IE58082B1 - A process for the preparation of compounds containing carboxamide groups, in particular of peptides - Google Patents

A process for the preparation of compounds containing carboxamide groups, in particular of peptides

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Publication number
IE58082B1
IE58082B1 IE235284A IE235284A IE58082B1 IE 58082 B1 IE58082 B1 IE 58082B1 IE 235284 A IE235284 A IE 235284A IE 235284 A IE235284 A IE 235284A IE 58082 B1 IE58082 B1 IE 58082B1
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IE
Ireland
Prior art keywords
reaction
preparation
base
peptides
group
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IE235284A
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IE842352L (en
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Hoechst Ag
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Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of IE842352L publication Critical patent/IE842352L/en
Publication of IE58082B1 publication Critical patent/IE58082B1/en

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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
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

1. A process for the preparation of compounds containing carboxamide groups by reaction of compounds which contain a carboxyl group, in the presence of dialkylphosphinic anhydrides, with compounds which contain a free amino group, which comprises maintaining the hydrogen ion concentration in the reaction mixture at an almost constant value in a range of 10**-5 to 10**-10 (mol/l) during the reaction and, after the reaction is complete, eliminating radicals which have, where appropriate, been introduced to protect other functional groups.

Description

This invention relates to a process for the preparation of compounds containing carboxamide groups, in particular of peptides.
A large number of processes are known for the preparation of carboxamide and peptide bonds (see, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Vol. XV, Part II, pages 1-364. Also Angew. Chemie 92:, 129 (1980)). All these processes aim, with varying success, at ensuring the criteria, which are necessary for the synthesis of peptides, of freedom from racemization, and of straightforward procedure under mild conditions with high yields and with readily accessible starting materials.
A process for the preparation of carboxamides is known from European Patent A1-56,618, in which compounds containing carboxyl groups are reacted with compounds which contain a free amino group in the presence of dialkylphosphinic anhydrides. The dialkylphosphinic acid which is liberated during the reaction is bound by an excess of an organic base or a basic buffer which is added to the reaction mixture at the start.
The present process represents a new way of optimizing the said conditions for an economic synthesis of peptides and amides.
It has been found that compounds containing carboxamide groups, in particular oligopeptides, can be prepared under mild conditions and in good yield by reacting compounds which contain a free amino group, in particular ami nocarboxy li c. acid derivatives or peptides whose carboxyl group is protected, in the presence of the anhydride of a dialkylphosphinic acid, with compounds which contain a free carboxyl group, in particular aminocarboxy Iic acids or peptides whose amino group is acylated. The new process comprises maintaining the hydrogen ion concentration of the reaction mixture, at an almost constant value in a range of —5 —1C to 10 (mol/l) during the reaction by metering in a base.
The radicals introduced to protect the functional groups can, in the case of synthesis of peptides, subsequently be eliminated in a customary manner.
Anhydrides of dialkylphosphinic acids are to be understood tc be compounds of the formula I R R O = P - O - P- =. O i R ‘ R in uhich R denotes alkyl. The substituents R shown in the formula can be identical or different. Anhydrides in which both P atoms have identical substituents are preferred.
Within the scope of the invention, anhydrides of the formula I in which R is in each case a lower alkyl, preferably one having 1 to 4 carbon atoms, are particularly suitable.
