JPH0466569A - Production of indole derivative - Google Patents

Abstract

PURPOSE:To obtain a 5-hydroxy-N-substituted indole derivative under mild conditions in simple treatment and good yield by reacting a phenol derivative having alpha,beta-unsaturated cyclic double bond at m-position with a diazonium salt as starting materials. CONSTITUTION:A phenol derivative expressed by formula I [R1, R5 and R6 are H, alkyl, halogen, alkenyl, alkoxy, aryl, acyl or aralkyl; H or a group capable of eliminating by diazo-coupling reaction may be attached at p-position to OH; Ra and Rb are mutually bonded to form a 4 to 12-membered ring consisting of nonmetallic atom (N, S and/O)] is subjected to coupling reaction with a diazonium salt expressed by formula II (R7 is diazonium salt residue; X is anion) in an inert solvent at low temperature to provide the aimed com pound expressed by formula III useful for various kinds of medicines or syn thetic intermediate for alkaloid, raw material for a series of antibiotics such as mytomycin.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing indole derivatives, particularly 5-hydroxyindole derivatives having a ring structure.

(Prior Art) A number of synthetic methods have been studied for indole derivatives, which are well known to have various physiological activities, from the viewpoint of pharmaceutical use. For example, the Fischer method,
B15chler method, Re5sert method or Nen
Synthesis methods such as the 1tzescu method are well known.

For these reactions, detailed reaction conditions and starting materials have been studied, and the reaction mechanisms have also been studied in detail.

For example, in the Fischer method, a simple method is to use hydrazine as a starting material, pass through hydrazone, and then react with an acid while heating.

However, what is produced is a 5-methoxy form, and it is difficult to easily obtain an indole having a hydroxyl group at the 5-position. (Honben, Journal of the Organic Synthetic Chemistry Society 38694 (198
0)) In the Bischler method, α-anilinoketone is used as a starting material and an acid is applied at high temperature to perform a dehydration reaction.

When the reaction conditions are harsh and a cyclically substituted ketone is used, there is a problem in which a mixture of isomers with different substituent positions is unavoidable. Moreover, few attempts have been made to obtain 5-hydroxyindole. The Relssert method uses β-7minoethylphenols derived from the reaction of m-hydroxybenzaldehyde and nitroalkane as a raw material, and it is very difficult to introduce a substituent into the 3-position of the indole ring. The method involves reacting a benzoquinone derivative with an enamine. Indole having a hydroxyl group at the 5-position is produced, but the yield is extremely low. The enamines used include
An electronic withdrawing group is essential for the double bond. For this reason, the indole derivatives produced are limited to compounds in which an electron-withdrawing group such as an acyl group or an alkoxycarbonyl group is introduced at the 3-position. (A l l e n, J, A
m, Chem, Soc.

88 2536 (1966)) A general method for producing an indole ring is described by Sumpte “He
terocyclic compounds wi
th Indole and Carbazol
e Systems 1954 Intersc
ience New York” and Hou l i
han, l n d o l e s PART T
Familiar with HREE1979 etc.

As another method, 5-hydroxy-3-methylindole has been synthesized by oxidizing an indole ring precursor such as cyhydroscatole with potassium nitrosone sulfonate.

However, this method has the drawbacks of complicated operations and low yield.

In particular, indole derivatives having a hydroxyl group at the 5-position, a cyclic bond (bonded at the 2-position and the 3-position), and indole derivatives according to the present invention are buffothiorzne.

dehydrobufoterzne, oxabaz
ole, methoxyhalmalane, ha 1
mal i ne,, methoxytetorah
ydorohalmalane, lb.

It is an important compound as a synthetic intermediate for various medicines and alkaloids such as gain and sarpagine, and as a raw material for a series of antibiotics known as mitomycin group compounds, and the development of a simple method for its synthesis has been awaited.

(Objective of the Invention) The object of the present invention is to achieve the following by simple operation and under mild conditions.
The object of the present invention is to provide a method for producing an indole derivative having a cyclic bond, particularly an indole derivative having a hydroxyl group at the 5-position and bonding between the 2- and 3-positions, with a good yield.

(Structure of the Invention) The object of the present invention is to react with a 5-hydroquine-N-substituted (3,4-cyclic) phenol derivative having an αβ-unsaturated cyclic heavy bond at the m-position with a cyazonium salt. This was accomplished by developing a method for producing indole derivatives.

The production method of the present invention can be expressed as a reaction formula as follows.

