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Last Updated: September 22, 2021

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Claims for Patent: 4,710,583

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Summary for Patent: 4,710,583
Title: Dipeptides and process
Abstract:Synthesis of phenylserine ester (a) via benzaldehyde and glycine ester using serine hydroxymethyltransferase; and (b) via methyl benzoylacetate. Synthesis of hydroxy-aspertame or derivative by enzymatic coupling of phenylserine or derivative with aspertic acid or derivative. Hydrogenation of the coupled product to give as final product aspertame or analog with related processes and products.
Inventor(s): Chmurny; Alan B. (Frederick, MD), Gross; Akiva T. (Rockville, MD), Kupper; Robert J. (Mount Airy, MD), Roberts; Rowena L. (Derwood, MD)
Assignee: W. R. Grace & Co. (New York, NY)
Application Number:06/789,595
Patent Claims:1. Process for producing a dipeptide of the formula ##STR28## wherein B represents hydrogen or Q; Q represents an amino acid protective group; V represents hydrogen or an alkyl group having 1, 2, 3, or 4 carbon atoms; C.sup.1 and C.sup.2 have the common natural configuration of naturally occurring amino acids; and Y is hydrogen and X is chloro or hydroxyl,

said process comprising:

reacting B-substituted aspartic acid of the formula ##STR29## wherein X, Y, and V are as defined above and the C.sup.2 carbon has the common natural configuration of naturally occurring amino acids;

said reaction being conducted in

(d) a water-immiscible solvent in the presence of a metallo-proteinase,

(e) a water-miscible solvent in the presence of a non-metallo-proteinase, or

(f) a water-immiscible solvent in the presence of a non-metallo-proteinase.

2. Process according to claim 1 in which the proteinase is immobilized.

3. Process according to claim 1 in which the proteinase is thermolysin, trypsin, pronase, prolysin, papain, collagenase, or crotulus atrox protease.

4. Process according to claim 1 in which Q is carbobenzoxy, p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, phenylacetyl, acetoacetyl, N-benzylidene, benzoyl, benzyl, t-amyloxycarbonyl; chloroacetyl, carbamyl, 3,5-dimethoxybenzyloxycarbonyl; 2,4,6-trimethylbenzyloxycarbonyl; p-phenylazobenzyloxycarbonyl; p-toluenesulfonyl; o-nitrophenylsulfonyl; or trifluoroacetyl.

5. Process according to claim 2 in which B and Y are H and X is --OH, thereby to make hydroxy-aspartame.

6. Process according to claim 2 in which B is Q and the mole ratio of the Q-protected aspartic acid to the second amino acid is 10:1 to 1:10.

7. Process according to claim 1 in which 10-3000 mg of proteinase is used per millimole of Q-protected aspartic acid.

8. A process for producing a dipeptide of the formula ##STR30## comprising treating an amino acid ester having the formula ##STR31## or a salt thereof, to replace X and Y with H, to provide a phenylalanine ester having the formula, ##STR32## and reacting said phenylalanine ester with B-substituted aspartic acid of the formula ##STR33## or a salt thereof; said reaction being conducted in (a) a water-immiscible solvent in the presence of a metallo-proteinase,

(b) a water-miscible solvent in the presence of a non-metallo-proteinase, or

(c) a water-immiscible solvent in the presence of a non-metallo-proteinase;

wherein B represents hydrogen or Q; Q represents an amino acid protective group; V represents hydrogen or an alkyl group having 1, 2, 3, or 4 carbon atoms; C.sup.1 and C.sup.2 have the common natural configuration of naturally occurring amino acids; and

(d) Y is hydrogen and X is chloro or hydroxyl.

