JPS6245591A - Bicyclic dipeptide - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R is t-butoxycarbonyl or fluoren-9-ylmethoxycarbonyl). EXAMPLE:2-Oxo-3-t-butoxycarbonylamino-7-thia-1-azabicyclo [ 4, 3, 0 ] nonane-9-car boxylic acid. USE:A reagent for analyzing active type conformation of physiologically active peptide. PREPARATION:For example, 2-oxo-3-amino-7-thia-1-azabicyclo[4,3,0]nonane-9- carboxylic acid is reacted with di-6-butyldicarbonate or 9- fluorenylmethylchloroformate, to give a compound shown by the formula I.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to bicyclic dipeptides.

(Structure of the Invention) The present inventors focused on the usefulness of bicyclic dipeptides as a test bridge for elucidating the active conformation of natural physiologically active peptides, and as a result of examining various possibilities, discovered a novel The present invention was achieved by discovering a compound suitable for fi in the synthesis of a type of conformationally restricted analogue.

To explain the present invention in detail, the bicyclic dipeptide of the present invention includes (a) [2-oxo-3-L-butoxycarbonyl in which R in formula 13 is a t-phytoxycarbonyl group;
thenylamino-7-thia-1-azahishik [ko[4,3
,01nonane-9-)l sulfonic acid (hereinafter referred to as Boc-[1T
(abbreviated as D-011) and (b) [l] 2-oxo-3-fluoren-7-ylmedoxycarponyl, where R is a furun-9-ylmethoxycarnyl group Amino-7-thia-1-azabicyclo[L3,0 cononane-9-carboxylic acid (hereinafter abbreviated as Fmoc-BTD-011) is mentioned, and both are novel compounds that have not been described in any literature.

The above compounds are, for example, tetrahetron letters (T
etrahedron Letters) Volume 26,
2-oxo-3-phthallimido-7-thia-1-azabicyclo[4,3,0
Cononane-9-carphonic acid (hereinafter referred to as Pt+t-BTD-
(abbreviated as Oll)).

That is, the compound (A) (Boc-BTt'l-01
1) is the above P h t, -B T D -CI I
By defthalylating t, 2-oxo-;3-
Amino-7-thia-1-azabicyclo[11,3,0]
] Nonane-9-cal;
(abbreviated as C1ll), and then treated with di-L-butyl cicarbonate-1 to replace the hydrogen atom of +1-81'[l-011 with an L-butoxycar;i[nyl group.

In addition, the compound (Fmoc-BTD-1) of ([co)]
It) is 9-
By treatment with fluorenyl methyl chloroformate, +
The hydrogen atom of 1-BTD-011 was converted to 11 by the 9-fluorenylmethoxycarbonyl method - Ci Co., Ltd. 1.

In addition, the known substance P b t -B T O-CI
It can be prepared by reacting, for example, N-phthaloyl-L-glutamic acid hydrate with thiophenol in the presence of cyclohexylamine according to well-known methods described in the literature.
A thiophenyl ester is obtained, and then a monothiophenyl-α-methyl ester is obtained using cyatsumethane, and then reduced with Raney nickel to obtain a γ-ruhinol compound,
It can be produced by oxidizing this with pyridinium chlorochromate to produce a γ-fludehyde-α-methyl ester, further condensing L-cysteine to produce a thiazolidine, and then removing methanol by heating.

(Effects of the Invention) The bicyclic di\butyto of the present invention is useful as a reagent for elucidating the active conformation of natural physiologically active peptides. That is, the bicyclic novelbutite of the present invention
Since it has a structure in which the conformation of the amino acid sequence is fixed without forming a turn (manufacturing), by incorporating this into various active peptides, the peptide activity and conformation (β-turn) can be determined. Important information can be obtained about the relationship between bioactive peptides (structures), and they can serve as samples for the analysis of bioactive peptides.

(Example) The present invention will now be described in more detail with reference to embodiments.

Example 1 2-Ogiso 3-1-F'toxocalmonylamino-7-thia I-azahicyclo[4,3,01nonane-
Preparation of 13-calfone m (Boc-BTD-Otl) 1.26 g (3,li + nM) of Pl + t-
BTU-Oll with 30m1 ethanol and U25
Mix ml of water a (78 is solved for k, this; this is 0.!J
ml (18mM) of human hydrated 30111
2I solution was added to ethanol at dM, and after heating under reflux for 2 hours, the solvent was removed under reduced pressure. Remove the formed precipitate by centrifugation, -h
After changing Qing to the east, the precipitate was washed several times with a small amount of water, and the wash Iα matched the old situation of the first month of July.

