WO1986004924A1 - Procede de preparation de n-formyl-l-peptides - Google Patents

Procede de preparation de n-formyl-l-peptides Download PDF

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Publication number
WO1986004924A1
WO1986004924A1 PCT/SU1986/000010 SU8600010W WO8604924A1 WO 1986004924 A1 WO1986004924 A1 WO 1986004924A1 SU 8600010 W SU8600010 W SU 8600010W WO 8604924 A1 WO8604924 A1 WO 8604924A1
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WO
WIPO (PCT)
Prior art keywords
synthesis
acid
αϊа
mixture
protected
Prior art date
Application number
PCT/SU1986/000010
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English (en)
Russian (ru)
Inventor
Valentin Mikhailovich Stepanov
Ljudmila Aronovna Ljublinskaya
Svetlana Evgenievna Chikindas
Original Assignee
Vsesojuzny Nauchno-Issledovatelsky Institut Geneti
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Vsesojuzny Nauchno-Issledovatelsky Institut Geneti filed Critical Vsesojuzny Nauchno-Issledovatelsky Institut Geneti
Priority to NL8620072A priority Critical patent/NL8620072A/nl
Priority to DE19863690076 priority patent/DE3690076T1/de
Publication of WO1986004924A1 publication Critical patent/WO1986004924A1/fr

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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
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione

