JPS62246548A - Urethanes of novel substituted carbonic acid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel substituted carbonic acid urethanes, processes for their production, and uses thereof.

A large number of protecting groups are known for use in the reaction of primary and secondary amines, especially amino acids, essential amines and amino sugars. These are recent publications, e.g. W, Wu
1-1oube edited by nsch and E0Mtll13r
n-Weyl ”Methoden der Qr
ganischenChemie', 15/1
．． (G eora T hi of Stat Garde
eme Publishers, 1914) and H,D.

J akubke and H, Jeschkeit″A 1i
nosauren-peptrae-Prote
ine”, 2nd edition (A kadea+i, Berlin)
e Publishing, 1973).

The usual amino fLlt group of urethane type (3oc.

Z) fulfills many of the requirements for a clearly advanced synthetic principle, but often requires removal under very mild acidic conditions and the use of protective groups. desired in the case of This is especially true for trifunctional amino acids, for example in synthetic methods with repeated coupling and deprotection steps (solid phase or liquid phase methods), since acid-active protecting groups allow for the most lenient treatment. It is. Also, for example, tryptophan contained in peptides exhibits a violet color change and a shift in UV absorption during deacylation reactions in more acidic media, often experiencing decomposition of the indole system.

This type of secondary reaction can be minimized by using mild deprotecting reagents.

Akira II of this invention! For convenience, we will use the following abbreviations.

Boc-t-butoxycarbonyl 8zl-benzyl Z-benzyloxycarbonyl DCC-dicyclohexylcarbodiimide DCHA-dicyclohexylamine DMF~dimethylformamide HOBt~ 1-hydroxybenzotriazole Ho
Su -N-hydroxysuccinimide Ph-phenylTriton B-trimethylbenzylammonium hydroxide A recently developed protecting group, Bpoc, [)dz.

Ppoc, AZOC (These abbreviations are derived from the premise HOUben -way + “Methoden
der O rganlshenC hemie”
f) H, D, Jakubke and H,
J eschkeit“AllinOSaUre
n-Peptide, protein, which follows the general rules of peptide chemistry) meet these requirements, but only the former two are in more widespread use. In these two cases, storage of the protected amino acids is not without problems such as autocatalytic degradation and/or photodegradation. Also, the introduction of the 3 poc group The commonly used Bpoc phenyl carbonate tends to decompose even at low temperatures, and the yield for the production of Bpoc-Trp-OH is very low.

The inventors of the present invention have developed a novel protective group for compounds having a primary amine group and/or a secondary amino group, particularly amino acids, amino sugars, and amines essential to living organisms, by the following compounds. ( blocking l
)rOUp), which has the following advantages over the prior art.

(1) Carbonic acid phenyl ester (Adpoc-OPh)
The introduction of protecting groups can be achieved through the use of stable, crystalline and reactive compounds such as esters and fluoroformates (Adpoc-F).

The +21 AdllOC group can be removed under very mild conditions.

Protecting groups of the t-butyl type remain unaffected. Tryptophan contained in the peptide remains stably under elimination conditions.

(3) This protecting group is resistant to alkali as well as hydrogenolysis reactions.

(4) Due to its remarkable lipophilicity, Adpoc residues have high solubilization performance, especially in the case of higher peptides.

(51 A dpoc- T rp- OH can be prepared in high yields. No transformation into derivatives occurred when this compound was stored at room temperature under normal light conditions for 3 months.

(It is possible to preserve the 61Adpoc residue and utilize it in methods commonly used in peptide chemistry (DCC/Hoar active ester coupling, hydrolysis, hydrogenation).

The protecting group, 2-adamantane-(13-propyl-2-oxycarbonyl group (hereinafter referred to as A dElGo), is protected by an acidic decomposition medium (acidol) which moderates its removal from the amine group.
ytic medium), i.e. preferably 3
This proves to be particularly advantageous in view of the fact that it can be achieved in 4-5 minutes at 0 DEG C. or in 2-3 minutes at room temperature with % trifluoroacetic acid-methylene chloride solution. In this method, wide deprotection selectivity is obtained for protecting groups of the [-butyl type.

Of course, the N-benzyloxycarbonyl, 0-benzyl ether and 0-benzyl ester groups also remain unchanged.

