DD218886A1 - PROCESS FOR THE PREPARATION OF N-URETHANE PROTECTED AMINO ACIDS - Google Patents

Abstract

The invention relates to a novel process for preparing urethane-protected amino acids or peptides by reacting asymmetric carbonates I with amino acids or peptides. The carbonates I in which R1 represents tert-butyl, alamantyl- (1), 2-biphenylpropyl, 9-methylfluorenyl, methylsulfonylethyl, benzyl or other radicals usual in peptide chemistry become N- (chlorocarbonyloxy) -5-norbornene -2,3-dicarboximide - obtained by reaction of N-hydroxy-5-norbornene-2,3-dicarboximide with phosgene and alcohols. Formula I

Description

Process for the preparation of urethane-protected amino acids

Field of application of the invention

The invention relates to a novel process for introducing the urethane group into amino acids or peptides using unsymmetrical carbonates.

Field of application of the invention is the pharmaceutical industry especially the synthesis of peptides «

Characteristics of known technical solutions A large number of symmetrical carbonates are known which are used for the introduction of urethane protecting groups into amino acids. The tert-butyloxycarbonyl (Boc) group is in addition to the benzyloxycarbonyl (Z) group. · The disadvantages of the hitherto most frequently used Boc introduction reagent tert-butyloxycarbonyl azide (Schwyzer, R · Sieber, P * u _e H Kappler, HeIv.), which are the most frequently used in the synthesis of peptides. Chim "Acta, 42" 2622 (1962)), a variety of new incorporation reagents have been developed, such as tert-butyl-o-dimethylpyrimidyl-2-thiol carbonate (Nagasawa, T, Kuriowa, K. J Ifarita, K _e ", Y« Isowa, Bull · Chem. Soc « ^: (Jap ·) 46. U ₉ A _# C _e Mc Gregor, J, Amer _e Chem« Soc «7 ^ j 6180 (1957), tert _e ~ Butyloxycarbonyloximino-2-phenylacetonitrile (Iteh M ₉ , Hagiwara, D »and T · Kamiya, Bull« Chenu Soo »(Jap _# ) 718 (1977), Tetrahedron Lett., 197, 4393), IT (tert. butyloxycarbonyloxy) phthalimide (Gross, H. u. ^J .. I Bilk, Liebigs Ann "Chem" 725, 212 (1969), K (tert "-Butyloxycarbonyloxy) succinimide (Pranket, M. ladkany, Dj Gilon,

C® u "Υ" Wolman, Tetrahedron Lett '1966', 4765 'Gross, Η® u »L. Bilk, Liebigs Ann Chem ·" 725 "212 (1969), W (t ~ _e butyloxycarbonyl) -1-butyl . -phenylcarbonat (Ragnarsson, U "K ar Is son, S * Μ« u «Β" e ₀ Sandberg, Acta Chem "Scand" 26 _Ai 2550 (1972); Org "Synth 32x 25 (1973), tert" - Butyl-S-ehinolylcarbonate (Rzesztotarska, B «u« S «Wiejak, Xiebigs Ann« Chem « 716« 216 (1968); Rzesztotarska, B «j Wiejak, S» u «Pawelozak, Org« Prep. Proc »Int · 5 ± 71 (1973), tert-butyl _e ~ 2,4,5-trichlorphenylearbonat (Broadbent, We j Morley, I "p u * Β" e "Stone;. J. Chem. Soc (C), 1967t 2632)% and di ~ shouldered-butyl dicarbonate (Tarbell, D · S .; Yamamoto, T · u B _@ M, Pope; Proc. Nat · "Acad" Sci USA 6 £ ± 730 (1972.); Org. Synthel, L .; Hallet, Α; Wünsch, E .; Keller, 0 * and G Wünsch, E .; Kelleri, 0, and Wersin, Hoppe-Seyler »Z. Physiol · Chem. 357« 1651 (1976). These commonly used protective groups are used for special purposes Synthesis Problems Further Important Protecting Groups Needed In recent years, protection groups have been found to be most effective in cleavage under milder conditions. "These include, for example, the 9-pluorenylmethyloxycarb © nyl group (Carpino I). J. Am. Chem. Soc. 92 »5748 (1970), the methylsulfonylethoxycarbonyl group (G.Tesser et al., Intern. J. Peptide Prot. Res. 2i (1975) 295) or I-adamantylocy- carbonyl protective group (E. Wünsch, L. Wackerle, et al L _e Moroder, Hoppe-Seylers Z ₉ Physiol. Chem., 357, 1647 (1976)) "All these last so-protecting groups are usually introduced via substituted phenols or hydroxy-succinimides (M ₉ Bodanszky, Y. S «Klausner and MA Ondetti in: Peptide synthesis, 2nd ed« ¹ , 3 * · Wiley Ν «Υ« 1976 ρ «32; Η« Big U * L * Bilk, Ann. Chem «72 ^ ₄ 212 (1969) A. Paquet, Can "J" Chem "52a 2775, (1979) and Can. J. Chem. 6O ₄ (8) 976 (1982) _β

The above-mentioned introduction reagents are characterized by the fact that remarkably high yields of urethane-protected amino acids are achieved. Their main disadvantage, however, is that in the majority both the syn-

synthesis of the starting materials as well as the preparation of the introduction reagent are associated with high preparative or technical effort and their storage stability is limited. "Often, the aminolysis rate is also limited."