Definitions

  • a phylum in the molecule is a must, as it is the person responsible for the interaction of the process and the incidence of impaired receptors The same reactions stimulate and certain other functions of the cells, such as aggregation, the separation of enzymes, and the use of toxic drugs.
  • omega-milleptides is the front-25 sixth parameter - umo-milaspartum, that is, methyl-omega-omega-ashilane.
  • BACKGROUND OF THE INVENTION There are various approaches to the synthesis of milieu. ⁇ lassiches ⁇ imi me ⁇ dami- ⁇ e ⁇ idn ⁇ g ⁇ sin ⁇ eza yavlya- 30 yu ⁇ sya ⁇ a ⁇ b ⁇ diimidny "me ⁇ d smeshanny ⁇ angid ⁇ id ⁇ v or a ⁇ ivi ⁇ vanny ⁇ e ⁇ i ⁇ v.
  • the synthesis of fuels that support the reaction with the azide method in the process of the processes of anilide syntheses is mild clay and
  • the azide method allows you to receive optically pure antagonists, - 3 -
  • the syntheses of anilide of phenyl-glycine and ethyl ester of ⁇ - / phenyl-enriched acids are described in a similar manner in the food chain. Therefore, it is difficult to talk about the availability of 5 azide-type equipment in the synthesis of friendly drugs. Otherwise, the azide method is two-stage, it will protect all additional functional groups with the following removal, which significantly complicates and improves the welfare.
  • the process is delivered with a high output reaching 90, when the physical process is removed and the process is secured. / ⁇ zothea G., ⁇ ⁇ ⁇ . , ⁇ with kato ⁇ . , ⁇ ⁇ . , ⁇ -
  • a cost-effective method of synthesizing an attribute is the use of quality-guarded damp for amine function of acid acid.
  • the source of the acylating agent used to introduce such protective groups in this case, they use, for example, nitrous-benzyl-benzyl-benzyl, is
  • ⁇ is used to use synthetic amino acids to receive the target product, it is useful
  • the embodiment of the present invention is disposed of in that, as a part of the external-urban environment, a single-dimethylated medium is used.
  • the methods of obtaining ⁇ -fomp-pepstidov represent a private fragment 20 active synthesis of drugs.
  • An advantageous enzyme synthesis of the test connection is a high process and regioselective process.
  • Use of the product as a part of biosynthesis at the stage of the preparation of the battery is free of charge and the device is in contact with the It does not require the primary protection of amino acids, which contain additional functional groups in large quantities of radicals. For example, taking into account the acidity of 30 acids, the compensation is only for a large group, since it is a big accident.
  • a protective deactivation of an etheric type can be carried out by metal, - 9 - Ethyl, benzyl esters.
  • amide type protecting groups amide, anilide, substituted anilides, in particular, nitric anilides, hydrazide and substituted hydrazides may be used. 5 Sections
  • the predominantly metal kinase does not impose a slight restriction on the cost of the aminogens that are not in use.
  • amino acid residues for example, alanyl-alanyl, alanyl-glycyl, glycyl-alanyl, glycyl-glycyl.
  • thermolysin 35 are close to thermolysin and could be used in the treatment of the analogous thermolysin.
  • ch ⁇ for ⁇ e ⁇ aniya ⁇ tsessa tseles ⁇ b ⁇ aznee vseg ⁇ is ⁇ lz ⁇ va ⁇ in ⁇ aches ⁇ ve is ⁇ dn ⁇ g ⁇ ⁇ a ⁇ b ⁇ siln ⁇ g ⁇ ⁇ m ⁇ nen ⁇ a ⁇ mil- 5 s ⁇ de ⁇ zhaschie ⁇ izv ⁇ dnye me ⁇ i ⁇ nina, ⁇ enilalanina, alanyl-alashna, as ⁇ a ⁇ agin ⁇ v ⁇ y ⁇ isl ⁇ y, and ⁇ aches ⁇ ve amin ⁇ m ⁇ nen ⁇ a- ⁇ -ni ⁇ anilidy ⁇ enilalashna and leucine or me ⁇ il ⁇ vy e ⁇ i ⁇ ⁇ eshlalashna.
  • ⁇ ⁇ edlagaem ⁇ m s ⁇ s ⁇ be sin ⁇ eza ⁇ - ⁇ mil- s - ⁇ e ⁇ - ⁇ id ⁇ v vys ⁇ aya e ⁇ e ⁇ e ⁇ sele ⁇ ivn ⁇ s ⁇ ⁇ e ⁇ men ⁇ a is ⁇ lzuem ⁇ - g ⁇ on s ⁇ adii ⁇ b ⁇ az ⁇ vaniya ⁇ e ⁇ idn ⁇ y communication ga ⁇ an ⁇ i ⁇ ue ⁇ 5 ⁇ b ⁇ az ⁇ vanie ⁇ l ⁇ ichessh chis ⁇ g ⁇ ⁇ du ⁇ a, ⁇ ichem is ⁇ lyu- chae ⁇ sya ⁇ sn ⁇ vnaya l ⁇ b ⁇ chnaya ⁇ ea ⁇ odya, ⁇ g ⁇ ashchivayuschaya ⁇ i- Menenius ⁇ mil-amin ⁇ isl ⁇ in ⁇ el ⁇ idn ⁇ m synthesis - ⁇ ⁇ ⁇ rect ⁇ ⁇
  • the quantity of the substance used in the reaction may vary in wide terms ⁇ “ ⁇ 0 to 10 * 10 mm per I mmole of the connected. ⁇ a ⁇ i- me ⁇ , ⁇ i sin ⁇ eze pi-sh ⁇ ashlida ⁇ mil-alanyl-alashl- ⁇ eshlalashna, umensheshe ⁇ liches ⁇ va ⁇ e ⁇ men ⁇ a d ⁇
  • the reaction is in the water or gadget environment.
  • As a distributor usually use dimethylamide.
