Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-12-06
2001-06-12
Lee, Howard C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C544S002000
Reexamination Certificate
active
06245934
ABSTRACT:
The invention relates to a method for preparing a salt of aspartylphenylalanine methyl ester from N-protected aspartylphenylalanine methyl ester involving cleaving off the protective group by treatment with an acid. The invention also relates, in particular, to a novel method for the deformylation of N-formylaspartylphenylalanine methyl ester by treatment with an acid.
Aspartylphenylalanine methyl ester, more in particular &agr;-L-aspartyl-L-phenylalanine methyl ester (also known under the name of aspartame and hereinafter for the sake of convenience also abbreviated as APM), is used as a sweetener in foods and drinks, as described, for example, in the American patent U.S. Pat. No. 3,492,131. The sweetening power of aspartame is about 200× that of sugar; aspartame is thus considered one of the intense sweeteners. In various preparative routes of APM the amino group of the aspartic acid used as the starting material is protected by means of a group which can be cleaved off by treatment with an acid, for example by means of a formyl group (see e.g. GB-A-2140805), in order to achieve selective coupling of an acid group of aspartic acid and the amino group of phenylalanine (methyl ester). In the preparation of the sweetener APM it is important, moreover, not only that both amino acids in aspartame are present in the L-form, but also that the peptide bond is established to the &agr;-carboxyl group of aspartic acid and not to the &bgr;-carboxyl group (i.e. with formation of &agr;-APM and not &bgr;-APM). In chemical coupling processes of L-phenyl-alanine (methyl ester) and N-protected aspartic acid, for example N-formyl-aspartic acid (hereinafter also referred to as F-Asp) the aim therefore is at the coupling already to achieve the highest possible ratio &agr;-APM/&bgr;-APM, and in subsequent process steps efforts are made to separate the A-APM selectively from the &bgr;-APM.
The preparation of a salt of aspartylphenylalanine methyl ester (APM) from N-protected APM by treatment with an acid, viz, oxalic acid, is disclosed by EP-A-0294860. In this case the oxalic acid salt of APM is obtained as a solid but as such, i.e. without further work-up to APM by neutralization (with recovery of oxalic acid), is of no further importance. The method in question, even though excellent yields are obtained and the formation of unwanted by-products such as the dimethyl ester of APM (abbreviated to APM
2
) and/or diketopiperazine (DKP) is generally low, moreover has the drawback that it is necessary to work at relatively low concentrations (i.e. usually less than 15 wt % of N-protected starting material to be treated) in a special solvent combination of methyl isobutyl ketone and methanol, at relatively high temperatures, e.g. from 30 to 60° C., after which the salt is worked up by cooling, washing etc. Complete removal of the strongly odorous methyl isobutyl ketone from the salt obtained proves difficult in this process.
There is therefore a need for an alternative method for preparing a salt of APM from N-protected APM, in particular from the corresponding N-formyl compound (hereinafter also referred to as F-APM), by treatment with an acid, which does not have the abovementioned drawbacks.
Surprisingly, it now has been found that N-protected APM can be converted in a simple manner into a salt if in a first step, N-protected aspartylphenyl-alanine methyl ester is caused to react in an aqueous medium and in the presence of methanol at a temperature of from 0 to 80° C. with from 0.8 to 2 equivalents of acesulphamic acid for at least such a time that the conversion to the salt of aspartylphenylalanine methyl ester and acesulphamic acid has been completed to an adequate degree, and in a second step the salt formed in the first step is isolated in precipitated form at a temperature of 30° C. or lower.
Acesulphamic acid is an organic sweetening acid corresponding to an intense sweetener not derived from aspartic acid, namely acesulphame-K. Acesulphame-K (6-methyl-1,2,3-oxathiazin-4(3K)-one-2,2-dioxide; hereinafter also referred to as AceK) has a sweetening power which is approximately 200× that of sugar. This intense sweetener is disclosed inter alia by U.S. Pat. No. 3,689,486. Acesulphamic acid (hereinafter also referred to as AceH) can be represented chemically as 6-methyl1,2,3-oxathiazin-4(3H)-one-2,2-dioxide.
The method according to the invention can, if desired, also be implemented in the presence of a mineral acid, for example hydrochloric acid, sulphuric acid or phosphoric acid. The amount of such an additionally present mineral acid may vary within wide limits, but will usually not exceed 0.5 molar equivalents with respect to the acesulphamic acid. The conversion according to the method of the invention can already be carried out, however, with particularly good results even without an additional amount of a mineral acid being present.
Other organic sweetening acids corresponding to intense sweeteners not derived from aspartic acid (hereinafter also simply referred to as organic sweetening acids) are known, but if they are used in the manner as described within the scope of the present invention for AceH, they behave in an entirely different manner and are therefore not suitable for use within the scope of the present invention. This is particularly surprising. Such other organic sweetening acids include, for example, the corresponding acids of other intense sweeteners currently available, which are derived not from aspartic acid but from other organic acids. An example of such an organic sweetening acid which cannot be used within the scope of the present method is saccharinic acid (the acid corresponding to saccharin-Na, i.e. sodium 2,3-dihydro-3-oxo-benzisosulphonazole; 300× sugar). As is known, the sodium, calcium and potassium salts in particular of the said organic sweetening acids have sweet properties.
The acesulphamic acid (AceH), which is used as an organic sweetening acid within the scope of the present invention, can be employed in the form of the respective free acid (6-methyl-1,2,3-oxathiazin-4(3H)one-2,2-dioxide), or alternatively be formed in situ (or possibly beforehand) by the corresponding potassium, sodium or calcium salt being treated with an at least equivalent amount of an inorganic mineral acid, e.g. hydrochloric acid, sulphuric acid or phosphoric acid. Most convenient, of course, is the preparation from AceK.
According to the method of the invention, the deprotection reaction involves formation of the salt of APM and AceH, hereinafter also referred to as APM.Ace. As disclosed by EP-A-0768041, salts of APM and organic sweetening acids and in particular of AceH, have excellent sweetening properties, and such salts (sweetening salts) can, like APM, be suitably used for sweetening foods such as soft drinks, dietary products, chewing gums, confectionery, sweets, etc.
If, within the scope of the method of the present invention, AceH is to be prepared beforehand, this can be effected in a very suitable manner by a reslurrying process, in analogy to the method described in EP-A-0768041 for preparing salts of APM and organic sweetening acids, on the understanding that the method in question is implemented without APM being present.
The method according to the present invention preferably employs AceH prepared in situ.
According to the method of the invention, the salt of APM and AceH, i.e. APM.Ace, which is particularly suitable as a sweetener, is formed in all cases.
The N-protected APM used can be any N-protected APM in. which the protective group can be removed by treatment with acid. Examples of N-protected APM are N-formyl-APM (F-APM), N-t-butyloxycarbonyl-APM and Dane salts of APM (these are products formed by coupling phenyl-alanine methyl ester to aspartic acid protected by means of a Dane group, i.e. aspartic acid in which the amino group has first reacted with an ester of acetoacetic acid, e.g. the octyl or octadecyl ester thereof, see e.g. EP-A-0143881).
The N-protected APM used is preferably N-formyl-APM (F-APM). Deprotection of F-APM, in particular o
Boesten Wilhelmus H. J.
van Soolingen Jacob
DSM NV
Lee Howard C.
Maier Leigh C.
Pillsbury & Winthrop LLP
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