DD217215A1 - PROCESS FOR PRODUCING UNSYMMETRIC CARBONATE - Google Patents

Abstract

The invention relates to a process for the preparation of unsymmetrical carbonates II, which are suitable for the introduction of urethane protecting groups in amino acids. The carbonates II are obtained by reacting N- (chlorocarbonyloxy) -5-norbornene-2,3-dicarboximide with alcohols. R stands for tert-butyl, adamantyl (1), 2-diphenylpropyl, 9-methylsulfonyl, benzyl or other radicals usual in peptide chemistry. Field of application is the pharmaceutical industry.

Description

, Process for the preparation of unsymmetrical carbonates -

Field of application of the invention

The invention relates to a process for preparing unsymmetrical carbonates which are suitable for introducing urethane protective groups into amino acids and their derivatives. «

The invention is used in the pharmaceutical industry, especially in the synthesis of peptides.

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Characteristic of known technical solutions ', '' A large number of symmetrical carbonates are known, which are used for the introduction of urethane scavenging groups into amino acids. The tert-butyloxycarbonyl (Boc) group represents

; next to the benzyloxycarbonyl (Z) group, the used in peptide synthesis most commonly protecting group is "For existing in the high toxicity and explosion inclination disadvantages of the hitherto most commonly used Boc-Einführungsreagenz tert _o -Butyloxycarbonylazids (Schwyzer, H ·; Sieber, P" u · H · Kappler, • - 'Helv Chim · · Acta, ^ g _x' 2622 (1962)) to avoid a variety of new introduction reagents have been developed, such as tert · - butyl-4,6-dimethylpyrimidyl-2-thiol carbonate (Efagasawa, T .: Kuriowa, Έ · j Uaritaj K · u · Y · Isowa, BuIl ₀ Chem »Soc _e (Jap ·) ^ 16, U. A · C. · Mc Gregor, J · Amer · Chem · Soc «T ^ jl 6180 (1957), tert" -Butyloxycarbonyloxyimino-2-phenylacetonitrile (itch.M;. Hagiwara, D · u T "Kamiya, Bull Chem · · Soc _e (Jap *) 50, 718 (1977); Tetrahedron Lett. 1975. 4393), H (t, »- butyloxycarbonyloxy) phthalimide (Gross, Η · u · L · Biik, Liebigs Ann · Chem» 725, 212 (1969), ir- (tert _e -Butyloxyoarbonyloxy) - succ3ffi ~ imid (Pranket, M. Ladkany, D ₈ ; Gilo n, C * and T · Wolman, Tetrahedron Lett · 1966, 4765, Gross, Η · u. L · Bilk, Liebigs

Ann * Chern. 7JL5j. 212 (1969), Ii ( ^: fcert "- Bu-fcyloxycarbonyl) -1H-1-j2,4-triazole (G * Bram, Tetrahedron Lett. 1j) 72jl 469), Tert.-. Butyl phenyl carbonate (Ragnarsson, U, Karlsson, S, M, & B E Sandberg, Act a Cheiiu Scand., ₄ , 2550 (1972), Org Synth 52, 25 (1973), tert-butyl -S ~ chinolylcarbonat (Rzesztotarska, Β "and" Se Wiejak ^ Iiebigs Ann Chem 716 "216 (1968);.. Rzesztotarska, B., How ^ jak, S · u _e K" Pawelozak, Org "Prep" Proo · Int _e 5χ 71 (1973), tert-butyl _{e-2,4-trichlorophenylcarbonate} (Broadbent, W®; Mörley, I "S" u · B ₉ e · Stone; J »Ohem" Soce (G), 2632 1967ft) ^ ma ~ Di tert butyl _e ~ dioarbonat (j Tarbell De Se; TamamotOj Ye u _e B _'s M Pope; Proo * BTAT "AOAD" Sol "USA 6 ^ j 730 (1972) 5 0RG _e Synth .§2χ.. 45 (1977); Moroder, Le; Hallet, A *; Wish ,: Keller, Wersin, Hoppe-Seyler Z, Physiol. Chem. 357, 1651 (1976) Frequently applied protecting groups require further important protective groups for special synthesis problems © Here, in recent years, protective groups have been found to be particularly effective in removing milder conditions under milder conditions * These are the 9-fluorenylmethyloxycarbonyl groups (Carpino, L, J * A «cs * _< §2 _A 5748 (1970) Methylsulfonylethoxycarbonyl group (G * Tesser et al * jIntern" J "peptides Protβ Res" I _x (1975) 295) or 1-adamantyloxycarbonyl protective group (E «Wünsch, L. Wackerle and * Moroder, Hoppe-Seylers Z. Physiol. Chem * \ 257jl ¹ ^ 47 (1976). All these last Protecting groups are usually introduced via substituted phenols or N ^ Hydroxysucoinimidester (M Bödanszky, Y * S. Klausner and "M * A * Ondetti in ι peptides synthesis, 2 nd ed * _e, J," Wiley If.Y. 1976 p 32; H, Groi3 u.'I.-BiIk, Ann. Chem. 725, 212 (1969). $ A * Paquet, Can. J., ^Ile, §, ^{2, 2,} 775j (1979) and Can. J _e Chem _e 6O ₁ (8) 976 (1982)