  • the content of it in a converted mixture is up to $ 50 and the complete separation of the source of amine and a large, commercially available mixture.
  • the active mixture contains 0.63 mmol of phenylmethylene and categorized-nitroanilide of leucine in 0.6 ml of dimethylphosphamide and 2 ml of 0, which is 2 mg or more than 2 mg / ml. -9, 2.5 mg of 20 (63 mmol) of thermolysin; the mixture is kept for 2 hours at 20 ⁇ and spend the night in the refrigerator, empty the filter and wash the pump in type I. - 16 -
  • Acidic composition Ra 1.99; Lb 1.01. Examples 11-14 cm and table 2.
  • the inactive mixture contains I mmol of phenylalanilalashne and ⁇ -nitrous phenylanilide in 0.4 ml of dimethylphosphamide and 0.6 ml of Caustic acid 6.9 / solution of 25 mg of sodium chloride.
  • the non-reactive mixture contains 0.5 ml of 1 * 10 ⁇ CaS ⁇ ⁇ . ⁇ 6.9.
  • the organic mixture contains 0.5 mmol of phenylalashl alashna and phenylalanine d-nitrile, 0.2 ml of methyl dimethylamide and 0.3 ml of water ( ⁇ , 6.7), which eliminates 20 bushes. 37.5 mg / ml, 10 that is 20 nm of the solids content, lasts 24 hours at the indicated temperature, then processes the analogous example I.
  • ku ⁇ name is compact per hour ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ... in%
  • the active mixture contains the indicated quantities of amine and carboxylic acid, 0.2 ml of dimethylphamide, 0.3 ml of water with a pH of 6.7 and 20 milliliters of a mixture of 10 mm, and are processing similar example I.
  • the mixture was 0 ⁇ 88.g (I mm ⁇ l) ⁇ mil-alanyl-alanine and 0.251 g (I mm ⁇ l) n-ni ⁇ anilida l 'eyschna ⁇ as ⁇ v ⁇ yayu ⁇ 15 I dime ⁇ il ⁇ mamida ml, 5 ml ⁇ ibavlyayu ⁇ ⁇ as ⁇ v ⁇ a 5 * 10 2 ⁇ SaS ⁇ ⁇ 6,8, ⁇ and ⁇ stirring. add 5 mg (133 nmol) of thermolysin, stand for 6 hours at 22 ° ⁇ , then spend the night in a cold place. Filter the precipitated plant, wash the filter in the same way as Example I, and dry it in 20 vacuum drying. ⁇ regulate 0.305 g (72.5)
  • Acidic composition Ley 1.0; ⁇ ier 1.0.
  • Example 29 Synthesis of methyl ether-methyl-alcohol-phenylalanine. 15 ⁇ 2, 1 g (10 mmol) of methylated phenylalachine is added to 0.66 g (4, 1 mmol) of phenylmethyl acid in 2.0 ml of water. After reconstitution of the original connected mixture, the resulting mixture is 6.6–6.8 plus 6 N of the process mixture. Then, the 20 sample is dispensed with 20 mg (530 nm) of thermolysine and mixed on a magnetic stirrer for 24 hours at 25 ° ⁇ . The extract is dissolved in 25 ml of I ⁇ acetic acid and is treated with 30 ml
  • Shchzhmeru 30 The synthesis of methyl ether-methyl-alcohol-feshlalashna. The synthesis of analogous example 29, proceeding from 35 2 mm of hydrochloric acid methyl phenylalachne and I mmol of acid-acid.
  • the plant grows and grows. - 20 - in 4.5 ml of acetic acid, dilute the solution with a solution of 40 ml of ethyl acetate, remove the precipitated salt, wash the solution with water and let the solution dry. K ⁇ k ⁇ d 5 0, 140 mg ($ 43). Pshmera 31.
  • a mixture of 0.376 g (2 mmol) of I-phyrmethyl-alanyl-alanine Yu and 0.430 g (2 mmol) of hydrochloride solution is suitable: alanine is dissolved in 0.5 ml of a non-corrosive mixture, but 6.7, 3 mg of metal acetate is introduced; Acetic acid Acetate is stirred for 24 hours at 25 ° £ .0 Garden is dissolved in ethyl 15 acetate and is replaced with water; The organic layer is dried over the sulphate of the country, then evaporated in a vacuum. Food product 0.25 g (32); ⁇ £ -_ 0.71.
  • Acidic composition Ra 1.98; Ley 1.02. Example 33.
  • Example 35 The synthesis of ⁇ -strained schlide ⁇ -promyl-phenylalashne and 29 mg (100 ⁇ mol) of ⁇ -nitroanilide phenylalachine was diluted in 0.2 ml of dimethylsulfonate and diluted with a small amount of 8 ml. Introduces 0.5 mg of the metalase kinase ⁇ as ⁇ iz al-u ⁇ o ⁇ i ⁇ as ⁇ and excrete 24 hours at 25 ° 0. The product is processed in a similar manner to Example 33. The yield of the product is 35.5 mg (76).
  • Acidic composition ⁇ 0.98; 1,0 ⁇ lingually 0.99; 1,0 ⁇ lingually 0.99; 1,0 ⁇ lingually 0.03.
  • Example 39 There is a similar procedure to Example 36 except that the active mixture is left at 2 ° C for 72 hours. ⁇ Play 0, 230 g ($ 18).
  • Example 39 •
  • Example 36 There is a similar procedure to Example 36, except that the active mixture leaves at 60 ° C for 24 hours. Food product 0, 14 g ($ 11).
  • 20 types are an attribute of an attribute - for mililaspa- tam, that is, methyl ether-free-phenylalanal.
  • the equipment is about 200 times good for sweeteners and can be used

