JPS5857432B2 - 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 intermediate 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 many studies have 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 middle ring.

That is, not only seven-membered ring compounds but also taxanes (T
axane), ophiobolan (0phiobol)
ane) skeleton is an 8-membered ring, caryofuran (Caryo
phyllane), Germac y7 (Germac
rane ), Humulane 7 and Cembrane skeletons are 9.
10. It is composed of 11- and 14-membered rings.

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.

(M, Kodama 1Y. Mat suk l, S,
lto, Tetrahedron Letters1
1121 (1976): E. J., Corey, E.

Hamanaka, J, Am, Chem, 5oc1.8
9.2758 (1967): Y, Kitagawa, A.
.

1toh1S, Hashimoto, HoYamamo
to, 1bld, Kametan, 3864 (1977); Masanobu Suzuki et al. 21st Natural Products Symposium (Sapporo, 1978) Abstracts,
p.

522: E, J, Corey, R, B, Mit
ra, H, Uda, J, Am, C'hem, So
c, , 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 middle ring amide sulfide compound of the present invention easily and in high yield as a process of synthesizing the middle ring skeleton, and completed the present invention. It is something.

The middle 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 a middle ring skeleton, particularly in the synthesis of a middle ring ketone useful as a raw material for fragrances.

The present invention will be explained below.

The novel intermediate ring amide sulfide compound of the present invention has the general formula: (where n represents 8.9.10.12).

), and a specific example is as follows.

Next, a method for synthesizing the intermediate ring amide sulfide compound of the present invention will be explained.

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

The above starting material (3) can be easily obtained, for example, by a known method (A, 1.Kiprianov an
d Z, N.

Pazeuko Zhur, Obschei, Kh
im, 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).

Using the above compound (3)' or its disulfide (3) as a starting material, the general formula obtained by reacting the bromic acid represented by the general formula with a chlorinating agent, such as 5OC12: (where n is 8.9 .1
It shows 0.12.

), a compound represented by the general formula: is quantitatively obtained.

Specific examples of the bromic acid chloride (2) include the following compounds.

(n=8) 8-bromo-octanoyl chloride (n=9) 9-bromo-nonanoyl chloride (n
= 10) io-bromo-decanoic acid chloride (n = 12) 12-bromo-decanoic acid chloride 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, glopanol, 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 producing the middle A-ring amide sulfide compound of the object compound of the present invention. (5) is obtained.

As an alkali, sodium ethoxide (EtONa
), sodium isopropoxide (i-PrONa
), potassium-t-butoxide (1-BuOK), and other alkali metal alkoxides such as sodium chloride (NaH
), sodium hydride, 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 inert gas atmosphere 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 middle ring ketone from the middle ring amide sulfide compound of the present invention will be described (in the case of n-10), that is, (6) (n=10) is oxidized with periodic acid to form a sulfoxide compound ( After treating this with lithium diisopropylamide (LDA), the resulting ketosulfoxide (8) is reduced with Al-Hg to obtain the corresponding 10-membered ring ketone.

This is illustrated in the figure below.

Next, the present invention will be explained by examples, but the present invention is not limited thereto.

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

Example 1 In the case of (n=8), bromic acid (1) (n=8.6407Q) was dissolved in SOCl2 (
After refluxing for 3 hours with 6 ml of
) (n=8) is dissolved in ether (2 ml).

This was combined with disulfide (3) (280η) and Et3N (
Add to a solution of 0.5 ml (0.5 ml) in nee chill (8 ml) while cooling with water and stirring.

After stirring at room temperature for 0.5 to 2 hours, water is added to the reaction solution, and then ether (or ethyl acetate) is added.

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

The oil obtained by distilling off the solvent was subjected to column chromatography using 5 (l) of SiO2.

Diamide disulfide (4) (n=8) from the part eluted with n-hexane-AcOEt (2/1-3/2) system
(94.6% yield from 660η(3)) is obtained as an oil.

((4) Physical properties of (n=8)) CCI IR, ν '1670cm,' NMR: δ3.30 (3H,S,N-CR2)3.3
9 (2H1t, J=6Hz, CH2Br) (n=9
) case (1) (n=9, t420~), 5OCI2 (14 mg
) to obtain (2) (n=9), apply (2) to (3) (752m9) and Et3N (1 ml), and (n=8)
The same process as in the case was performed.

After SiO2 chromatography, n-hexane-AcOEt (3/
Elution was carried out using step 1) to obtain 1548 ml of oil (yield 78.5% from step (3)).

(Physical properties of (4,) (n=9)) NMR: δ3.31 (3H,S,N-Me)3.
42 (3H,3J=6Hz,,CH2Br) Pilstein test: If positive (n=10) (], ) (n=10.230m9) and SOCl2
(2) (n=10) was obtained from (3 ml), and this was converted into (3)
(10omy) and Et3N (0.27M1), and the resulting crude product is purified by SiO2 column chromatography.