The introduction reagents mentioned are characterized z-rT. from that remarkably high yields of urethane-ge protected amino acids can be achieved. Their disadvantage, however, is mainly that -that in the majority both the synthesis of the starting materials as well as the production

of the Admixture Agent is associated with high preparative or technical effort and its storage stability is limited. "Often the rate of aminolysis is also limited";

Object of the invention

It is the object of the invention to provide novel, advantageous unsymmetrical carbonates which are suitable for introducing urethane-sohut groups into amino acids and whose production is characterized by a low technical complexity and by good accessibility of the starting products.

DESCRIPTION OF THE INVENTION It is an object of the present invention to develop a preparation process for novel unsymmetrical carbonates, the general formula II, starting from durable and easily accessible compounds. The problem has been solved by using N- (chlorocarbonyloxy) 5-norbornene-2,3-dicarboximide I (Cl-CO-ONB) with corresponding alcohols to the carbonates II, wherein R is tert -butyl, adamantyl- (i) »2-biphenylpropyl, 9-methylfluorenyl, methylsulfonylethyl, Benzyl or other best in peptidohemy stands best (Pormelschema) ··. D "'^; · ·' ^ C

+ HOR -y

The title compounds II are prepared by a process not described in the literature, which excludes the disadvantages of the previous methods (pH-stat, Hait

The invention will be explained in more detail by means of exemplary embodiments.

Au sf u c tio n sb EXAMPLES Example Is

ΰ, ι Get N-uhiorcarbonyloxy-5-norbornene «2,3 <-dicarboximide CuI-CO-ONB) I wire! dissolved in 150 ml of an inert solvent (ζ Tol _β toluene, benzene, ΤΗ £, halogenated hydrocarbons) and at 10 ⁰ C- 15 ⁰ C, a solution of 0.1 mol of an alcohol (Table 1) and 0.1 mol of a tert. Amine in 40 ml of an inert solvent (as indicated above) added. Then it is stirred for one hour at room temperature and for 3 hours at a temperature of 35 ⁰ C. It is allowed to stand overnight. The precipitate consisting of amine hydrochloride is separated off and the filtrate is concentrated. In order to remove residues of the amine, it is also possible to wash the solution with ice-cold 5% strength NaHCO 3 before concentrating (Table 1). '

Example 2:! ,

To a solution of phosgene (9.9 g, 0.1 mol) is added dropwise a solution consisting of 17.9 g of HÜNB, 12 g of N, N-dimethylaniline in THF / benzene (about 200 ml) at 0 ° to 5 ⁰ C added. The mixture is then stirred for an hour at this temperature and allowed to stand overnight. Now without isolation; of the Cl-CO-ONB as indicated in Example 3.

At game 3:. _i '. , ^j · Vi / ie.Beispiel 1, with pyridine as tert "amine.

Formelsohema

CD

O IO IOσ:

CQ

O I

O * χ I. ο ο ο ο ro ω ro X O

I o

Table 1

Molecular weight Sumraenformel

Methylfluorenyl 129 CBL-- S - CH CH _{0 0} 145

401.1

313.26

Eleraentaranalyse

C H Ii

", C HI

71.81 4.77 3.49 71.7 4.5 3.57

49.84 4.83 4.47 49.87 4.73 4.31

MS (M ⁺ )

adamantyl 220 357.1 C ₂₀ H ₂₃ KO ₅ 6,49 6,52 3.92 3.87 357.1 ^; tert "butyl 124 279.3 C ₁₄ H ₁₇ KO ₅ 6.07 5.17 279.3 , 67.21 67.43 60,50

401.4

313

2-biphenyl-propyl 121

417.4 71.99 5.55 3.36 71.80 5.42 3.21

417.4

Claims (3)

Invention Claim> i · Process for the preparation of unsymmetrical carbonates II, characterized in that U- (chlorocarbonyloxy) -5-norbornene-2,3-dicarboximide I are reacted with alcohols in which E is tert-butyl, adamantyl- (1), 2 ~ Diphenylpropyl, 9-methyl-fluorenyl, methylsulfonyl, benzyl or other radicals customary in peptide chemistry are · ROH - » 2 · Process according to item 1, characterized in that N- (chlorocarbonyloxy) -5-norbornene-2,3,4-diocarboximide I used by reaction of K-hydroxy-5-norbornene-2 _? 3 * -dicarboximide is obtained with phosgene * 3 · Process according to item 1 and 2 _9, characterized in that the unsymmetrical carbonates II without isolation of the Ii - (chlorocarbonyloxy) -5-norbornene-2,3-dicarboximide I after the reaction of 'F-hydroxy-5-norbornene 2,3-dicarboximide can be obtained with phosgene in a dripping process