Under the cleavage conditions described above, it is possible to cleave this new .N-urethane protecting group orders of magnitude more rapidly than the N-t-butoxycarbonyl group. However, N-[2-piphenyl-4]]-oxycarbonyl is preserved! In contrast to (Bpoc), Adpoc amino M is approximately 2-3 times more stable than the former under acidic degradation conditions.

These compounds are thus represented by the general formula (I).

R'' ■ Ad-C-0-Go-X (I) In the formula, Ad is an alkyl group of C1 to B, an alkoxy group of C1 to B, a nido group, or a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) a 1-7 damantyl residue which can be substituted by (atom) or an unsubstituted 1-adamantyl residue, preferably the latter.

R1 and R2 are alkyl groups having Ci to 8, preferably methyl groups; , optionally substituted with an alkyl group), an alkoxy group, N-oxysuccinimide, or a residue of the formula (Ad has the same meaning as above).

The novel compound of the general formula (I) can be obtained by reacting the corresponding lower alkyl 1-adamantanecarboxylic acid ester (preferably ethyl ester) with the corresponding alkylmagnesium halide (preferably iodite) to obtain the novel compound of the general formula (■ ): Ad -C-OH(II) ' R (in the formula, each symbol is the same as above) A compound of the formula % (in the formula, one of ×3 and ×4 is a halogen atom, The other is a halogen atom, an azide group, a substituted or unsubstituted I-noxy group, an alkoxy group, an N-oxysuccinimide group, or a group represented by the formula (Ad has the same meaning as above). be able to.

The above-mentioned 1-adamantanecarboxylic acid esters can be prepared by a method known per se, for example, by treating the corresponding acid with an acid halogenating agent.
For example, it can be produced by treatment with a suitable phosphorus halide and reaction with an alcohol.

Examples of 1-adamantanecarboxylic acids include:

Reference is made to J. Raber et al. "TETRAHEDRON" Vol. 27, p. 3 (1971).

Here, lower alkyl means an alkyl group having C1 to B.

The reaction formula in the above method is exemplified as follows (1'V
) This invention provides an alkyl group having the general formula % formula %) (where Ad is an alkyl group having 1 to 8 carbon atoms,
1-adamantyl residues substituted or unsubstituted with alkoxy groups, nitro groups or halogen atoms having 1 to 8111 carbon atoms, R'' and R2 are 1 to 8 fl
residues of primary or secondary amino compounds of Al having l carbon atoms, in particular residues of l, l or l, amino acids, essential amines or amino sugars) This is what we provide.

Amino acids are to be understood as meaning organic compounds having a carboxyl group and additionally a -NHz or NH group, in particular glycine, alanine, Oisine, isoleucine, serine, threonine, cysteine, cystine. , methionine, proline, human O-oxyproline,
Lysine, hydroxylysine, arginine, histidine,
These include aspartic acid, asparagine, glutamic acid, glutamine, phenylalanine, tyrosine, tryptophan, etc. Biologically active amici include tyramine, dopamine, noradrenaline, adrenaline, tryptamine, serotonin, melatonin, histamine, cysteamine, buOpanolamine, ethanolamine, cadaverine, butrescin, agmatine, and the like, among others.

Amino sugars refer to monomeric or polymeric hydrocarbon compounds having primary amino 1 (-NH2) or secondary amino M (':, :NH), such as glucosamine (2-amino-2- deoxyglucose) and galactosamine (2-amino-2-deoxygalactose).

The compounds of this invention can be used for peptide synthesis, TRH1LH/
It is very suitable for the synthesis of FSH-R1-1, entoicin, secretin, gastrin, fuisalemin, glucagon, adrenocorticotropin, oxytocin, pappressin and somatostatin. In particular, the following compounds may be mentioned: In the following formula, Adpoc represents a 2-7 damantane-(1)-propyl-2-oxycarbonyl group, and other symbols are abbreviations commonly used in peptide chemistry.

Adpoc-Gly-OH, Adpoc-L-Ala-
DCHA, Adpoc-L-Gln-OH, Adpo
c-L-Trp-OH, Adpoc-L-Trp-Q
3u.

A dpOC-L -T rl)-L -L yS(Z
) -08.