The dialkylphosphinic anhydrides used according to the invention are colorless liquids. They are stable at room temperature and can be distilled under reduced pressure without decomposition. They are.readily soluble in most non-aqueous solvents, especially in lipid solvents, such as chloroform or methylene chloride, but also in polar solvents, such as DMF and DMA.
Examples of anhydrides of dialkylphosphinic acids which may be mentioned are: methy I ethy Iphosphinic anhydride, methyIpropy I phosphinic anhydride, methyI butyIphosphinic anhydride, diethyI phosphinic anhydride, di-n-propylphosphinic anhydride and di-n-buty I phosphinic anhydride.
The preparation of the dialkylphosphinic anhydrides can be carried out in a manner known per se by, for example, reaction of the dia IkyIphosphinoyI chlorides with alkyl dia IkyI phosphinates at 150-160°C (Houben-Weyl, Methoden der Organischen Chemie, G . Thieme V e r I., Stuttgart 1963, Vol. XII, pages 266 et seq.). Processes in which dialkylphosphinic acids, their salts or esters are reacted with phosgene are particularly preferred (German Patent 2,129,583, German Offenlegungsschrift 2,225,545).
The process according to the invention is preferably carried out in a mixed aqueous, single- or 2-p h as ε system, within a narrow pH range, preferably at approximately constant pH. It is possible for the pH of the re action isixtures to be 5-10 and, advantageously, it should be in the neutral or weakly acid range; pH values between 5.0 and 7.0 are particularly preferred. However, it is also possible to carry out the syntheses in the weakly alkaline range. The pH is preferably controlled by metered addition of concentrated aqueous solutions of alkali metal hydroxides, but .it is also possible to use organic bases, such as N-e t h yIm o r p h ο I i n e, triethylamine or trialkylamine having up to 6 carbon atoms.
For the preparation of oligopeptides by the process according to the invention, the starting materials used are, on the one hand, an aminoacid or a peptide having a protected carboxyl group and, on the other'hand, an aminoacid or a peptide having a protected amino group.
It is possible to use for the protection of the carboxyl groups all the protective groups customary in peptide synthesis. Esters of straight-chain or branched aliphatic alcohols, such as methanol, ethanol and tert.butanot, are particularly suitable. Esters of araliphatic alcohols, such as benzyl alcohol or diphenylmethylcarbinol, can also be used.
Likewise, it is possible to use for the protection of the amino groups all the protective groups customary in peptide synthesis. Examples of particularly suitable groups which may be mentioned are the carbobenzoxy radical and the carbo-tert.-buty I oxy radical.
It is possible to use as the solvent all the anhydrous inert solvents customary in peptide synthesis, for example methylene chloride, chloroform, dimethylformamide, dimethylacetamide, dioxane or tetrahydrofuran.
Solvents which can be used in the single-phase mixed aqueous procedure for the reaction are mixtures of water and an organic solvent which is miscible with water, such as, for example, dioxane, tetrahydrofuran, dimethylformamide or dimethylacetamide. The use of systems of this type is especially advantageous when linking peptides which are mainly soluble in water.
For the two-phase mixed aqueous procedure for the reaction, it is possible to use systems such as, for example, ethyl acetate, propyl acetate, n-butyl acetate, methylene chloride, glycol dimethyl ether, 3-methyltetra5 hydrofuran and chloroform, each in a heterogeneous mixture with water.
As a rule, the reaction takes place sufficiently rapidly at room temperature. Gentle warming is not injurious. Higher temperatures, say above 30°C , are not advisable, especially in peptide synthesis, because of the danger of racemization. A reaction temperature between 0 and 30°C is preferred, and one between 5 and 25°C is particularly preferred.
