JPS5817754B2 - Novel intermediate ring amide sulfide compounds and their synthesis method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel medium ring amide sulfide compound and a method for producing the same.

In recent years, the synthesis of macrocyclic compounds, including macrolide antibiotics, has attracted attention, and research on multiple compounds has been reported.

As an essential step in promoting these synthetic studies, methods for synthesizing macrocyclic lactones are making rapid progress.

On the other hand, in nature, there are many carbocyclic compounds having a ring.

That is, not only seven-membered ring compounds but also taxanes (T
axane), offioborane (0phiobo
lane) skeleton is an 8-membered ring, caryophylla 7 (Car
yophyllane), germacrane (Germ
acrane), Humulane 7 (Humulane)
) and Cembrane skeletons are composed of 9, 10, 11 and 14-membered rings, respectively.

Possible methods for synthesizing the skeletons of these compounds include (1) cyclization reaction, and (2) ring expansion or reduction reaction, etc. Compounds with 10 or more membered rings are mainly formed by (1) cyclization reaction. A method for synthesizing caryoolefin having a 9-membered ring based on (2) ring expansion reaction has been reported.

CM, Kodama, Y. Matsuki, S.
, lto, Tetrahedron Lette
rs.

1121 (1976): F. J., Corey, E.

HamanakalJ,Am,Chem,Soc,,υ
, 2758 (1967); Y, Kitagawa,
A.

1toh, S, Hashimoto, H, Yam
amotollbid, , 3864 (1977);
Suzuki Masanobu et al. 21st Natural Products Conference (Sapporo, 1978) Abstracts p. 522: E, J, Corey, R
, B., Mitra, H., Uda, J., Am, C.
hem, 5oc6.86, 485 (1964), etc.

However, it is generally considered difficult to form these 8- to 12-membered ring skeletons by cyclization, and it has been desired to establish a general method for synthesizing intermediate rings and for cyclization.

Therefore, the present inventors succeeded in synthesizing the medium ring amide sulfide compound of the present invention easily and in high yield as a process of synthesizing the ring skeleton of the inner ring, and completed the present invention. It is something.

The medium-sized ring amide sulfide compound of the present invention has the general formula (as described below) and is an extremely useful intermediate in the synthesis of ring skeletons in fillings, particularly in the synthesis of medium-sized ring ketones useful as raw materials for fragrances and the like.

The present invention will be explained below.

The novel medium ring amide sulfide compound of the present invention has a structural formula: % Formula % Next, a method for synthesizing the medium ring amide sulfide compound of the present invention will be described.

The starting material was O-mercaptomethylaniline (3
or its disulfide (3).

The above starting material (3) is, for example, CA easily obtained by a known method; 1. Kiprianov an
dZ, N.

Pazeuko Zhur, ObschellKhi
m,, 19.1523 (1949): Chem, Ab
str, 44°3487g (1950)).

Disulfide (3) can also be easily obtained by contacting (3') with air or heating in DMSO (dimethyl sulfoxide).

When the above compounds (3 or their disulfides (3) are used as starting materials, they are reacted with bromic acid chloride represented by the formula: obtained by reacting bromic acid represented by the formula with a chlorinating agent, for example, SOC1°). A compound represented by the formula: is quantitatively obtained.

The above reaction is performed using a base such as triethylamine (Et3N).
), pyridine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. in a solvent such as tetrahydrofuran (THF), ether, pyridine, benzene, chloroform, methylene chloride, carbon tetrachloride, acetonitrile, ethanol, noropanol, etc. Preferably, the reaction temperature and reaction time are each about 0 to 25
°C for about 0.5 to 2 hours is suitable.

The compound (4') thus obtained is treated with an alkali, or (4) is treated with an alkali in the presence of a reducing agent to cause ring closure, thereby forming the intermediate ring amide sulfide of the object compound of the present invention. Compound (5) is obtained.

As an alkali, sodium ethoxide (EtONa
), sodium isopropoxide (i-PrONa)
, potassium A-j-butoxide (1-BuOK4 alkali metal alkoxide pond sodium hydride (NaH),
Sodium hydroxide, potassium hydroxide, etc. can be used.

As a reducing agent, sodium borohydride (NaBH4
) is optimal.

Also, as a solvent, ethanol, isopropanol, t-
It is preferable to use a mixed solvent of alcohol such as butanol and dioxane, tetrahydrofuran (THF), benzene, etc.

This reaction is carried out using the so-called high dilution method.
The compound (4) or (4') is added dropwise to a solution of the alkali dissolved in the solvent under an atmosphere of an inert gas such as nitrogen.

The reaction temperature is suitably about 50 to 80°C, and the reaction time can be appropriately determined depending on the amount of compound (4) or (4') used, but is usually suitably 5 to 30 hours.

Next, the obtained (5) is methylated to obtain (6), which is the target compound of the present invention.

Methyl iodide (Mel) is suitable as the methylating agent used in the above reaction, and the reaction is carried out in a solvent such as dioxane, THF, benzene, etc. in the presence of n-BuLi and diisopropylamine.