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

Des N-formyl-L-peptides de formule générale (I) sont obtenus par condensation d'un composé carboxyle N-formyl-protégé de formule générale (II) avec un acide aminé présentant une protection sur le groupe carboxyle et une formule générale (III) en présence de la métalloprotéinase produite par un micro-organisme de genre Bacillus. La condensation est effectuée dans un milieu aqueux ou aqueux-organique, à un pH compris entre 6,0 et 9,0 et à une température comprise entre 0 et 60oC. For -A-B-X (I), For -A-OH (II), H-B-X (III), où For - formyl; A - Asp, Met, Gly, Ala, Gly-Gly, Gly-Ala, Ala-Gly, Ala-Ala, Tyr, Phe; B - Phe, Leu, Ile, Val; X - -OCH3 -OC2H5; -OCH2C6H5; -NH2; -NH-C6H5; -p-NH-C6H4-NO2 -NH-NH2; -NH-NH-C6H5.
PCT/SU1986/000010 1985-02-15 1986-02-13 Procede de preparation de n-formyl-l-peptides WO1986004924A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
NL8620072A NL8620072A (nl) 1985-02-15 1986-02-13 Werkwijze voor de bereiding van n-formyl-l-peptiden.
DE19863690076 DE3690076T1 (fr) 1985-02-15 1986-02-13

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SU3855631/23 1985-02-15
SU3855631 1985-02-15
SU4014768/28 1986-02-10
SU4014768 1986-02-10

Publications (1)

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WO1986004924A1 true WO1986004924A1 (fr) 1986-08-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0272564A2 (fr) * 1986-12-22 1988-06-29 Hampshire Chemical Corporation Réactions d'accouplement par voie enzymatique
WO1998016546A1 (fr) * 1996-10-15 1998-04-23 Holland Sweetener Company V.O.F. METHODE ENZYMATIQUE POUR PRODUIRE DU N-FORMYL-α-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4116768A (en) * 1975-04-29 1978-09-26 (Zaidanhojin) Sagami Chemical Research Center Process for producing a peptide
US4119493A (en) * 1975-10-23 1978-10-10 (Zaidanhojin) Sagami Chemical Research Center Process for producing a peptide
US4284721A (en) * 1979-04-03 1981-08-18 Sagami Chemical Research Center Method for manufacturing dipeptides
DE3203292A1 (de) * 1981-02-02 1982-09-16 G.D. Searle & Co., 60076 Skokie, Ill. Verfahren zur herstellung von aminogeschuetzten l-aspartyl-l-phenylalanin-alkylestern
EP0149594A2 (fr) * 1984-01-16 1985-07-24 Monsanto Company Accouplement enzymatique de N-formyl amino-acides et/ou de restes peptidiques
CH651067A5 (de) * 1980-09-02 1985-08-30 Searle & Co Verfahren zum verestern von alpha-l-aspartyl-l-phenylalanin.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4116768A (en) * 1975-04-29 1978-09-26 (Zaidanhojin) Sagami Chemical Research Center Process for producing a peptide
US4119493A (en) * 1975-10-23 1978-10-10 (Zaidanhojin) Sagami Chemical Research Center Process for producing a peptide
US4284721A (en) * 1979-04-03 1981-08-18 Sagami Chemical Research Center Method for manufacturing dipeptides
CH651067A5 (de) * 1980-09-02 1985-08-30 Searle & Co Verfahren zum verestern von alpha-l-aspartyl-l-phenylalanin.
DE3203292A1 (de) * 1981-02-02 1982-09-16 G.D. Searle & Co., 60076 Skokie, Ill. Verfahren zur herstellung von aminogeschuetzten l-aspartyl-l-phenylalanin-alkylestern
EP0149594A2 (fr) * 1984-01-16 1985-07-24 Monsanto Company Accouplement enzymatique de N-formyl amino-acides et/ou de restes peptidiques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0272564A2 (fr) * 1986-12-22 1988-06-29 Hampshire Chemical Corporation Réactions d'accouplement par voie enzymatique
WO1998016546A1 (fr) * 1996-10-15 1998-04-23 Holland Sweetener Company V.O.F. METHODE ENZYMATIQUE POUR PRODUIRE DU N-FORMYL-α-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER

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Publication number Publication date
DE3690076T1 (fr) 1987-03-12
NL8620072A (nl) 1986-12-01

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