Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06104—Dipeptides with the first amino acid being acidic
  • C07K5/06113—Asp- or Asn-amino acid

Definitions

• This invention relates to compounds that are useful for the synthesis of artificial sweetener compounds comprising L-aspartyl-D- ⁇ -aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amides.
• L-aspartyl-D-alanine-N-alkyl amides such as disclosed in U.S. Patent No. 4,411,925, are known to be useful as artificial sweeteners:
• aniline amides of L- aspartyl-D-alanine.
• the individual members of this family of aniline amides were disclosed to have a sweetness potency that was at most 75 times that of sucrose except for the highly substituted
• the sweetener compounds were prepared by coupling a ( ⁇ -C00H/ ⁇ -NH 2 )-diprotected L-aspartic acid with a second D-amino acid to give a ( ⁇ -C00H/o-NH 2 )-diprotected L-aspartyl-D-amino acid.
• This material was in turn coupled with a (S)- ⁇ -alkylbenzylamine to give the ( ⁇ - C00H/ ⁇ -NH 2 )-diprotected L-aspartyl-D-amino acid amide. Removal of the protecting groups then produced the free sweetener .1.
• An object of the present invention is to provide compounds that are useful for preparing chemically stable artificial sweeteners having high sweetness potency.
• an object of the present invention is to provide compounds that may be used to prepare artificial sweeteners using economic reaction processes and inexpensive reagents.
• an object of the present invention is to provide compounds that may be used to produce artificial sweeteners using reaction processes having high yields using economic, safe and convenient reaction materials.
• Another object of the present invention is to provide artificial sweeteners having high heat stability at temperatures typically used for preparing foods.
• the present invention provides an N-protected- D-amino acid-(S)- ⁇ -alkylbenzyl amide having the structure:
• the subject invention relates to adding the L- aspartic acid moiety to compound 2. followed by deprotection as the final steps in the preparation of the artificial sweetener.
• An additional subject of this invention relates to the addition of the (S)- ⁇ - alkylbenzyl amine to a suitably protected dipeptide followed by deprotection as the final steps in the preparation of the artificial sweetener .
• the L-aspartyl-D-amino acid amides of the present invention may be obtained by preparing a suitably protected dipeptide using any of several known methods for the coupling of amino acids, (e.g.. M. Bodansky, Principles of Peptide Synthesis. Berlin, (1984), Springer Verlag) , and then coupling the dipeptide with an amine to produce the desired amide. This method is hereinafter referred to as the "dipeptide-intermediate" method.
• a diprotected L-aspartic acid is condensed with N-hydroxysuccinimide to produce the activated L-aspartyl-N-hydroxysuccinimide ester.
• the diprotected L-aspartic acid is a ⁇ -benzyl-N- carbobenzyloxy ("CBZ") derivative which is commercially available. Condensation of the CBZ-derivative with hydroxysuccimide is achieved by use of dicyclohexylcarbodiimide (DCC) as the coupling agent.
• DCC dicyclohexylcarbodiimide
• the DCC coupling agent is also readily available from known commercial sources.
• the activated L-aspartyl succinimide ester may be reacted with an appropriate D-amino acid in dioxane-water with triethylamine to produce the ⁇ -benzyl- N-carbobenzyloxy-L-asparty1-D-amino acid.
• the preferred compounds that are useful for the preparation of artificial sweeteners using the dipeptide- intermediate method include compounds having the following structure:
• the preferred D-amino acids include D-alanine, D-valine, D-o-aminobutyric acid, D-phenylglycine and D- ⁇ - aminopentanoic acid.
• the most preferred D-amino acids of this invention are D-alanine, D-o-amino-butyric acid and D-valine.
• the reaction product of the second step may be activated with DCC and coupled in dioxane with an appropriate amine to produce the ⁇ -benzyl-N- carbobenzyloxy-L-aspartyl-D-amino acid amide.
• the preferred amines of this invention include amines such as ⁇ -methylbenzylamine, o-ethylbenzylamine, ⁇ - isopropylbenzylamine, o-t-butylbenzylamine, o-n- propylbenzylamine, ⁇ -phenylbenzylamine, o-cyclopropyl benzylamine, and ⁇ -isobutylbenzylamine.
• the (S)- enantiomer or a racemic mixture of these amines may be used.
• the most preferred amine of this invention is (S)- ⁇ - ethylbenzylamine.
• the sweetener compound is obtained by deprotection of the product of the third step by catalytic hydrogenation in an alcoholic solvent using Pd/C as catalyst.