The above reaction is carried out under cooling with dry ice-acetone etc. for about 1
The reaction time is 0 minutes to 1 hour.

Next, a method for synthesizing a medium ring ketone from the middle ring amide sulfide compound of the present invention will be described.

That is, compound (6) is oxidized with periodic acid to obtain sulfoxide compound (7), which is treated with lithium diimpropylamide (LDA) to obtain ketosulfoxide (8).
) is reduced with Al-Hg to give the corresponding 11-membered ring ketone.

This is shown in the figure as follows.

Next, the present invention will be explained by examples, but none of them were successful.

The light is not limited to these.

The compounds represented by formulas (4), (5) and (6) are new compounds.

Example 1 Bromic acid (1) (6907V) was dissolved in SOCl 2 (6m
l! ) for 3 hr, excess 5OC12 was distilled off under reduced pressure to obtain oily (crude) bromic acid chloride (
2) Dissolve (720%') in ether (Jml).

This was combined with disulfide (3) (3337n9) and Et3
Add to a solution of N (0.4 ml) in ether (8 ml) while cooling with water and stirring.

Stir at room temperature for 0.5 to 2 hours, add water to the reaction mixture, and further add ether (or ethyl acetate).

The organic layer is separated, washed with water, and dried with MgSO4.

The oil obtained by distilling off the solvent is subjected to column chromatography using 501 SiO□.

Diamide disulfide (4) was extracted from the part eluted with the n-hexane-AcOEt (4/1 to 2/I) system (9
301n9 (100% yield from (3))) taken as an oil.

[Physical properties of (4)] ■R:・CCl41670bo-1 ax diamide disulfide (4) (910η) dioxane (15rILl) solution heated in a 70°C bath
BH4 (200In?) and NaH (50% oil/
The mixture was added dropwise to a solution of 230rrI9) in isopropanol (40 ml) over 20 hours while stirring in a nitrogen stream, and then refluxed for 1 hour.

After cooling, water was added to the reaction solution to dissolve the white precipitate, and most of the solvent was distilled off under reduced pressure to give CHCl3 or Ac0.
Extract with Et.

After drying the extract over MgSO4, the solvent is distilled off, and the resulting crude product is purified by SiO2 column chromatography.

From the n-hexane-AcQEt (4/1') elution fraction, 15-membered lactam sulfide (5) was obtained as colorless crystals 609rn9 (yield 84.4% from (4)).

・When recrystallized from CHCl3-hexane, it becomes colorless prismatic crystals.

[Physical properties of (5)] mp: 87-88°C ■R: ・CC'1667CTl' NMR: δ3.18 (3H, S, N-CH5) Elemental analysis: Calculated value (C18H2□N08): C, 70, 77;
H, 8,91; N, 4.59; S, 10.50 Experimental value: C, 70,93; H, 8,93; N14.59
;S, 10.44 Mass spectrometry: m/e 305 (M+) Example 3 A solution of 15-membered ring lactam sulfide (5) (722 m9) in dry THF (9.2 m1) was placed in a dry ice-acetone bath under an Ar flow. Cool it down.

In this, diisopropylamine (i-Pr2NH:
0.45ml (11.5 equivalents)) Then, n-BuLi-hexane solution (1.5 equivalents) was added and stirred for 10 minutes.

Methyl iodide (Me 1 ; 0.5 ml) was added to the reaction solution.
The mixture was stirred in a dry ice-acetone bath for 1 hour, in an aqueous salt bath for 2 hours, and then at room temperature for 30 minutes, and then cooled in a dry ice-acetone bath.

After dipping the reaction mixture with excess saturated NH4Cl aqueous solution C, the mixture was warmed to room temperature and extracted with CHCl3.

The extract was filtered through a short column of SiO2, and the solvent was distilled off.

The obtained crude crystals are purified by Si02 column chromatography.

660 drops (yield 87.6%) of lactam sulfide (6) was obtained as colorless crystals from the n-hexane-AcOEt (4/1) eluate, and when recrystallized from CHCl3-n-hexane, colorless plate-like crystals were obtained. Obtained.

[Physical properties of (6)] mp: 94-96℃・■R:・CC1'1667cm' Cut δ0.98 (3H, d, j=7Hz, CH-C
H3) 3.12 (3H, S, N-CH3) Elemental analysis: Calculated value (C19H29NO8): C171
,42;H19,15;N,4.38;S,10.04 Experimental value:C,71,49;H19,18;N,4.41
;S, 10.06

Claims (1)

[Claims] 1. A novel medium ring amide sulfide compound represented by the general formula: (wherein R represents a hydrogen atom or a methyl group). 2. The compound according to claim 1, wherein R is a hydrogen atom. 3. The compound according to claim 1, wherein R is a methyl group. 4 A compound represented by the formula: or its disulfide is used as a starting material, and this is reacted with a compound represented by the formula: to obtain a compound represented by the formula: or its disulfide, which is treated with an alkali to undergo ring closure. A novel method for synthesizing a medium ring amide sulfide compound, which comprises obtaining a compound represented by the formula: and methylating it to obtain a compound represented by the formula: