JPS63216890A - Production of chuanghsinmycin analog - Google Patents

Abstract

PURPOSE:To easily obtain the titled compound useful as a synthetic precursor for chuanghsinmycin, by thermally decomposing a specific hydrazone derivative in the presence of a base. CONSTITUTION:The objective compound of formula II can be produced by the thermal decomposition of a hydrazone derivative of formula I (R is H or lower alkyl; X is arenesulfonyl) in the presence of preferably 1-1.2 equivalent of a base (e.g. sodium hydride) usually in a solvent such as THF preferably at 140-170 deg.C.

Description

Detailed Description of the Invention "Industrial Application Field" The present invention relates to the general formula (1) (wherein R is a hydrogen atom or a lower alkyl group).
The present invention relates to a method for producing a cheansinmycin analog represented by

More specifically, general formula (n) (wherein R is a hydrogen atom or a lower alkyl group, x
is an arenesulfonyl group. The present invention relates to a method for producing a thiansinmycin analog represented by the general formula (1), which comprises thermally decomposing a hydrazone derivative emitted by () in the presence of a base.

The compound represented by the general formula (I) is a chemical compound known as a mild antibiotic.
a Hsueh Hsueh Pao, 34.129
(1976)) and its analogues (see Reference Examples below).

``Prior art'' The conventional method for producing thiansinmycin involves dehydration and ring closure of (+)3-acetel-4-(methoxycarbonylmethylthio)indole to form the methyl ester of dehydrothiantsinmycin, and (II) catalytic hydrogenation of this. The methyl ester of Yoshicheansinmycin, (li+
) Next, hydrolysis was performed. (J, Am,
(See Chem, Soc, 1982.104.7622゜) ``Problems to be Solved by the Invention'' However, the above method does not involve converting the methyl ester of dehydrocheancinmycin into the methyl ester of dehydrochyancinmycin by catalytic hydrogenation. During conversion, the reaction is difficult to proceed and there are many problems in terms of efficiency, such as desulfurization.

The present inventors have completed the present invention as a result of intensive studies aimed at developing an efficient method for synthesizing cheansinmycins. That is, the main point of the present invention is to solve the problem of C-ring formation in the synthesis of cheansinmycins.

"Means for Solving the Problems" The present invention provides a method for solving the problems by thermally decomposing a hydrazone derivative represented by the general formula (n) in the presence of a base.
This is a method for producing the Cheankumycin analog represented by 1).

The hydrazone derivative represented by the general formula (II) used in the present invention is 4-(cyanomethylthio)indole m
It can be synthesized according to the following steps (a) and (b).

N (See Reference Examples below) That is, (A) is subjected to the Vilsmeier-Haack reaction using an amide or the Fr1-Crafts reaction using an acid chloride to form 3-acyl-4-(cyanomethylthio)indole. (V) (wherein R is a hydrogen atom or a lower alkyl group). Here, examples of the acid chloride include acetyl chloride, propionic acid chloride 9, and methanoic acid chloride 9. In addition, as a catalyst, ordinary Fr
Although any compound used in the 1adel-Grafts reaction may be used, tin tetrachloride is particularly suitable. Examples of the solvent include benzene, dichloromethane, dichloroethane, and chlorotetraform, and a reaction temperature of around room temperature is sufficient. (b) (V) is condensed with an arenesulfonylhydrazine such as benzenesulfonylhydrazine or tosylhydrazine. The condensation is carried out in a lower alcohol such as methanol or ethanol containing an acid such as acetic acid or propionic acid.

Although the reaction proceeds at room temperature, it is more efficient to heat it to 60-80°C.

4-cyano-5-thiabenz represented by the general formula (1) of the hydrazone derivative represented by the general formula (II)
Conversion to cd'' indole derivatives is accomplished by thermal decomposition in the presence of base. Examples of the base include sodium hydride, potassium hydride, methyllithium, potassium t-butoxy, etc., and the amount used is 0.5-2 equivalents relative to (n), especially 1- Preferably, an amount of 1.2M is used. Further, the reaction is preferably carried out in a solvent, and examples of the solvent include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, benzene, and toluene. The reaction is 8
The reaction proceeds at a temperature of 0 to 180°C, but is preferably carried out at a temperature of 140 to 170°C from the viewpoint of reaction efficiency and product selectivity.