9. Process according to claim 1 of making a dipeptide comprising

(I) in a first reaction, reacting B-substituted aspartic acid of the formula ##STR34## or a salt thereof with a second amino acid having the formula ##STR35## thereby to form a compound of the formula ##STR36## and (II) treating said latter compound to replace X and/or Y with H; or, when B is Q, to replace Q with H;

wherein B represents hydrogen or Q; Q represents an amino acid protective group; V represents hydrogen or an alkyl group having 1, 2, 3, or 4 carbon atoms; C.sup.1 and C.sup.2 have the common natural configuration of naturally occurring amino acids; said first reaction being conducted in

(d) a water-immiscible solvent in the presence of a metallo-proteinase,

(e) a water-miscible solvent in the presence of a non-metallo-proteinase, or

(f) a water-immiscible solvent in the presence of a non-metallo-proteinase.

10. Process according to claim 9 in which the solvent is chloroform, ethylene dichloride, ethyl acetate, isopropyl acetate, butyl acetate, isobutylacetate, methylisobutyl ketone, benzene, toluene, butanediol, glycerol, dimethylformamide, dimethylsulfoxide, triethylene glycol, acetonitrile, ethanol, methanol, dioxane, isopropylether, tetrachloroethylene, trichlorethylene, t-butanol, or cyclohexanol.

11. Process according to claim 9 in which Q is carbobenzoxy, p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, phenylacetyl, acetoacetyl, N-benzylidene, benzoyl, benzyl, t-amyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 2,4,6-trimethylbenzyloxycarbonyl; p-phenylazobenzyloxycarbonyl; p-toluenesulfonyl; o-nitrophenylsulfonyl, trifluoroacetyl, chloroacetyl, or carbamyl.

12. Process according to claim 9 in which the compound resulting from catalytic hydrogenation in (II) is hydroxy-aspartame.

13. Process according to claim 9 in which the hydrogenation is conducted at 0.degree.-150.degree. C., at a hydrogen pressure ranging from atmospheric to 1500 psig, in the presence of a catalyst of Pt, PtO.sub.2, Pd, Pd black, or Pd(OH).sub.2 on carbon, barium sulfate, or alumina; or in the presence of a catalyst of Raney Ni or Raney Co.

14. Process according to claim 13 in which the hydrogenation is conducted at a temperature in the range of room temperature to 45.degree. C., at a hydrogen pressure ranging from 45 to 60 psig, in the presence of Pd(OH).sub.2 catalyst.

15. Process according to claim 9 in which first one and then the other of X and Y is replaced with hydrogen.

16. Process according to claim 9 in which B is Q, and Q, but not X or Y, is replaced with H.

17. A method according to claim 1 for manufacturing a dipeptide from an N-substituted aspartic acid and (S,S)-beta-phenylserine lower alkyl ester, said method comprising subjecting said N-substituted aspartic acid and said phenylserine lower alkyl ester to a reaction in an organic solvent immiscible with water in the presence of a water-containing immobilized metallo-proteinase.

18. Method according to claim 17 in which dipeptide product is N-carbobenzoxy-L-alpha-aspartyl-L-erythro-beta-phenylserine methyl ester or N-butoxycarbonyl-L-alpha-aspartyl-L-erythro-beta-phenylserine methyl ester.

19. The method according to claim 9 of preparing a dipeptide, being L,L-aspartame or its lower alkyl ester homolog, comprising

(A) subjecting Q-substituted aspartic acid and beta-phenylserine lower alkyl ester, said ester containing (2S,3S) isomer, to reaction in an organic solvent immiscible with water in the presence of a water-containing immobilized metallo-proteinase, thereby to form a first dipeptide of the formula ##STR37## (B) treating said first dipeptide to replace Q with H and thereby forming a second dipeptide of the formula ##STR38## and (C) catalytically hydrogenating said second dipeptide thereby forming aspartame or its lower alkyl ester homolog.

Details for Patent 4,710,583

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Smith And Nephew SANTYL collagenase OINTMENT;TOPICAL 101995 001 1965-06-04 ⤷  Free Forever Trial W. R. Grace & Co. (New York, NY) 2039-03-29 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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