Object of the invention

It is the object of the invention to introduce a novel advantageous process for the preparation of urethane-protected amino acids in the peptide synthesis · A reagent is to be found whose production is characterized by a low technical complexity and good accessibility of the starting materials and has a high reactivity and hydrolytic stability "

Explanation of the essence of the invention

The object of the invention is to develop a preparation process for urethane-protected amino acids starting from long-lasting and easily accessible compounds. The object has been achieved by using unsymmetrical carbonates I obtained by reaction of N-chlorocarbonyl-oxy) -5- norbornene-2,3-dicarboximide (Cl-CO-OUB) II are obtained with corresponding alcohols, with amino acids or '' Peptlden containing an unprotected Arainogruppe, ums- 'setsrt.' The Cl-CO-OlTB II in turn is prepared from N-hydroxy-5-norbornene-2,3-dicarboximide HONB III or ' his ITatriumsalz IV and phosgene won. R ¹ represents tert-butyl, adamantyl-O), 2-biphenylpropyl, 9-methylfluorenyl, methylsulfonylethyl, benzyl or other radicals customary in peptide chemistry (formula scheme), R _{2 represents} amino acid or "peptide radicals"

The title compounds are prepared by a process not described in the literature, which excludes the disadvantages of previous methods (pH-stat, stability of the starting compounds, stability, accessibility). The invention will be explained in more detail by means of exemplary embodiments

Introduction of protection groups

The respective amino acid is dissolved in a mixture of water / acetone, water / dioxane or water / t-butanol (evt ^"suspended) and with the two to four times the molar amount of triethylamine added. Subsequently, the reagent is added in an excess of 10% · The mixture is stirred at room temperature for several hours (depending on the amino acid, wherein introduction of the Bpoc Schutζgruppe the reaction temperature is 45 ⁰ C). The organic 18sungsmittelanteil is removed in vacuo and the remaining residue with 1Obiger KHSO. acidified.

Partition between methylene chloride and KHSO.-solution and separate the organic phase. The organic phase is thoroughly removed with water to remove the remaining HONB

(',

washed and over MgSO. dried. It is concentrated and triturated with η-hexane *

I ₉ Βοο-ΟϊίΒ Mp ( ⁰ C) Yield (#) derivative 82 87 Boc-Ala-OH 85-87 85 Boc-Gly-OH 79-83 91 Boc-Leu-OH 132-33 88 Boc-Pro-OH 136-38 86 Boc "Trp-OH 79-81 84 Boc-.beta.-Ala-OH 82-84 91 Boc-Phe-QH

2 «MO C-OKB

derivative

* ( ⁰ C)

yield

MQC-Ala-OH MOC-Gly-QH MOC-Leu-OH Ä> C-Plie-QH MOC-YaI-OH MOC-Ser-OH

144

172-74 153-55 180-82 142-4 ^ · 86-88

95 87 91 95 85 87

('

3 _β Adoc OÜB. I ¹ P * ( ⁰ C) Yield (#) AS 60-63 82 Phe 140-41 84 Ala 141-42 87 Gly 4. BpOC-OIiB I ¹ P. ( ⁰ C) Yield (#) AS 122-124 81 Per 85-87 85 Phe

fl'0-.C-OR

0 R ² -NH-COR ¹

2e process according to item 1, characterized in that unsymmetrical carbonates I are used which are obtained by reacting alcohols with L- (chlorocarbonyloxy) -5- ^> norbornene-2,3-dicarboximide, which in turn is obtained by reaction of U-hydroxy- 5-norbornene-2- _i- 3-dicarboximide or "its sodium salt with phosgene is obtained"

O I

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= / jfcO Ο == (> =

CNJ

Z ι

O = O ι

O ι

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Formeleohema

QQ

CJ V)

χ "ο

CM

O ro

XO

CD O

O =

GQ

2 ο ο · O I CO ο CO ο X ω O

13

Claims (1)

te. grfindungsanspruch
1. Process for the preparation of urethane-protected Aminosäurenj characterized in that unsymmetrical carbonates I ₉ in which R is tert-butyl, adamantyl (i), 2-Biphenylpropylj 9-methylfluorenyl, methylsulfonylethyl, Benz $ rl or other usual in peptide chemistry residues and R Amino acid or peptide residues are reacted with amino acids or peptides.