The conversion of the 4-cyano-5-thiabenzrcdJ indole visiting conductor represented by the general formula (1) to thianecincinmycins is achieved by hydrolysis using rR or a base catalyst. Acids include hydrochloric acid, hydrobromic acid, sulfuric acid,
Examples include perchloric acid, and examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. In an acid catalyst system, the reaction is usually carried out at a temperature of 60 to 120°C, particularly around 100°C, using a lower fatty acid such as acetic acid or propionic acid, or a mixture of these and water as a solvent. In the base catalyst system, methanol, ethanol, tetrapanol, butanol, etc. are used as the solvent, and the reaction is carried out at room temperature to around 100°C.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference Example I 0.55111 (5.9 mmol) of oxychloride was added to 1.5 d of DMF at room temperature in an argon stream, and the mixture was stirred for 30 minutes. The solution was cooled to 0°C and 1359
A solution of ~(1.9 mmol) dissolved in 8 m of THF was added and stirred for 10 minutes. An appropriate amount of ice was added to the reaction mixture, and the mixture was stirred for 10 minutes, and then an aqueous solution of hydrogen carbonate was added, and the mixture was stirred for 2 days. After the reaction was completed, the reaction mixture was transferred to a separating funnel and extracted with ethyl acetate.

The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The condensate was applied to a silica gel column and flushed out with dichloromethane, followed by a 4:1 mixed solvent of dichloromethane and ethyl acetate. Obtained with a yield of 90.4%.

One point: 150.0-151.5°C (colorless needle crystals, recrystallized from ethyl acetate).

2H), 7.24-7.74 (m, 3H), 8.22-
8.32 (m, IH), 10.63 (s, IH), 11
．． 20-11.80 (m, IH) Sir Mass (m/z, %); 216 (M+, 100), 1
98(33).

183(29), 176(49), 175(47).

148(60), 104(57).

Elemental analysis value: Calculated value (%) as C□□H3N25o;
C, 61,09; H, 3,73; N, 12.95;
S, 14B2° actual value (%); 0,60.94;H
, 3,65; N, 12.94;
y SuA/honylhydrazine 388η (2,1mmoA
) and 1 d of acetic acid were added to 10 au of ethanol and stirred at room temperature for 40 minutes. After the reaction was completed, the precipitated solid was poured into the solution, and 3 was obtained with a yield of 567η and 74.3%. Concentrate the condensate, transfer the condensate to a silica gel column, dichloromethane, and then dichloromethane and ethyl acetate for 10 minutes.
When I poured it out with :l mixed solvent □, 3 was added to 196
~． Obtained with a yield of 25.7%. (The reaction progresses quantitatively) Melting point: 184.0-186.0°C (colorless columnar crystals, recrystallized from ethanol) IR (KBr): 3390, 3210, 2250, 13
55°3H), 3.81 (s, 2H), 7.06-7.
96 (m, 8H).

9.02 (Sow fine coupling
, IH).

9.64-10.00 (m, IH), 10.80-11
．． 00 (m.

IH) pps Ma”(”/Zt%, 15 eVin-bea
m method); 384 (M+, 4).

202 (30), 201 (88), 200 (100).

160 (36), 156 (31), 148 (35).

139(30), 92(93), 91(29).

Elemental analysis value; C, 8H□, N, til value (%) as S20□; c, 56.23; H, 4,19; N, 14.
57; S, 16.68° Actual value (%); (:456.
18; H, 4, 19; N, 14.46; S, 16.69
゜Example 1 3.567 m9 (1.5 mmol) was added to diglyme (
Diethylene glycol dimethyl ether/') 10m6!
Sodium hydride 6279 (6 (EJ oily, l, 5 rnrno
1) was added, stirred for 20 minutes, and then heated under reflux for 10 minutes.

After the reaction was completed, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The solid product was applied to a silica gel column and flushed out with a 4:1 mixed solvent of dichloromethane and hexane, yielding 4 in a yield of 183 μm and 62.0 μm.

Melting point: 204.0-207.0°C (colorless columnar crystals, recrystallized from ethyl acetate and hexane) IR (KBr): 3340.2240m-"IHNMF
t(acetone-(16,400MHz); 3.37(
a-a-d, J=15.8Hz, 4.2Hz, 1
．． 6Hz, IH).