Adpoc-L-Thr(Bzl)-OH, Adp
OC-L -Thr(8zl) -L-Phe OC
H3,Adl)QC-L-Thr (Bzl) -L
-Phe-OH, Adpoc-L -Thr(Bzl)
-L -phe -L-Thr(Bzl) -L-8
er(Bzl)-0CHs, AdEIOC-L-
Trf)-L-LvS(Z>-L-Thr(BZI)
-L-Phe -L-Thr(8zl) -L-8e
r(OBzl)-0CHs, and Adpoc-L
-Trp-L-Lys(Z) -L-Thr(Bzl)
-L-Phe-L-Thr(Bzl) -L-3er
(08zl) -L-Cys(Trt)-OH0 Preferred compounds according to formula (I) include those of the following formula.

(In the formula, X' means a fluorine atom, chlorine atom, bromine atom, azide group or phenoxy group.) This compound has 1-
Adamantane carboxylic acid and phosphorus pentachloride/ethanol are reacted, and the product is reacted with methylmagnesium iodite (Grinard reagent from methyl iodite and magnesium) to obtain 2-7 damantane-(11-propanol-(21) and cotLk ”Co (X') 2 (
In the formula, X' is the same as defined above).

For the preparation of compounds of general formula (I), apart from the methods described above, compounds of formula (I) can be prepared by treating the corresponding 1-adamantanecarboxylic acid with an acid halogenating agent (e.g. phosphorus halide or thionyl chloride). treatment and reaction with alcohol to produce 1-adamantane alkyl ester (
(preferably ethyl ester) and reacting it with a corresponding alkylmagnesium halide (preferably iodite) to obtain the formula (IF) R' Ad-C-OH (II) (where Ad, R'' and R2 are the same as above) ), and may be produced by reacting the compound with the formula X s -CO-X 4 (X s and X4 are the same as above).

Preferred compounds of formula (I) include:

(I[I) (IV) As mentioned above, these new compounds include, in addition to those exemplified above,
It can be used to synthesize various peptides including calcitonin, angiotensin, pradikinin, collidin, phyllokinin, gramicidin, bacitracin, peptide antibiotics, peptide toxins, peptide insecticides, somatostatin, and partially similar products thereof. Such a conductor can be made by reacting the corresponding amino acid with a compound of formula (1) and Triton-8. In addition, tryptophan-containing peptides such as those mentioned above, cortecothrobins, furanotrabins, LH/FSH-
It can be used to produce various peptides such as RH, glucagon, calcitonins, gastrins, somatostatin and partially homologous thereof.

The invention thus described, it will be obvious that the same may be varied in many ways. Such modifications should not be considered a departure from the spirit and scope of this invention, and all such modifications are intended to be included within the scope of the claims of this invention.

(The following margins continue on the next page.) The present invention will now be described by way of examples for the purpose of illustrating, but not limiting, O. Unless otherwise specified, percentages are by weight. The melting point was measured using an apparatus by Tottti f4,
No corrections have been made. The optical rotation was measured using a Zeiss Digital Bolarimeta-OLf. The thin plate is Merck's instant TLC plate, silica gel 60F.
, , , and nincedrine and chlorotridine reagents as indicators, the measurement was carried out at UV254nffl.
The mobile phase used for thin layer chromatography is as follows.

A: Chloroform/methanol/benzene/water (40:
40:40:5) B: butanol/glacial acetic acid/water (3:1) C: methanol/chloroform r2:1) Example 1 Carbonic chloride fluoride (65 % fuming sulfuric acid 6oy and fluorotrichloromethane 25+++e) t M-40
19.4y of 2-adamantane-(1)-propanol-(2), 0.1 mol (Tetra
Hedron 2 and 3 (manufactured by Hedron 2, 1971)) for condensation. During this step, triethylamine hydrochloride precipitated out. After gas evolution ceased, the mixture was left at -20°C overnight and then heated to 200 torr (BHg).
and degassed at 10°C. The residue after filtration was washed additionally with dry ether on the filter. F solution is 22.
9 y's Aapoc-? It contained. This compound is
It can be used directly as an ether solution or concentrated under reduced pressure. After removing the solvent under reduced pressure, the title fluoroformate can be obtained in crystalline form.

Carbinol was detected using the product obtained by this method using a spectroscopy spectrum, but no carbinol was detected.

Melting point = 52°C Engineering R = = (KBr) 1815 on Yield = 22.
9y (95%) Elemental analysis C+4H210□F (240,32) Calculated value (1! 69.9 1(8,81 Experimental value c
70.25 Preparation of H8,99B, Adpoc Amino Acid 10 mmol of the amino acid was heated and dissolved in 4.5 cc of a methanol solution of approximately 40% Triton B (benzyltrimethylammonium hydroxide).