However, R, R, and R represent a group selected from a hydrogen atom, an alkyl group, a halogen atom, an alkenyl group, an alkyl group, an aryl group, an acyl group, an aralkyl group, and the like. A hydrogen atom or a group that leaves in a diazo coupling reaction may be attached to the p-position of the hydroxyl group. R,
, R, are 4 to 1 consisting of nonmetallic atoms bonded to each other
Forms a two-membered ring. This ring may also form part of another cyclic structure. Further, a nitrogen atom, sulfur atom or oxygen atom may be included between ring members or in a substituent. R7 represents a diazonium salt residue. ×
represents an anion.

As can be seen from this reaction formula, the method of ring formation in the reaction of the present invention is completely different from that of the conventional method. The advantage of indole synthesis is that it is easy to handle and provides high yields under mild conditions because it does not include any steps that produce by-products such as water, alcohol, or amines, and uses a diazo coupling reaction that proceeds at low temperatures. There is.

Furthermore, due to the specificity of the reaction, even if R,, R, has a cyclic structure and further has a substituent, the position of the substituent
has the great advantage that it is uniquely determined according to the original double bond.

In the present invention, it is not clear why an indole ring is formed from a phenol having a highly strained cyclic unsaturated bond, or through what intermediates it is formed.

The present inventors discovered that after a diazo coupling reaction occurs at the p-position of a hydroxyl group, proton transfer occurs through the keto type of the main nonimine type, and β of the unsaturated bond.
It is speculated that an indole ring is formed only with the participation of a hydrogen atom in this position.

Examples of phenol derivatives having an αβ unsaturated cyclic double bond at the m-position in the method of the present invention include the following.

Preferably, the phenol has a carbon-carbon unsaturated double bond at the m-position and one hydrogen atom at the β-position of the unsaturated bond. As for the ring structure, a 4- to 12-membered ring structure is used, and particularly preferred are cycloalkanes, azacycloalkanes, oxacycloalkanes, thioxacycloalkanes, etc. having substituents.

For example, cycloalkanes, azacycloalkanes, diazacycloalkanes, oxacycloalkanes or thioxacycloalkanes substituted with one or more alkyl groups, alkoxy groups or halogen atoms are particularly preferred. These may form salts and quaternary salts. Among them, 6- to 8-membered ones are preferable in terms of yield and have the advantage that raw materials can be procured advantageously.

Specific examples include 3-cyclopentenylphenol, 3
-Methylcyclohexenylphenol, 3-dimethylcyclohexenylphenol, 3-trimethylcyclohexenylphenol, 3-tetramethylschiffOhexenylphenol, 3-chlorocyclohexenylphenol,
3-dimethylchlorocyclohexenylphenol, 3-
Trimethylmethoxycyclohexenylphenol, 3-tetramethylcyclo-predominant dienylphenol, 3-chloromethylcyclohexenylphenol, 4-m-hydroxyphenylcyclohexenecarboxylic acid, 3-m-hydroxyphenylcyclooctene, 4- m-hydroxyphenyl-N-methyltetrahydropyridine, 4-m-hydroxyphenyl-N-butyltetrahydropyridine,
4-m-hydroxy-p-methoxyphenyl-N-methyltetrahydropyridine, 4-m-hydroxyphenyl-
N-benzyldihydropyridine, 3-m-hydroxy-
p-chlorophenyl-N-butyltetrahydropyridine, 2-m-hydroxy-p-ethoxyphenyl-N-2
-ethylhexyltetrahydropyridine, 4-m-hydroxyphenyl-N-benzyltetrahydropyridine,
2-m-hydroxyphenyldihydronaphthalene, l-
m-hydroxyphenyl-4-benzyldihydronaphthalene, 4-m-hydroxyphenyl-1-oxacyclohexene, 4-m-hydroxyphenyl-1-thioxacyclohexene, 4-m-hydroxyphenyl-N-
cumyldihydropyridine, l-m-hydroxyphenyl-3,3-dimethylcyclohexene, l-m-hydroxyphenyl-3,3,5-trimethylcyclohexene,
4-m-hydroxyphenyl-N-cinnamoyldihydropyridine, l-m-hydroxyphenylcycloheptene, 4-m-hydroxyphenyl-N-penzyldihydroquinoline, 3-m-hydroxy-p-methylphenyl-N- Butyldihydroquinoline, 2-m-human Oxy p-methoxyphenyl-N-cinnamyltetrahydropyridine, 4m-hydroxyphenyl-N-benzyl-N
Methyltetrahydropyridinium chloride, 4-m-
Examples include hydroxyphenylcyclohexene-1,1-ethylene diketal.