3.58 (d-a-a, J=15.8Hz, 4.01
1z, 0.711z, .

IH), 4.69 (dd, J=4.2Hz, 4.
011z, IH).

6.91 (da, J = 7.3Hz, 0.6
h, IH), 7.11 (dd, J=8.2Hz,
7.3Hz, IH), 7.26(d-d.

J=8.2Hz, 0.6Hz, IH), 7.2
5-7.29 (m, IH).

10.26-10.37 (m, IH)P.

Mass (m/z, %); 200 (M”y 100),
173(75)*160(48).

Elemental analysis value; Calculated value (%) as C1□H3N25; 0,65.98; H, 4,03; N, 1
3.99; S, 16.01° Actual value (%); C, 65
,94;H,3,94;N,13.90;S,16.2
2゜Reference example 3 4 26W (0.13 mmo)), hydroxide-t tom 26'li (0.65 mmol) and water 0.1 d
was added to ethanol 2W11 and heated under reflux for 6 hours. After the reaction was completed, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. When the extracted layer was washed with saturated saline and dried with magnesium sulfate, 5 was 24~. Obtained in a yield of 84.3-.

Melting point: 180.0-182.5°C (pale red columnar crystals, recrystallized from ethyl acetate and hexane) IR (KBr): 3455, 1698 cm-'IHNM
R(7s)/-d6,400MHz); δ3.27 (
d-dd, J=15.5Hz, 9.3Hz,
1.411z, IH), 3.50(a-a-d, J
=15.5Hz, 3.711z, 0.9Hz, I
H).

4.21 (6-d, J=9.3Hz, 3.7H
z, 1) (), 6.82 (eL-d, J = 7.
3Hz, 0.6Hz r I H)t 7-03 (
d-d rJ=8.211z, 7.3Hz, IH)
, 7.12-7.16 (m, IH).

7.15 (dd, J=8.2Hz, 0.6Hz, I
H), 10.02-10.16 (m, IH) Pllm Mass (In/z, %); 219 (M+, 100),
174(83).

173(71), 160(62).

Elemental analysis value; C□, mLr1li as H9NSO2 (
%); C, 60,26; H, 4,14; N, 6.3
9;S, 14.62°Actual measurement value (@;C,60,24
;H,4,13;N,6.28;S,14.34゜Reference example 4 1 1.0511 (5,6 mmoA) was converted into benzene 12
0.64 rttl of acetyl chloride (9, OmmoJ) was added to a solution dissolved in a mixed solvent of m1 and 16xl of 1,2-dichloroethane at 0°C in an argon stream, and the mixture was stirred for 20 minutes. Because of this dissolution, V tin chloride 1.0
A solution of 5111 (9.0 mmol) dissolved in 8 d of benzene was added, and the mixture was stirred at 0° C. to room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into saturated brine and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. When ethyl acetate was added to the concentrate and crystallization was carried out, 800 ml of 6 was obtained in a yield of 62.1%. When the oral fluid was concentrated, applied to a silica gel column, filtered with dichloromethane, and flushed out with a 4:1 mixed solvent of dichloromethane and ethyl acetate, 6 was found to be 275%, 21.3%.
was obtained in a yield of . (Total yield 83.4%) Melting point: 157.5-159.0°C (colorless needle crystals, crystallized from ethyl acetate) IR (KBr): 3330, 2245.1640 cm-
"IHNMR (acetone-d6t 100MHz) pδ
2,51 (s.

3H), 4.03 (8, 2H), 7.24-7.56 (
m, 3H).

8.24-8.32 (m, IH), 10.80-12.
00 (m.

IH) pIJI Mass (m/m, %): 230 (M+, 100), 1
97(42).

190 (41), 175 (58), 162 (30).

118(33), 43(32).

Elemental analysis value; Calculated value (chi) as C engineering 2H1°SN 20; C, 62,56; H, 4,38; N, 12.16
; S, 13.92° actual measurement value (@; C, 62,42; H
, 4, 42; N, 12.04; S, 14.09° Reference example 5 6 4051JIL! (1,8 mmoA), p-t/I
/! :/ Honylhydrazine 344■ (1,9
mmol) and 0.8 d of acetic acid were added to ethanol 10- and heated under reflux for 9 hours. After the reaction was completed, the reaction mixture was concentrated.