• step 4 steps of the dipeptide- intermediate method have proven convenient and were used in preparation of all of the compounds described in the tables that follow, other steps may be envisioned which could prove equally advantageous.
• activation of the acid groups of the first and third steps could be achieved using an alkyl chloroformate and a tertiary amine base in place of the DCC.
• other protecting groups for the aspartic acid moiety such as the combination of ⁇ -t-butyl ester and N-t- butyloxycarbonyl can be envisioned. In this case, deprotection in step 4 would require acid catalysis rather than catalytic hydrogenation.
• preparation of the sweetener compounds involves preparation of an amide-intermediate by coupling an N-protected o-amino acid with an (S)-alkylbenzylamine (R 2 -NH 2 ) as a first step, as shown, wherein R x and R 2 are alkyl, phenyl or phenyl-containing alkyl groups.
• the amide-intermediate method is distinguished from the dipeptide-intermediate method in that the D-amino acid group is combined with an amine before the D-amino acid group is combined with the L- aspartyl group.
• a dipeptide is formed first, that is, before it is combined with an amine.
• the protecting group of the N-protected D-amino acid group is removed to produce a free amine or amine salt.
• this is achieved by catalytic hydrogenation.
• This new amine is then reacted in a third step with N- carbobenzyloxy- ⁇ -benzyl-L-aspartic acid and a condensing agent such as DCC to produce a N-carbobenzyloxy- ⁇ -benzy- L-aspartyl-D-amino acid-(S)-o-alkylbenzyl amide.
• the sweetener product is then obtained in a fourth step by catalytic removal of the protecting groups using known methods of hydrogenation over Pd/C catalyst.
• an N-protected D-amino acid 2 is coupled to an (S)-o-alkylbenzylamine using isobutyl chloroformate and N-methylmorpholine at 0 * C in tetrahydrofuran as the activating reagent [M. Bodansky, "Principles of Peptide Synthesis", Springer Verlag, Berlin, 1984; pp. 21-27], (where X, R* and R" are as
• the second preferred method for preparing the amide intermediate is the conversion of the N-protected D-amino acid 2. to the corresponding oxazolidinone 5_, (where X and R" are as defined above) .
• the preferred oxazolidinones that may be useful for the preparation of artificial sweeteners include a D- amino acid oxazolidinone having the structure:
• X C0 2 CH 2 ⁇ , CHO or C0 2 -tert-butyl
• R" CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 or ⁇ ;
• R' H, CH 3 , CH 2 CH 3 , CH(CH3) 2 , C(CH3) 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , ⁇ or CC1 3 .
• the coupling of the free amine to a suitably protected L-aspartic acid may be achieved, for example, by using any of the following different routes.
• N-formyl-( ⁇ - methyl)-L-aspartic acid may be used as the mixed anhydride that is prepared in situ with isobutyl chloroformate/N-methylmorpholine, to which the free amine of 2 may be added.
• the coupled product 1 that results may be readily hydrolyzed to the sweetener 1 by stirring with 5N HC1 at 50 * C for 2 hours.
• the ( ⁇ -methyl) -protected intermediate £ may be observed as a transient species, (where R' and R" are as defined above) :
• Intermediate £ may in principle also be obtained from the coupling of ( ⁇ -methyl)-L-aspartic acid-N-carboxyanhydride 2. [J.S. Tou and B.D. Vineyard, J. Or ⁇ . Chem.. .5J2 , 4982- 4984 (1985) ] to the free amine obtained from the amide- intermediate compound 2.
• a sample of £ may be prepared by hydrogenation of the N-carbobenzyloxy derivative I ⁇ , (where R' and R" are as defined above) .
• Another procedure for activating the N-protected aspartic acid involves formation of the anhydride.
• Coupling of amines with aspartic anhydrides may give some of the unwanted ⁇ -aspartyl amides, but they can be removed from the final product by fractional crystallization.
• N-carbobenzyloxy-L-aspartic acid anhydride see C.P. Yang and CS. Su, J. Or ⁇ . Chem. 51 5186 (1986) .
• N-formyl-L-aspartic anhydride see U.S. Patent No. 3,879,372 or U.S. Patent No. 3,933,781.
• the N-carbobenzyloxy-L- aspartic acid- ⁇ -benzyl ester is the preferred diprotected derivative.
• this ester is coupled to the free amine of 2 by adding isobutyl chloroformate/N-methyl morpholine as the coupling agent.