These compounds are synthesized using various techniques. For example, techniques such as dehydration or deacetic acid treatment after synthesizing the secondary or tertiary alcohol are convenient. Secondary or tertiary alcohols can be obtained according to Grignard reactions, reduction reactions, etc. (Refer to the Round Cover of the Experimental Chemistry Course) On the other hand, the components that perform the diazocambling reaction are:
Conventional diazonium salt-forming compounds are advantageously utilized. Aromatic amines are particularly advantageous. The aromatic ring may be a Hensen ring or a naphthalene ring composed of carbon atoms, or a ring containing one or more nitrogen atoms, oxygen atoms, sulfur atoms, etc., such as a pyridine ring, thiazole ring, or furan ring containing a petro atom. Furthermore, a fused ring such as a benzothiazole ring or a hensifuran ring may also be used.

Furthermore, these aromatic rings contain one or more alkoxy groups, alkyl groups, aryl groups, alkenyl groups, sulfo groups, dialkylamino groups, nitro groups, alkoxycarbonyl groups, halogen atoms, thioalkoxy groups, hydroxy groups, alkoxycarbonyl groups, etc. May be replaced. Aromatic amines having at least one amino group capable of forming diazonium salts are advantageously used.

Specific examples include aniline, anisidine, chloraniline, phenetidine, dichloromethylaniline, toluidine, nidroaniline, aminobenzoic acid, aminobenzenesulfonic acid, aminonaphtholcarboxylic acid, α-aminonaphthalene 4-sulfonic acid, diaminobenzene,
Aminobenzothiazole, aminocoumarin, aminocarbazole, aminomethylnaphthyridine-2-thiol, N-4-amino-2-methylphenyl-4-chlorophthalimide, paramineflu B, aminoazobenzene,
Examples include aminomethoxypyridine, aminomethylhendithiazole, aminonaphtholcarboxylic acid, aminonaphtholcarboxylic acid, aminonaphthoic acid, xylidine, p-methoxyphenylazobenzene, trichloroaniline, dimethylaminophenylenediamine, and the like.

The diazotization reaction is carried out under conventional conditions.

The diazotization reaction is already well known as a unit operation, and detailed information can be found in books.

For example, Zollinger Azo and D.
iazochemistry” 1961ntersc
It is described in detail and can be referred to in the ieence Pub, New York.

Further, the substituent at the 1-position of the indole derivative obtained as above undergoes an elimination reaction quantitatively by catalytic reduction. In the reduction reaction, various catalysts including Pd, Nyam, Zn, etc. can be used.

The reduction reaction can also be carried out under pressure of hydrogen gas.

Synthesis Example 1 l-m-methoxyphenylcyclohexanol obtained from m-methoxyphenylfuromite and cyclohexanone was synthesized by M, Carissini rArzeimFor
sch, 26 506 (1976) J, using pyridine hydrochloride as a catalyst, treatment was carried out at 195°C for 3 hours to obtain l-m-hydroxyphenylcyclohexene.

Synthesis Example 2 l-m-methoxyphenylcyclopentanol obtained from m-methoxyphenyl bromide and cyclopentanone was treated in the same manner as in Synthesis Example 1 to produce l-m-hydroxyphenylcyclopentene as white crystals, 88.5~ 89.5
It was obtained as ℃.

Hereinafter, the method of the present invention will be explained in detail by giving examples.

(Embodiments of the Invention) Example 1 60 ml of methanol, 100 ml of acetone, and 0.01 mol of 1-m hydrobovine diphenylcyclophenol were weighed into a Niro flask equipped with a stirrer and a thermometer. While supplying nitrogen gas, add 2.9 g of caustic solution and 5 ml of water, and mix well. Below 10 degrees, this is 0.93
A diazonium salt prepared using gram of aniline and 0.72 grams of sodium nitrite is added in 15 minutes, then stirred for 1 hour at 5 degrees.

After neutralizing with ice-cooled diluted hydrochloric acid, the mixture was extracted with ethyl acetate. Using silica gel as a carrier, hexane and
The mixture was separated using an ethyl acetate mixed solvent as a developing solvent. When treated with a mixed solvent of benzene and hexane, the melting point is 170-1.
Provided 1.6 grams of 9-anilino-1,2,3,4-tetrahydro-6-hydro-oxycarbazole at 72°C.

Claims (1)

[Claims] A method for producing a 5-hydroxy-N-substituted indole derivative, which comprises reacting a phenol derivative having an αβ unsaturated cyclic double bond at the m-position with a diazonium salt.