When ethanol was added to the concentrate and the precipitated solid was poured into the mouth, 7 was found to be 520~. Obtained with a yield of 74.2%.

IR (KBr); 3360, 3230, 2250, 13
55゜1157偲-1"HNMR (DMSO-a6, 100MHz); δ2.
26 (s, 3H), t2.38 (a, 3H), 3
．． 62 (s', 2H), 7.04-7.92 (m,
8H), 10.06-10.44 (m, IH)
.

11.44-11.76 (m, IH) IN.

Mass (m/z, %); 398 (M, 4), 214
(86).

213(71), 199(34), 175(38).

174 (100), 173 (52), 92 (50).

91(77), 65(47).

Example 2 7.254 W (0.64 mmoA) was added to Diglyme 3
Hydrogenated sodium chloride A2'j9 (60% oily, 0.73 mmol) was added to the solution dissolved in d at room temperature under an argon atmosphere.
was added and stirred for 13 minutes, followed by heating under reflux for 10 minutes.

After the reaction was completed, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed with dichloromethane, 8 was found to be 91% and 66%.
．． A yield of 6 ml was obtained. 8 is a 43:57 mixture of stereoisomers 8a and 8b. By crystallizing from ethyl acetate, only 8b was isolated as a mature product.

8b Melting point: 203.5-205.5°C (recrystallized from ethyl acetate) IR (KBr): 3390, 2240 cm-"-ci IHNMR (acetone I7J, 400 MHz);
δ1.62 (d.

J=6.8Hz, 3H), 3.57 (q-d-d
, J=6.8Hz.

4.0Hz, 1.5Hz, IH), 4.53(d
, J=4.0Hz, IH).

6.93 (dd, J=7.3Hz, 0.5Hz,
IH), 7.12 (dd, J=8.2Hz,
7.3Hz, IH)t 7.26 (dd, J
=8.2Hz, 0.5)1z, IH), 7.30
~7.33 (m.

IH), 10.26-10.42 (m, IH)P.

Mass (m/z, %); 214 (M”, 100), 1
99(55).

174 (73).

Elemental analysis value; Calculated value (%) as C engineering 2H1oN2S;
C, 6'/, 26; H, 4,70; N, 13.07;
S, 14.96° actual measurement (direct); C, 67,21;
H, 4,64; N, 13.02; S, 14.75°J
=6.8Hz, 1.29H), 1.60 (d,
J=6.8Hz.

1.71H)? 3.54 (q-dd, J=6
．． 8Hz, 4.0Hz.

1.5H7,,0,57H)? 3.72 (q-d-d
, J=6.8Hz.

4.4Hz, 0.7Hz, 0.43H), 4.3
1 (d, J=4.4Hz.

0.43H), 4.47 (d, J=4.0Hz
, 0.57H).

6.90-6.95 (m, IH), 7.08-7.15
(m, IH).

7.23-7.33 (m, 2H), 10.23-10.
43 (m.

IH) Solution.

Reference example 6 HH 8,73~(0,34mmo/), sodium hydroxide 7
0 mW (1,75 mmoA) and 0.25 d of water were added to 5 ml of ethanol and heated under reflux for 8 hours and 30 minutes. To the reaction mixture was added 40 yq (l, Q Q m
moA ) was added thereto, and the mixture was further heated under reflux for 19 hours. After the reaction was completed, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with saturated saline, dried over magnesium sulfate, and concentrated.9 was 751N! , with a yield of 94.4%.

This is a mixture of cis and trans forms (Syszuku C)
OX9 body Nidorans body = 38:62) Adashi, N enemy Dashime'
Cheansinmycin was obtained by fractional crystallization from ≠≠-ether.

Melting point 190-191'C (Reference [(he)-Cheansinmycin: 192-a)

Claims (1)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R is a hydrogen atom or a lower alkyl group, and
is an arenesulfonyl group. ) is a general formula consisting of thermal decomposition in the presence of a base. There are mathematical formulas, chemical formulas, tables, etc. (In the formula, R is a hydrogen atom or a lower alkyl group.)
A method for producing a chuansinmycin analog represented by