From the n-hexane Ac0Et (4/1) eluate, (4) (n=10) was obtained as an oil (264 m9 (yield 98.2% from (3))).

(Physical properties of (4) (n=to)) IR: y"C'1670cm' NMR: δ3.32 (3H,S,N-CR2)3.4
4 (2H,3J=6Hz, CH2Br) Pilstein test: positive (n=12) (1) (n=12.2.5 (1) and SOCl2 (15
(2) (n=i2) is obtained from Et3N (
(3) ('31 omy) in the presence of 0,4TLl).

n-hexane-AcOEt (3/1
) 765 to (85.8%) of (4) (n = 12) was obtained as an oil from the eluate.

(Physical properties of (4) (n=12)) NMR: δ3.23 (3H,S,N-CR2)3.4
0 (2H, t, J=6°5 Hz, CH2Br
) Example 2 (n=8) A solution of diamide disulfide (4) (n=8.575~) in dioxane (10 ml) was heated in a 70°C bath with N
Improper tool of aBH4, (1357n9) and NaH (50% oil dispersion: 155η)
(27 ml) solution was added dropwise to the solution 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 (452~) is purified by SiO2 column chromatography.

n-hexane-AcOEt (4/1) 1 from the elution part
Two-membered ring lactam sulfide (5) (n=8) as colorless crystals in 343m9 (yield 7 from (4) (n=8)
8%) was obtained.

Recrystallization from CHCl3-hexane results in colorless prism crystals.

(Physical properties of (5) (n=8)) mp: 94-95°C CI IR: ν '1660Cr/l' NMR: δ2
．． 9~3.2 (2H1m) 3.24 (3H1S, N
-CR2) Elemental analysis: Calculated value (CI 5 H2, NOS) C, 6
840; H2S, 04; N, 5.32; Sl 12
．． 17 Experimental values: C, 68,60; H, 8,08; N, 5.29; S,
12.16 Quantitative analysis: m/e 263 (M+) (n=9) (4) (n=9.1540η)-dioxane (26,a
ml) was ring-closed with NaBH4 (348 ~) NaH (50% oil dispersion: 400η)-impropatol (69.5 ml) in the same manner as above, and purified by SiO2 column chromatography to obtain 13-membered lactam sulfide (5
)(n=9) is 925~((4)(n
= 9) with a yield of 77.3%).

Recrystallization from CHCl3-hexane results in colorless prism crystals.

[Physical properties of (5) (n=9)] mp: 102-104°G IR:yC"1665m-1 NMR: δ324 (3H, S, N-CF2) Elemental analysis:
Calculated value (C16H23NO8): C, 63, 27; N
18.36; N, 5.05; Sl 11.56 Experimental value: C169,36; H, 8,33; N15.09; S1
1.4.7 Mass spectrometry: m/e 277 (M+) (n=10) for (4,) (n=10.7007Q)-dioxane (11
,5m1) to NaBH4(150mt;t)-Na
SiO after ring closure using H(50% oil distribution ni 172m9)-isopropanol (31 ml).

Purify by column chromatography. 14-membered ring lactam sulfide (5) (n=10) as colorless crystals 481771&
(Yield 87.6% from (4), (n=10)) was obtained.

When recrystallized from CHCl3 n-hexane, colorless prismatic crystals are obtained.

[Physical properties of (5) (n=10)] mp: 82-85°C, CCI IR, ν 41667C! n,' NIVIR: δ3.21 (3H, S, N-CF2) Elemental analysis: Calculated value (C17H25NO8): C170,
06; N18.65; N, 4.81; S, 11.
00 Experimental value: C, 70,05; N18.62; N14.76; S
, 10.89 Mass spectrometry: m/e 291 (M+) (4) for (n=12) (n=x2.760rn9)-dioxane (11
,5TLl) to NaBH4(1547n9)-Na
After ring closure with H (50% oil dispersion: 177~)-isopropanol (31 ml), column chromatography purification was performed on SiO2.

16 from the n-hexane-AcOEt (4/l) elution part
Member ring lactam sulfide (5) (n = 12) as a colorless oil 512■ (Yield 83 from (4) (n = 12)
．． 8%) was obtained.

(Physical properties of (5) (n = 12)) NMR: δ3
．． 23 (3H,S,N-CF2) elemental analysis: Calculated value (
C18H29NO8): C171,42; N19.15
;N, 4.38;S11.0.04 Experimental value: C,70,97;N19.13;N, 4.30;
S, 9.90 Mass spectrometry: m/e 319 (M+) Example 3 (n=8) 12-membered ring lactam sulfide (5) (n=s, 5267
/lp) in dry THF (8 Tll) is cooled in a dry ice-acetone bath under a stream of Ar.

In this, diisopropylamine (i-Pr2NH:
Then add n-8uLi-hexane solution (1.5 equivalents) and stir for 10 minutes.

Methyl iodide (Mel; 0.32 rul) 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 adding an excess of saturated NH4Cl aqueous solution to the reaction mixture, the mixture is returned to room temperature and extracted with CHCl3.

