 1995, 60, 8318-8319; EP 0 636 603 (Sigma-Tau)), consists in the fact that the use of reactants such as methane-sulphonic anhydride and sodium azide, of dimethyl-sulphoxide as a solvent, and of a catalytic reduction step is avoided. What is more, the volumes involved are lower, thus allowing better management of the reactions and of any purification of intermediate products. In fact, the process according to the invention presents the additional advantage that all steps can be carried out avoiding purification of the intermediates, without this jeopardising the purity of the end product. This advantageous characteristic is obvious to the expert in the art; in particular, the fact will be appreciated that that no purification operations are necessary which would place an additional burden on the synthesis process in terms of economic costs, time, materials, specialised personnel and equipment.
As compared to the process described in
Journal of Medicinal Chemistry
, 1987, 30, 1458-1463 (Takeda), involving the use of benzyloxycarbonyl-L-asparagine as the starting product (with 7 steps and a 24% overall yield), the advantage at industrial level of avoiding reactants such as diazomethane, silver benzoate and dimethyl-sulphate appears obvious. In another process (
Bioorganic
&
Medicinal Chemistry Letters
, 1992, 2 (9), 1029-1032), (R)-aminocarnitine is obtained starting from a derivative of aspartic acid (the tert-butylester of N-benzyloxycarbonyl-L-aspartic acid) in seven steps with a yield of 24% 22%, but again using reactants such as diazomethane and silver benzoate, a catalytic hydrogenation step, and methylation with methyl iodide.
In these previously mentioned syntheses, the only product that can be obtained is (R)-aminocarnitine. The great versatility of this new route allows

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