The process according to the invention makes it possible for the first time to follow the course of the reaction by the consumption of the base which is used when the pH is approximately constant. For this purpose, the reaction is preferably carried out in an automatic recording pH-stat, advantageously with vigorous mixing of the mixed aqueous system containing the reactants, the carboxyl component, the amine component and the dialkylphosphinic anhydride. The graph provided by the recorder of the consumption of base as a function of time shows a curve which becomes asymptotic toward the end of the reaction (cf. the curves reproduced in the Fig.). Thus, the process according to the invention makes it possible to detect the endpoint of the synthetic reaction in a straightforward manner It ought to be noted that the apparent pH values in these mixed aqueous systems measured using the method described can differ from the true pH values in these systems .
When buffer solutions are used in a known manner to trap the dialkylphosphinic acid, then it is unavoidable 5 that excess salts, composed of inorganic salts, occur in the mother liquors of the batches. When carrying out the process industrially, they make it difficult to recover the di a IkyIphosphinic acid produced from the condensing agent, and they can give rise to effluent problems.
During isolation of the reaction product by extraction from alkali solution with a lipoid phase which is miscible with water to only a limited extent, the alkali metal salts which are formed during the course of the reaction when alkali metal hydroxides are used as the bases in this variant of the process according to the invention are, because of their relatively high hydrophi I icity and in contrast to the salts resulting when some tertiary organic bases are used, relatively easy to remove. Furthermore, contamination of the lipoid phase by extracted tertiary base is avoided in this procedure.
The process according to the invention is straightforward to carry out and provides peptides of high optical purity and in high yield. In addition, it is economical and environmentally acceptable.
The dialkylphosphinic anhydrides have low molecular weights, are readily obtained and purified and have a high proportion of reactive groups per unit weight and have high IipophiIicity. The dialkylphosphinic anhydrides and the corresponding dialkylphosphinic acids are lipid8 soluble. This makes it possible to work up water-soluble peptide derivatives via a first precipitation step using suitable lipid solvents.
The dialkylphosphinic acid obtained from the dialkylphosphinic anhydride during the course of the peptide synthesis can be recovered from the solutions remaining after the synthetic reaction. Recovery of the dialkylphosphinic acids from a relatively large amount of aqueous mother liquors from the synthesis can be carried out by extraction with solvents such as chloroform and isobutanol followed by work-up by distillation. In this context, it is of particular industrial interest that the dialkylphosphinic acids can be distilled in vacuo without decomposition. The dialkylphosphinic acids thus recovered from the work-up can then readily be converted into the corresponding dialkylphosphinic anhydrides by the process of German Offenlegungsschrift 2,225,545.
In the mixed aqueous procedure described, it is possible to replace the organic base by alkali metal hydroxide solutions, and this considerably simplifies the recovery of the dialkylphosphinic acids during the work-up after the synthesis as described above. In this case, it is possible to dispense with the extraction step. After liberation, the dialkylphosphinic acid can then be distilled directly out of the evaporated mother liquor from the synthesis or, in the two-phase procedure, it is recovered from the aqueous phase, after removal of the lipoid phase, by acidification and extraction. The neutral inorganic salts then remain in the aqueous phase.
Example 1: Ethyl ester of carbobenzoxyglycine: 7.0 g (0.05.mole) of H-Gly-OCHj.HCI are added, with stirring at -5°C, to a solution of 10.5 g (0.05 mole) of carbobenzoxygIycine in 120 ml of ethyl acetate. 20 g of methyIethyI phosphinic anhydride are added dropwise to the resulting suspension. The pH of the reaction mixture is then adjusted to 7.0 at a temperature of 0° to +10°C by dropwise addition of 4 N NaOH using an autotitrator, and the batch, which is thoroughly mixed by high-speed stirring, is maintained at this pH until the recorder connected to the autotitrator shows that the curve of consumption of sodium hydroxide solution has become asymptotic with the time axis. This is the case after about 60 minutes.