The extract was filtered through a 5i02 short column, and the solvent was distilled off.

The obtained crude crystals are purified by SiO2 column chromatography.

From the n-hexane-AcOEt (4/1) eluate, 5431n9 (yield 97.8%) of lactam sulfide (6) (n=8) was obtained as colorless crystals, and CHCl3-
Recrystallization from n-hexane gave colorless needles.

(Physical properties of (6) (n=8)) mp: 109-110°C CI IR: '1660crrL' NMR: δ1.03 (3H, d, J=6.4Hz, C
H-CH3) 2.9-3.3 (2H,m) 3.19 (3H1S,,N-CH5) Elemental analysis: Calculated value (C16I(23NO8):C16
9,27; N18.36; N15.05; S11.
56 Experimental value: C169,29; N18.37; N15.02; S
, 11.45 (n=9) 13-membered ring lactam sulfide (5) (n=9.440
η) in THF (6.4ml) solution as above.
NH (1,5 eq) -n -13uLi-n -hexane (1,5 eq) then Mel (0,35 m/
) to act.

When the obtained crude crystals were purified by column chromatography using SiO2, lactam sulfide (6) (n=
9) was obtained in 450~ (yield 97.4%).

Recrystallization from ether-n-hexane gave colorless needles.

(Physical properties of (6) (n=9)) mp: 109-110℃ NMR: δ1.05 (3H, d, J=6Hz.

CH-CH,) 3.24 (3H1S, N-CH5) Elemental analysis: Calculated value (C1□H25NO8): C170,
06; N18.65; N, 4.81; 5111.
00 Experimental value: C, 70,09; H, 8,65; N14.80; S,
10.91 (n=10) 14-membered lactam sulfide (5) (n=to, 43
(5) (n=8) in THF (6 ml) solution of 57n9)
As in the case of 1.5 equivalents of 1-Pr2NH1 and n-
BuLi-n-hexane then Mel (0.33ml
) to act.

The obtained crude crystals were purified by column chromatography using SiO2 to obtain 452 rv of lactam sulfide (6) (n=10) as colorless crystals (yield 99.1%).

(Physical properties of (6) (n=10)) mp: 58-64°C NMR: δ1.05 (3H, d, J=6.6Hz.

CH-CH,) 2.9-3.3 (2H, m, S-CH2) 3.24
(3H, S, N-CH5) Elemental analysis: Calculated value (C18H, NO8): C, 70, 7
7; N18.91; N14.57; Sl 10.5
0 Actual measurement value C, 70, 77; H, 8, 98; N, 4.54; 5
110.29 (n=12) 16-membered ring lactam sulfide (5) (n=12.74
A THF (9 ml) solution of 07Q) was treated with 1.5 equivalents of 1-Pr2NH1 and n-BuLi-n-hexane, followed by Mel (0.51 ml) in the same manner as above, and the resulting crude crystals were purified by column chromatography using 5i02. ,(6)(
n = 12) as colorless crystals, 753 my (yield: 97
．． 5%) was obtained.

When this is recrystallized from ether-n-hexane, colorless prism crystals are obtained.

(Physical properties of (6) (n=12)) mp: 75-77°C NMR: δ1.05 (3H, d, J=7Hz.

CH-CH,) 2.8-3.1 (2H, m, S-CH2) 3.18
(3H,S,N-CH5) Elemental analysis: Calculated value (C20H31NO8): C, 72
,02;H,9,37;N,4.20;S19.61 Experimental value: C171,88;H,9,36;N,4.15;S
,9.61

Claims (1)

[Claims] 1 General formula: (In the formula, R represents a hydrogen atom or a methyl group, and n
indicates 8.9.10.12. ) A novel intermediate ring amide sulfide compound represented by 2. The compound according to claim 1, wherein R is a hydrogen atom and n is 8. 3. The compound according to claim 1, wherein R is a hydrogen atom and n is 9. 4 Claim 1 in which R is a hydrogen atom and n is 10
Compounds described in Section. 5 Claim 1 in which R is a hydrogen atom and n is 12
Compounds described in Section. 6. The compound according to claim 1, wherein R is a methyl group and n is 8. 7 The compound according to claim 1, in which R is a methyl group and n is 9. 8 The compound according to claim 1, in which R is a methyl group and n is 10.
Compounds described in Section. 9 Claim 1 in which R is a methyl group and n is 12
Compounds described in Section. Using a compound represented by the formula 10 or its disulfide as a starting material, it is reacted with a compound represented by the general formula: (wherein, n represents 8.9.10.12), A compound represented by the general formula: (wherein, n is the same as above) or its disulfide is obtained, and this is treated with an alkali to close the ring to form the general formula: (wherein, n is the same as above) A novel intermediate ring amide sulfide compound characterized by obtaining a compound represented by the following formula and methylating it to obtain a compound represented by the general formula: (wherein n is the same as above) synthesis method.