AU626608B2 - A process for the preparation of tripeptides - Google Patents

A process for the preparation of tripeptides Download PDF

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Publication number
AU626608B2
AU626608B2 AU45328/89A AU4532889A AU626608B2 AU 626608 B2 AU626608 B2 AU 626608B2 AU 45328/89 A AU45328/89 A AU 45328/89A AU 4532889 A AU4532889 A AU 4532889A AU 626608 B2 AU626608 B2 AU 626608B2
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denotes
compound
formula
trp
tyr
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AU4532889A (en
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Hans-Wolfram Flemming
Manfred Rukwied
Manfred Schmidt
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Hoechst AG
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Hoechst AG
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    • 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
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • C07K1/082—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing phosphorus
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Process for preparing tripeptides of the general formula I U-A-B-C-OH I in which U is hydrogen or a urethane protective group and A, B and C are amino acids, by reacting a compound of the general formula II U'-B-OH II in which U' is a urethane protective group which can be eliminated by hydrogenolysis, with a compound of the general formula III H-C-OR III in which R is alkyl, by the PPA method, eliminating U', reacting the compound obtained in this way with a compound of the general formula IV H-B-C-OR IV by the PPA method and subsequently eliminating R enzymatically.

Description

BOX fill 0
CA
26 F8 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class tnt. Class Application Number: S S S. Lodged: *Complete Specification Lodged: Priority Published: Related Art: 0
S.
S
S~
0
U.
I me of Applicant Adidress of Applicant HOE CHST AKrIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main of Germany 80, Federal Republic Actual Inventor Add -ess for Service HANS-WOLFRAM FLEMING, MANFRED RUKWIED, MANFRED SCHMIDT WATERMARYr PATENT TRADEMARK ATTORNEYS, 29r) BurwtL-d Road, Hawthorn, Victoria, Australia Complete Specification for the invention entitled: A PROCESS FOR THE PREPARATPION OF TRIPEPTIDES The following statement is a full description of this invention, Including the best method of performing it known to us i ii HOECHST AKTIENGESELLSCHAFT HOE 88/P 327 Dr. MY/je Description A process for the preparation of tripeptides Tripeptides are important intermediates in the synthesis of bioactive peptides such as, for example, the hypothalamus hormone gonadorelin and its analogs. For this purpose the tripeptides must be available in the most straightforward manner possible, on che one hand in good yields and, on the other hand, in high purity. The processes hitherto disclosed for the preparation of tripeptides do not meet these requirements in an optimal manner and are associated with disadvantages, some of which are serious. Thus, for example, even the products prepared by the process described in EP-A 156,280 are contaminated with byproducts which become disadvantageously evident in the subsequent synthetic steps. Thus the object of the present invention is to provide a process for the preparation of tripeptides which does not have the said disadvantages and provides, in a straight- 20 forward manner, products of high purity in good yields.
Accordingly, the invention relates to a process for the preparation of tripeptides of the general formula I U A B- C OH in which •*25 U denotes hydrogen or a urethane protective grou; A denotes a natural a-amino acid or derivatives thereof B denotes a natural a-amino acid or derivatives thereof and C denotes an aromatic a-amino acid, which comprises reacting a compound of the general formula II U' B OH 1 2 in which U' is a urethane protective eliminated by hydrogenolysis, and mentioned meaning, with a compound of
III
group which can be B has the abovethe general formula H C OR in which R represents alkyl ha' ing 1 to and C has the abovementioned meaning, in propylphosphonic anhydride, eliminating group U' by hydrogenolysis, reac 'ng compound of the general formula IV 4 carbon atoms, the presence of the protective the resulting @0 6 6 6 0 6*6 0 *0* *6
S
*6 ft ft H B C OR with a compound of the general formula V U A OH in the presence of propylphosphonic anhydride, finally eliminating R enzymatically.
V
and ft 060@*O 6 6
S
The urethane protective groups representing U are preferably the urethane protective groups customary in peptide chemistry, as are described, for example, in Kontakte Merck 3/79, page 14.
The benayloxycarbonyl and the tert.-butyloxycarbonyl groups are particularly preferred.
A urethane protective group U' which can be eliminated by hydrogenolysis is preferably the benzyloxycarbonyl group.
.N tn a~r~nai~n~- v r, ~1- ^roroe-Qon4- 4, cv -Natur-1- -c--a.ino acds or +rhe-r fgkit 4 A and/or B are preferably Gly, Ala- Ser, Thr, Val, Leu, Ile, Glu, Gin, p-Glu, Tyr e, Trp and His. Ser, Thr, Trp and Phe are partu-larly preferred.
An aromat' a-amino acid representing C is preferably Tyr
L
iwc- U- II-: 2a Natural a-amino acids or their derivatives representing A and/or B are preferably Gly, Ala, Ser, Thr, Val, Leu, lie, Glu, Gin, p-Glu (pyro-glutaminic acid formed from L-glutaminic acid by cyclisation when heated) Tyr, Phe, Trp and His. Ser, Thr, Trp and Phe are particularly preferred.
An aromatic a-amino acid representing C is preferably Tyr or Phe *o o o *o *Oo*e* 3 3- R in the general formula IV preferably denotes methyl.
A process in which U and U' denote benzyloxycarbonyl, A denotes Trp, B denotes Ser, C denotes Tyr and R denotes methyl is very particularly preferred.
The formation of a peptide linkage in the presence of propylphosphonic anhydride is known as the PPA method (Angew. Chem. Int. Ed. _19, 133 (1980)). This reaction is preferably carried out in polar solvents such as, for example, dimethylacetamide, dimethylformamide, dimethyl 10 sulfoxide, phosphoric tris(dimethylamide), N-methylpyrrolidone or water. However, chloroform, methylene chloride or ethyl acetate are also employed.
It is also possible in an advantageous manner to use mixtures of the said solvents with water. An ethyl 015 acetate/water mixture is particularly preferred. The synthesis can be carried out between -10°C and room temperature. It is preferable to start at about 0 C and subsequently to raise to room temperature.
The elimination of the U' protective group by hydrogenolysis is advantageously carried out in a known manner with hydrogen on a Pd/C catalyst.
The enzymatic esterolysis in the last reaction step is preferably carried out with trypsin and/or a-chymotrypsin (Hoppe-Seylers Zeitschrift f. physiol. Chemie, 336, 248 (1964)). Trypsin is particularly preferred. Where appropriate, enzymes which are immobilized by known methods on a support are also used, such as described, for example, in EP-A 178,553. In this case, the enzymes are advantageously employed in amounts of 0.01 to 20 by weight relative to the amount of substrate. An amount of 2 by weight of enzyme is particularly preferred.
Examples of solvents which can be employed are water, dimethylformamide, methanol, ethanol, isopropanol, butanol, ethyl acetate, butyl acetate, toluene or i' L 4 methylene chloride.
An ethyl acetate/water mixture is preferred. The temperatures are advantageously between 0 and 60"C. A temperature range from 20 to 35 0 C is preferred. The pH of the reaction medium is preferably in the range between 4 and particularly preferably between 4 and 8.
The process according to the invention can be carried out in such a way that each intermediate is isolated. However, it is preferably carried out in a one-pot process, that is to say without isolation of the intermediates.
The starting compounds of the general formulae II, III and V are known and can be obtained by the customary methods.
The process according to the invention surprisingly 15 provides products of high chemical and optical purity, which can be employed without difficulty in further syntheses. The yields are likewise excellent and are between 40 and 50 based on the amount of the compound of the general formula III employed.
*6'*20 It has to be regarded as particularly surprising that the process according to the invention is distinctly superior, in terms both of purity and of yield, to the process of EP-A 156,280, which has only three stages.
Example oS Z-Trp-Ser-Tyr-OH a) 350 ml of water are placed in a 2 1 stirred apparatus, and 47.8 g (0.200 mol) of Z-Ser-OH, 46.4 g (0.200 mol) of H-Tyr-OMexHCl and 150 g of sodium chloride are introduced. Also added are 700 ml of ethyl acetate and, after everything has dissolved, the pH of the mixture is adjusted to 5.0 by addition of about 25 ml of N-ethylmorpholine. During the addition of about 220 ml (0.42 mol) of PPA solution L i 1 (w(PPA) in 50) in about 30 minutes at a maximum of 30 0 C (cool somewhat at the end), about 110 ml (0.86 mol) of N-ethylmorpholine are added via a pHstat pump at pH 5.0. The PPA addition is terminated when a precipitate forms in the reaction mixture.
The precipitate is redissolved by subsequent addition of 350 ml of water. The aqueous phase is separated off in a separating funnel and then the ester phase is washed with 700 ml of potassium bisulfate solution (w(KHSO 4 in 10) and 700 ml of sodium bicarbonate solution (w(NaHC03) in The aqueous phase from the reaction and the wash phases are discarded.
b) About 700 ml of ester phase from the 1st coupling, 15 200 ml of water and 3.3 g of palladium on carbon w(Pd) in 2.5 are placed in a 2 1 stirred apparatus and a stream of hydrogen is passed in at 0 C. During the reaction the pH is maintained at with a pH-stat pump and addition of about 160 ml (0.16 mol) of hydrochloric acid c(HC1) 1 mol/l.
After the reaction is complete, when no more hydrochloric acid is consumed, (about 30 minutes) the reaction mixture is filtered through a suction funnel, and the aqueous phase is separated from the ester phase in a separating funnel. The ester phase is discarded.
c) About 430 ml of aqueous phase from the hydrogenolysis and 700 ml of ethyl acetate are placed in a 2 1 stirred apparatus and 50.7 g (0.15 mol) of Z-Trp-OH and 125 g of sodium chloride are added.
After everything has dissolved, the pH is adjusted to 5.0 with about 19 ml of N-ethylmorpholine. During the addition of about 220 ml (0.42 mol) of PPA solution (w(PPA) in 50) in about 30 minutes at a maximum of 30°C (cool somewhat at the end), about 110 ml (0.86 mol) of N-ethylmorpholine are added via a pH-stat pump at pH 5.0. The PPA addition is -6terminated when a precipitate forms in the reaction mixture. The precipitate is redissolved by subsequent addition of 350 ml of water. The aqueous phase is separated off in a separating funnel, and then the ester phase is washed with 700 ml of potassium bisulfate solution (w(KHS04) in 10) and several times with 700 ml portions of sodium bicarbonate solution (w(NaHCO 3 in 5) until Z-Trp-CH has been completely removed (according to TL analysis). The aqueous phase from the reaction and the wash phases are discarded.
d) About 700 ml of ester phase from the 2nd coupling and 700 ml of water are placed in a 2 1 stirred apparatus and heated to 35-40 0 C, and 1 g of trypsin is initially added. The reaction starts immediately and, during it, the pH is maintained constant at pH 7.0 with about 110 ml (0.11 mol) of sodium hydroxide solution (c(NaOH) 1 mol/1). The reaction lasts about 7 hours and, during this, the rate is increased now and again by further addition of 0.5 g of trypsin. It is complete when trypsin addition now brings about only a slight increase in the rate of absorption of sodium hydroxide solution, or TLC S• analysis shows hardly any starting material remain- ""25 ing. The reaction solution is clarified through a suction funnel, and the ester phase is separated *oo* from the aqueous phase in a separating funnel. The ester phase is discarded.
The aqueous phase is initially extracted by shaking twice at pH 5.8-6.0, by addition and dissolution of g of potassium dihydrogen phosphate, with 700 ml of ethyl acetate each timte. The ester phases are discarded. The aqueous phase is then extracted by shaking three times at pH 5.0, adjusted by addition of about 5 ml of glacial acetic acid, with 700 ml of ethyl acetate each time. The aqueous phase is discarded. The ester phases contain the tripeptide which, on evaparation to dryness in vacuo, remains in the form of loosely packed cryst!IJs. The product is dried in a vacuum oven at 40 0
C.
Weight: 51.2 g Yield: 42.0 based on H-Tyr-OMexHCl Purity: 98.2 (determined with HPLC LiChrosorb Si buffer) ComparisBon iOxample Z-Trp-Ser-Tyr-OH was prepared by the process specified in EP-A 156,280.
Yield: S0* Purity: 78.8 (determined with HPLC LiChrosorb Si *e,60/peptide buffer)
S
555505
S
S. S 50