The ethyl acetate phase is now removed, extracted twice with 50 ml of saturated sodium bicarbonate solution, dried with sodium sulfate, and, after removal of the solvent in vacuo at room temperature, 12.25 g (84% of theory) of Zdipeptide ester having a melting point of 81°C are obtained.
Example 2: Carbobeηzoxyphenylalanine cyclohexylamide: 3.0 g (0.01 mole) of Z-Phe-OH and 1.0 g (0.01 mole, 1.2 mt) of eye lohexy I amine are dissolved in a mixture of ml of tetrahydrofuran and 5 ml of water. After cooling the reaction mixture to -5°C, 4 g of methy I ethy I phosphinic anhydride are added, with stirring, and the pH of the reaction solution is adjusted to 6.0 with 4 N NaOH, and is maintained constant throughout the reaction time by metered addition of sodium hydroxide solution as described in Example 1. The reaction is virtually complete after 60 minutes, as can be seen from the consumption of alkali metal hydroxide. The reaction solution is evaporated in vacuo at room temperature, the residue is taken up with ethyl acetate, and the ethyl acetate solution is washed with 5% strength potassium bisulfate solution, saturated sodium bicarbonate solution and water, dried over sodium sulfate and, after removal of the solvent in vacuo at room temperature and drying of the product in vacuo over P2O5, 3.0 g of final product of melting point 167°C are obtained, Ιαίθ = -3.0° (c = 1, DfiF).
Example 3: Z-Trp-Gly-0CH? 3.35 g (0.01 mole) of Z-Trp~Or! are dissolved in 20 ml of isopropyl acetate, 1.25 g (0.01 mole) of H-Gly-OCHj is added, the vigorously stirred suspension is cooled to -5°C, and 4.0 ml of methylethylphosphinic anhydride are added at this temperature, at the same time adjusting the pH to 5.7 by metered addition of 4 N NaOH using an autotitrator as described in Example 1. When the phases are thoroughly mixed, the reaction is finished within 60 minutes. The ethyl acetate phase is removed and worked up as described in Example 2. Yield: 3.53 g <86% of theory) C al 2θ=-13.50 (c = 0.1, glacial acetic acid).
Example_4 : Z-Phe-Arg-Trp-Gly-OCH^ 1.55 g (0.005 mole) of H-7rp-Gly-OCH^.HCI is added to a solution of 2.26 g (0.005 mole) of Z-Phe-Arg-OI! in ml of isopropyl acetate, and the vigorously stirred suspension is cooled to -5°C. Then 2 ml of methylethylphosphinic anhydride are added dropwise, maintaining the pH constant at 5.2 using 4 N NaOH as described in Example 1. After 15 minutes, the temperature of the reaction mixture is allowed to reach room temperature.
The reaction is virtually complete after 70 minutes as is shown by the graph of the consumption of NaOH with reaction time. The ethyl acetate phase is now removed, washed with water and saturated sodium bicarbonate solution, and the reaction product is isolated from the dried solution by evaporation in vacuo at room temperature and digestion of the residue with absolute diethyl ether.
Yield after recrystailization from ethanol/ether: 3.0 g (84.5% of theory), CaT^°= -25.7° (c = 0.1, DMF). Example 5 7.Lys(Boc)-Val-Tyr-0CH? - 1.91 g (0.005 mole) of Z-Lys(Soc)-0H are dissolved in 25 ml of butyl acetate which is saturated with water, and 1.65 g (0.005 mole) of H-Va l~Ty r--0 C H^ . H C I are added, the vigorously stirred reaction mixture is cooled to -5°C, and the pH of the rapidly stirred mixture is brought to 7.0 with 4 N NaOH as described in Example 1, and it is maintained at this value throughout the reaction time (70 minutes). The temperature during the first 10 minutes of the reaction time is maintained at -5°C to 0° C , and is then allowed to warm to room temperature. The working up of the butyl acetate phase containing the final product is carried out as indicated in Example 2.
Yiel'd after recrystallization from ethanol/ether: 3.0 g (91% of theory), Coip = -25° (c = 1z ethanol).
Example 6 Z-Gly-Leu-Arg-OCH3 1.3 ml of methylethylphosphinic anhydride is added to a solution of 642 mg of Z-Gly-Leu-OH and 449 mg of HArg-Ofle.HCl in 3 ml of dimethylacetamide and 0.5 ml of water, and the pH during the reaction which now takes place is maintained at 7.2 with a mixture of N-ethylmor10 pholine and water (1:1, vol/vol) using a pH-stat. The reaction is complete after 40 minutes according to the graph on the recorder. The working up is carried out as described in Example 2z but without the extraction of the ethyl acetate phase with 5% potassium bi sulfate solution mentioned there.
Yield: 700 mg (71% of theory) :α30°= -24.4° (c = 1, CH30H)