• the resulting compound 11 may be converted to the sweetener 1 by catalytic hydrogenation (Pd/C) .
• Still another preferred method for coupling the free amine obtained from the amide-intermediate compound 2 with the aspartic acid group comprises using the N- protected L-aspartic acid oxazolidinone 12. as the activated form of L-aspartic acid:
• the sweetener compound 1 may then be obtained by heating in dilute acid or by mild base treatment of the 12/1A mixture to obtain pure 12, followed by removal of the X-protecting group.
• this may be achieved by catalytic hydrogenation in methanol using 10% Pd/C.
• acid hydrolysis is used for the removal of the N-tert-butoxycarbonyl and N-formyl groups.
• R 1 H, CH 3 , CH 2 CH 3 , CH(CH3) 2 , C(CH3) 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , ⁇ or CC1 3 .
• the ⁇ -alkylbenzylamines used with the present invention are known in the prior art, and may be prepared by reduction of the corresponding ketoxime with sodium in ethanol.
• the ketoximes may be obtained from the corresponding ketones, which are commercially available.
• the amines used in the examples had boiling points corresponding to literature values and H and 13 C NMR spectra consistent with their assigned structures.
• N-carbobenzyloxy-L- aspartic acid N-carbobenzyloxy- ⁇ -benzyl-L-aspartic ac the N-hydroxysuccinimide, isobutylchloroformate, N- methylmorpholine, dicyclohexylcarbodiimide (DCC) , and D-amino acids, including D-alanine, D-valine, D-o- aminobutyric acid, D-phenylglycine and D-o-aminopentan acid are all readily available commercially.
• the results of the sweetness potency measurements for the disclosed sweeteners of this invention are summarized in Tables 1-4.
• the sweetness potency was determined by having four tasters compare sweetness of various dilutions of the test compound wi a 200 ppm solution of aspartame, at which concentratio the sweetness potency of aspartame was taken to be 180 times sucrose.
• the sweeteners of this invention may be used to provide desirable properties of sweetness in any orally ingestible product.
• specifically ingestible materials include: fruits, vegetables, juices, meat products such as ham, bacon and sausage; egg products, fruit concentrates, gelatins and gelatin-like products such as jams, jellies, preserves, and the like; milk products such as ice cream, sour cream and sherbet; icings, syrups including molasses; corn, wheat, rye, soybean, oat, rice and barley products, nut meats and nut products, beverages such as coffee, tea, carbonated and non-carbonated soft drinks, beers, wines and liquors; confections such as candy and fruit flavored drops, condiments such as herbs, spices and seasonings, flavor enhancers such as monosodium glutamate and chewing gum.
• the sweeteners of this invention may also be blended with other sweeteners known to the art, such as, for example, sucrose, fructose and other polyols, as well as other high potency non-nutritive sweeteners including but not limited to saccharin, cyclamate, aspartame, acesulfame-K, alitame, sucralose, stevioside and the like, which are useful for sweetening edible materials.
• saccharin salts include the sodium, potassium, calcium and ammonium salts.
• sweeteners of this invention also include their sulfates, malates, hydrochlorides, carbonates, phosphates, citrates, acetates, tartrates, benzoates and the like.
• the compounds of this invention may reduce or completely mask the well known, undesirable bitter aftertaste of the saccharin.
• the invention is further illustrated by the following non-limiting examples.
• Sweetness - 180 times sucrose (The sweetness potency was determined by comparison, using well known methods, against 200 ppm aspartame solution, adopting for aspartame the sweetness potency value of 180 times sucrose.)
• Example 8 Synthesis of L-aspartyl-D-alanine-N- (R. Si -a- ethylbenzvl amide .
• Example 16 Cola Bevera ⁇ e L-aspartyl-D- ⁇ -aminobutyric acid-N-(S)- ethylbenzylamide (0.16 g) is dissolved in 500 ml water and the volume adjusted to one liter. Citric acid (1 g) , phosphoric acid (2 g) , caramel color (10 g) , cola flavoring (10 g) and a benzoate preservative (2 g) are dissolved in the liter solution of sweetener. The resulting cola concentrate is diluted with 3 liters of water to provide a single strength beverage. Carbonation produces a satisfying effervescent carbonated cola drink having a palatable sweetness.
• Example 18 Dietetic Hard Candv A hard candy is prepared according to the following formulation and procedure:
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener. In a small beaker dissolve the sweetener in water, add color, flavor and citric acid and mix well to dissolve. In a separate beaker combine polydextrose and water.
• a gelatin dessert is prepared according to the following composition and procedure .