Claims (10)

1. A process for the preparation of tripeptides of the general formula I U A -B C OH I in which U denotes hydrogen or a urethane protective group A denotes a natural a-amino acid or derivatives thereof t B denotes a natural a-amino acid or derivatives thereof and C denotes an aromatic a-amino acid, :r which comprises reacting a compound of the formula II U' B OH II in which U' is a urethane protective group which can be eliminated by hydrogenolysis, and B has the above- mentioned meaning, with a compound of the formula III *4 H C- OR III in which R represents alkyl having 1 to 4 carbon atoms, and C has the abovementioned meaning, in the presence of propylphosphonic anhydride, eliminating the protective group U' by hydrogenolysis, reacting the resulting *0 4* compound of the formula IV H B C OR IV with a compound of the formula V U A OH V in the presence of propylphosphonic anhydride, and finally eliminating R enzymatically.
2. The process as claimed in claim 1, wherein U denotes 9 benzyloxycarbonyl or tert.-butyloxycarbonyl.
3. The process as claimed in claim 1 and/or 2, wherein A and/or B denote Gly, Ala, Ser, Thr, Val, Leu, Ile, Glu, Gin, p-Glu, Tyr, Phe, Trp or His.
4. The process as claimed in one or more of claims 1 to 3, wherein A and/or B denote Ser, Thr, Trp or Phe.
The process as claimed in one or more of claims 1 to 4, wherein C denotes Tyr or Phe.
6. The process as claimed in one or more of claims 1 to 5, wherein U' denote benzyloxycarbonyl. Va
7. The process as claimed in one or more of claims 1 to S* 6, wherein R denotes methyl.
8. The process as claimed in one or more of claims 1 to 7, wherein the reactions are carried out in the presence of propylphosphonic anhydride in an ethyl acetate/water S* mixture.
9. The process as claimed in one or more of claims 1 to 8, wherein the enzymatic esterolysis is carried out with trypsin and/or a-chymotrypsin. a
10. The process as claimed in one or more of claims 1 to 9, wherein U and U' denote benzyloxycarbonyl, A denotes Trp, B denotes Ser, C denotes Tyr and R denotes methyl. DATED this 20th day of November 1989. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD, HAWTHORN. VIC. 3122.
AU45328/89A 1988-11-22 1989-11-21 A process for the preparation of tripeptides Expired AU626608B2 (en)

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Application Number Priority Date Filing Date Title
DE3839379A DE3839379A1 (en) 1988-11-22 1988-11-22 METHOD FOR PRODUCING TRIPEPTIDES
DE3839379 1988-11-22

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AU626608B2 true AU626608B2 (en) 1992-08-06

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JP (1) JP2843618B2 (en)
AT (1) ATE124053T1 (en)
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CA (1) CA1335493C (en)
DE (2) DE3839379A1 (en)
DK (1) DK173690B1 (en)
ES (1) ES2075028T3 (en)
IE (1) IE67293B1 (en)
IL (1) IL92368A0 (en)

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DE102004029811A1 (en) * 2004-06-19 2006-01-12 Clariant Gmbh Process for the preparation of alkenes by elimination of water from alcohols with alkylphosphonic anhydrides
DE102004029812A1 (en) 2004-06-19 2006-05-24 Clariant Gmbh Process for the preparation of nitriles from aldehyde oximes by reaction with alkylphosphonic anhydrides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4691008A (en) * 1984-03-27 1987-09-01 Hoechst Aktiengesellschaft Process for the low-racemization preparation of peptide intermediates of the synthesis of gonadorelin and gonadorelin analogs, and new intermediates for this process
AU1525988A (en) * 1987-04-30 1988-11-03 Millipore Corporation Bop reagent for solid phase peptide synthesis
AU4188789A (en) * 1988-03-11 1989-10-05 Bioresearch Inc. Urethane-protected amino acid-n-carboxyanhydrides

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE7801373L (en) * 1978-02-07 1979-08-08 Kabi Ab EASY SPLABLE SUBSTRATE FOR QUANTIFIATION OF PROTEASES
US4293648A (en) * 1979-12-12 1981-10-06 G. D. Searle & Co. Process for esterification of α-L-aspartyl-L-phenylalanine
DE3438189A1 (en) * 1984-10-18 1986-04-24 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING AROMATICALLY SUBSTITUTED L-AMINO ACIDS

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4691008A (en) * 1984-03-27 1987-09-01 Hoechst Aktiengesellschaft Process for the low-racemization preparation of peptide intermediates of the synthesis of gonadorelin and gonadorelin analogs, and new intermediates for this process
AU1525988A (en) * 1987-04-30 1988-11-03 Millipore Corporation Bop reagent for solid phase peptide synthesis
AU4188789A (en) * 1988-03-11 1989-10-05 Bioresearch Inc. Urethane-protected amino acid-n-carboxyanhydrides

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JP2843618B2 (en) 1999-01-06
ES2075028T3 (en) 1995-10-01
DK584489D0 (en) 1989-11-21
EP0370399A3 (en) 1991-09-18
JPH02219587A (en) 1990-09-03
IL92368A0 (en) 1990-07-26
DK584489A (en) 1990-05-23
DE3839379A1 (en) 1990-05-23
AU4532889A (en) 1990-05-31
EP0370399A2 (en) 1990-05-30
IE893717L (en) 1990-05-22
ATE124053T1 (en) 1995-07-15
DE58909308D1 (en) 1995-07-27
DK173690B1 (en) 2001-06-25
IE67293B1 (en) 1996-03-20
CA1335493C (en) 1995-05-09
EP0370399B1 (en) 1995-06-21

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