Claims (9)

CLAIMS :
1. A process for the preparation of a compound containing -a caiboxamide group by reaction of a compound which contains a carboxyl group, in the presence of a dial kyl phosphinic anhydride, with a compound which contains a free amino group, which comprises maintaining the hydrogen ion concentration in the reaction mixture at an almost constant value in a range of 10~5 to 10~1θ (mol/l) curing the reaction hy metering in a base and, after the reaction is complete, eliminating radi cal s which have, where appropriate, been introduced to protect other functional groups.
2. A process as claimed in claim 1 for the preparation of peptides.
3. A process as claimed in claim 1 or 2, wherein the reaction is carried out in a homogeneous or heterogeneous mixed aqueous medium.
4. a process as claimed in one of claims 1 t o 3 Z wherein the base used is an aqueous solution of an alkali metal hydroxide.
5. A process as claimed in one of claims 1 to 3, wherein a trialkylamine is used as the base.
6. A process as claimed in one of claims 1 to 5, wherein the end-point of the synthetic reaction is established with the aid of the graph recorded by a pH-stat (consumption of base versus reaction time).
7. A process as claimed in one of claims 1 to 6, -14wherein the reaction is carried out between 0 and 30°C.
8. A process as claimed in Claim 1 for the preparation of a compound containing a carboxamide group, substantially as hereinbefore described with reference to the accompanying 5 Examples.
9. A compound containing a carboxamide group whenever prepared by a process claimed in a preceding claim.
IE235284A 1983-09-16 1984-09-14 A process for the preparation of compounds containing carboxamide groups, in particular of peptides IE58082B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19833333456 DE3333456A1 (en) 1983-09-16 1983-09-16 METHOD FOR PRODUCING COMPOUNDS CONTAINING CARBONIC ACID AMIDE, IN PARTICULAR PEPTIDES

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IE842352L IE842352L (en) 1985-03-16
IE58082B1 true IE58082B1 (en) 1993-06-30

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EP (1) EP0135183B1 (en)
JP (1) JPS6084249A (en)
AT (1) ATE33251T1 (en)
AU (1) AU570724B2 (en)
CA (1) CA1285698C (en)
DE (2) DE3333456A1 (en)
DK (1) DK160041C (en)
ES (1) ES535919A0 (en)
GR (1) GR80370B (en)
HU (1) HU189936B (en)
IE (1) IE58082B1 (en)
IL (1) IL72943A (en)
PT (1) PT79195B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3333454A1 (en) * 1983-09-16 1985-04-11 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS
DE3333455A1 (en) * 1983-09-16 1985-04-11 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2901843A1 (en) * 1979-01-18 1980-07-31 Hoechst Ag METHOD FOR PRODUCING CARBONIC ACID AMIDES AND PEPTIDES
DE3101427A1 (en) * 1981-01-17 1982-09-02 Hoechst Ag, 6000 Frankfurt "METHOD FOR PRODUCING COMPOUNDS CONTAINING CARBONIC ACID AMIDE, IN PARTICULAR PEPTIDES"
DE3333454A1 (en) * 1983-09-16 1985-04-11 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS
DE3333455A1 (en) * 1983-09-16 1985-04-11 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS

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DK160041B (en) 1991-01-21
ES8505939A1 (en) 1985-06-16
CA1285698C (en) 1991-07-02
IL72943A (en) 1988-07-31
IE842352L (en) 1985-03-16
DE3333456A1 (en) 1985-04-11
ATE33251T1 (en) 1988-04-15
HU189936B (en) 1986-08-28
IL72943A0 (en) 1984-12-31
JPH0417177B2 (en) 1992-03-25
DK440184D0 (en) 1984-09-14
EP0135183A3 (en) 1986-03-05
DK440184A (en) 1985-03-17
GR80370B (en) 1985-01-11
AU570724B2 (en) 1988-03-24
EP0135183A2 (en) 1985-03-27
DE3470162D1 (en) 1988-05-05
HUT36083A (en) 1985-08-28
PT79195B (en) 1986-09-10
JPS6084249A (en) 1985-05-13
EP0135183B1 (en) 1988-03-30
DK160041C (en) 1991-06-10
PT79195A (en) 1984-10-01
AU3307384A (en) 1985-03-21
ES535919A0 (en) 1985-06-16

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