The mixture was evaporated under reduced pressure, the residue was taken up in 5-10 cc of dimethylformamide, the mixture was evaporated again and the process was repeated. The mixture was then dissolved in 1°C of dimethylformamide (cooled to -10°C) and diluted with -10'
Adpoc-IF 2.65y (11 mmol) in C
Mixed with 6 cc of triethylamine salt. The tl compound was stirred at -5°C for 3 hours, at 0°C for 2 hours, and allowed to warm to room temperature. The reaction solution was poured into 20 ca of ice water.

The mixture was diluted with ether-petroleum ether ('l:1).
Extract twice each, acidify the aqueous phase with citric acid, and use a total of 80 cc of ether! Extracted twice.
The ether extracts were combined and washed with water. Ether tears Na
! After brief drying with SO4, it was distilled under reduced pressure.

Residue directly or DC! It crystallized after being converted into HA salt. Table 1 shows the properties of Adpoc amino acids produced by this method.

Example 2゜Dichloromethane 1oon11' and pyridine 12.0mf
2-77゛manthane-(1)-propanol-(
2) 19.41;'(0,17l)t-30 at -5℃
Mixed within minutes with a solution of pheny/I/15.21 nt' chloroformate in 50 rne of dichloromethane. The precipitate that formed during the dropwise addition was redissolved after stirring overnight at 0°C. The dichloromethane mixture was poured into water, diluted with 150 ff of dichloromethane, and the organic phase was separated.
After washing three times with water, the organic phase was dried over sodium sulfate at 30°C.
It was evaporated under reduced pressure to obtain colorless crystals.

Melting point = 72°C Yield = 26.25 g (83.5%) Elemental analysis 0
20 H2603 (814,43) calculation @ C76,
40H8,8 (experimental value C76,55H8,48 B), Preparation of Adpoc amino acids, 10 mmol of amino acids were dissolved in approximately 40% Triton B methanol solution 4.60% under mild heating. Water was removed by azeotropic distillation twice with each 80°C of dimethylformamide.The residue was placed in 30°C of dimethylformamide at 50°C, and Adpo
combined with 8 g (12 mmol) of c-OPha,
The mixture was stirred at 50°C for 3 hours. To work up the reaction mixture, it was mixed with water and diethyl ether-petroleum ether (1:1).
), and the separated aqueous phase was thoroughly extracted with diethyl ether at 0° C. with IN-citric acid and acidic KL (PH 2-8). The ether extract was washed, dried in a conventional manner and evaporated to dryness under reduced pressure. The remaining material was crystallized either directly or by introducing into DCHA@.

The properties of the Adpoc amino acids produced by this process are shown in Table 1.

(Margin below)

Claims (1)

[Claims] 1. Formula (I a): ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I a) (In the formula, Ad is an alkyl group having 1 to 8 carbon atoms,
1-adamantyl residue substituted or unsubstituted with an alkoxy group having 1 to 8 carbon atoms, a nitro group or a halogen atom, R^1 and R^2 are alkyl having 1 to 8 carbon atoms The group, 2. Formula: Adpoc-Gly-OH, Adpoc-L-
Ala-DCHA, Adpoc-L-Gln-OH, A
dpoc-L-Trp-OH, Adpoc-L-Trp
-OSu, Adpoc-L-Trp-L-Lys(Z)
-OH, Adpoc-L-Thr(Bzl)-OH, A
dpoc-L-Thr(Bzl)-L-Phe-OCH
_3, Adpoc-L-Thr(Bzl)-L-Phe
-OH, Adpoc-L-Thr(Bzl)-L-Ph
e-L-Thr(Bzl)-L-Ser(Bzl)-O
CH_3, Adpoc-L-Trp-L-Lys(Z)
-L-Thr(Bzl)-L-Phe-L-Thr(B
zl)-L-Ser(OBzl)-OCH_3, Adp
oc-L-Trp-L-Lys(Z)-L-Thr(B
zl)-L-Phe-L-Thr(Bzl)-L-Se
r(OBzl)-L-Cys(Trt)-OH or A
dpoc-L-Thr(Bzl)-L-Phe-L-T
hr(Bzl)-L-Ser(Bzl)-L-Phe-
Oh. (In the formula, "Adpoc" is a 2-adamantane-(1)-propyl-2-oxycarbonyl group, and other symbols are abbreviations commonly used in peptide chemistry.) Compound.