This supernatant lα was transferred to a column of 011-type anion exchange resin (
It has a diameter of 2.0 cm and a length of 24 (・m). Hyperactive hydrazine is not absorbed into the column but is ejected, so after washing the column with water, it is eluted with IM acetic acid, the ninhydrin-reactive fraction is collected, and the solvent is distilled off under reduced pressure.

Add water to the residue and repeat vacuum distillation three times to completely remove acetic acid. The residue was dissolved in hot water for 7J, ethanol was added, and the mixture was cooled with water.The resulting crystalline product was filtered through the precipitate.
03g (2,9mM) of the formula +1-BTD-1 was obtained. Melting point of this substance, ratio 1 degree light 11! The L and 7cζ analysis values were as follows.

Melting point: 300°C or higher - Specific optical rotation:
[α]p 275.8 = (c ” l + water)
Elemental analysis (1α: C11N S Calculated value: 44.4I35.59 12.95 14
．． 83 analysis i+cf: 44.13 5.39
13.11 14.53 +1- B T obtained above
0. of D-011. (i3z (2,9mM) in water
12 ml and 2.9 ml of IN sodium hydroxide solution
After cooling with water, add 12 ml of di-t-butyl dicarbonate (0.83 g < 3.8 mM) to the solution.
Add Solu α dissolved in Dio-Hatsan and heat at room temperature for 1★('F) for 3.5 hours.
10'L: Add citric acid dropwise to adjust pH to ~2. This was then extracted four times with 30 ml each of ethyl acetate.
Collect ethyl acetate jΔ and wash with 10 Z citric acid saturated saline? Prognosis, add city water fR sodium acid and dry.

After removing the desiccant by filtration and evaporating the I solution to dryness, it was dissolved in the residual methanol and precipitated by adding petroleum ester.
0.91 g of 10 product designated as oc-BTD-Off
I got it. This was recrystallized from ethyl acetate to obtain O, GII g
The purified product is 11). The melting point, specific optical rotation, and U-substance analysis of this substance were as follows.

Melting point: ItiO'C decomposition specific optical rotation: -218.4° at [α (c=l, methanol) Elemental analysis value: CHNS Calculated value: 49.35 G, 37 8.85
10.13 analysis (lα: 49.21 6.26
8.77 10.20 Example 2 2-oxo-3-fluoren-9'-ylmethoxycarmonylamino-7-thia-1-7zabinoclo[4,3
,0cononane-9-carboxylic acid (Fmoc4TI-1)
11) Manufacturing example of 1ζ 3-kero II-BTU-01
87 mg (0.4+nM) of the compound represented by 1 was added to 1
0 = Sodium carbonate water rW 1 (Xil, dissolved in 0 ml, cooled in water, stirred under rf 10 (l mz (0,
4mM) of 9-fluorenylmethylchloromethane (4mM)
0.8 ml of anhydrous dioxane anon α containing 1.
Add dropwise.

After reacting for 3 hours at room temperature, the reaction mixture was poured into 20 ml of regular water, and then the transparent aqueous eyelid was acidified with 10% citric acid under water cooling, and then diluted with ethyl acetate. 2 each
Extract 3 times with 0ml. The ethyl acetate layer was collected, washed with saturated brine, and diluted with anhydrous sulfuric acid -)-thorium overnight.
Dry and remove the sodium sulfate.1. After distilling off the iJ medium, it was recrystallized with acetonitrile to obtain F m o (-81
'D-(III) 71 mg of the compound shown as
:)Ta. The melting point, specific rotation, and elemental analysis (lα is as follows) of this substance.

Melting point: 217 ~ 2 + 9' (Specific optical rotation: [α coma - 147' (C = 1. [Group ")
Elemental analysis Il! ′! : CHN 5

Claims (1)

[Claims] (1) In the form of free acid, the following formula [1] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ---- [1] (In the formula, R is a t-ptoxycarbonyl group or a fluorene-
9-ylmethoxycarbonyl group).