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener.
• Premix the first five ingredients add to boiling water and stir to dissolve completely. Add cold water and stir briskly. Transfer to serving dishes and refrigerate until set.
• Low calorie table sweeteners are prepared according to the following formulations: A. A powder form of sweetener is prepared by blending the following ingredients. Ingredients % bv weight (approximate)
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener.
• a table sweetener in liquid form is prepared as follows.
• a sweetener
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener.
• a vanilla sugarless frozen dessert is prepared according to the following formulation by conventional practice.
• Nonfat milk solids 10 Mono- and diglyceride emulsifier 0.25
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener.
• Fresh Pears are washed, peeled, cored, sliced into pieces and immersed in an aqueous solution containing 0.05% by weight of ascorbic acid.
• the sliced fruit is packed into screw-cap jars and the jars filled with a syrup containing the following ingredients: Tn ⁇ redients % bv weight (approximate)
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener.
• the jars are capped loosely and placed in an autoclave containing hot water and processed at 100 * C for 45 minutes. The jars are removed, immediately sealed by tightening the caps and allowed to cool.
• a sweetener Carboxymethyl cellulose 2.4
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener.
• a vanilla cake may be prepared employing the following recipe:
• the sweetener is an L-aspartyl-D- ⁇ - aminoalkanoyl-(S)-N- ⁇ -alkylbenzyl amide as disclosed herein, e.g. L-aspartyl-D- ⁇ -aminobutyric acid-S- ⁇ - ethylbenzyl amide or L-aspartyl-D-valine-S- ⁇ -ethylbenzyl amide.
• the quantity of sweetener added is varied depending on the sweetness potency of the sweetener. Combine nonfat dry milk, whole milk powder. polydextrose solution and emulsified shortening. Mix at low speed until creamy and smooth (about 3 minutes) , add eggs and beat until a homogeneous creamy mix is obtained.
• Dissolve sweetener in water add to creamy homogenate and mix 2-3 minutes. Add remaining ingredients and mix until creamy and smooth (3-5 minutes) . Place 120 g. of batter in small pregreased pan and bake at 350 * F. (176 * C.) for 30 minutes.
• Example 27 D-a-aminobutvric acid-(Si- ⁇ -ethylh ny.yl amide, (D)-(-)-tartrate a)
• the precipitate was washed twice with 50 ml deionized water. Drying the precipitate in vacuo produced 4.32 g. This was recrystallized from ethyl acetate-hexane to produce 2.93 g, having a melting point range of 167-168 * C.
• Example 30 ⁇ -Methvl-L-aspartvl-D-a-aminobntyric aoi ⁇ - (Si-e-ethylbenzyl amide acetate.
• Example 32 Synthesis of N-carbobenzyloxy-D-a- aminobutyric acid- (S) - ⁇ -ethylbenzylamide. a) To a solution of 4.2 g of D-3-carbobenzyloxy-4-ethyl-5-oxazolidinone in 30 ml of toluene was added 3.0 g of (S) - ⁇ -ethylbenzylamine. This was heated to 60-5'C and stirred overnight. The solution was concentrated under reduced pressure and taken up in 200 ml of EtOAc.
• Example 33 Synthesis of N-carbobenzyloxy-N- hydroxymethyl-L-aspartvl-D- ⁇ -aminobutyrir; arid-(Si-a- ethylbenzyl amide.
• Example 34 Synthesis of N-carbobenzvloxy-L-aspartyl- D-a-aminobutyri acid-(Si-a-ethylbenzyl amide.
• Example 35 S y nthesis of L-as p artvl-D-a-ami nohutyric acid-(S)-g-ethylbenzyl amide.
• Example 36 p-Methyl-N-formvl-L-aspartvl-D-a- aminobutyric acid.
• Example 37 Acid Hydrolysis of ⁇ -methvl-N-formvl-I,- aspartyl-n-a-aminobutvric acid-(Si- ⁇ -ethvlbenzvl amide.
• N-formyl-L-aspartyl-D-o-aminobutyric acid- (S)- ⁇ -ethylbenzyl amide were added four 230 mg portions of the same protected sweetener at 30 minute intervals, at which time previously added material was in solution. Hydrolysis was continued for 2 hours at 50 * C subsequent to the last addition of material. Thereafter, the preparation,diluted to 5 ml with deionized water, was placed in a room temperature water bath and adjusted to pH 7.0 with 33% (w/w) sodium hydroxide solution while stirring rapidly.

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