JPS6229573A - Production of carbostyril derivative - Google Patents

Abstract

PURPOSE:To obtain in high yield the titled novel high-purity compound useful as an intermediate for a cyan coupler for photography without forming by- products, by nitrating an easily obtainable 8-chloro-3,4-dihydro-5-hydro xycarbostyril derivative as a raw material. CONSTITUTION:A 8-chloro-3,4-dihydro-5-hydroxycarbostyril derivative shown by the formula I (R<1> and R<2> are H or aliphatic group) is used as a raw material and nitrated with a nitrating agent (preferably a mixed solution of nitric acid and conc. sulfuric acid or mixed solution of nitric acid and glacial acetic acid; the amount of nitric acid is preferably 1.1mol-1.3mol based on 1mol compound shown by the formula I), to give a novel compound shown by the formula. The starting compound shown by the formula I, for example, is synthesized by a ring formation reaction of an acrylic amide shown by the formula III (R<3> is H or aliphatic group) or by a ring formation reaction of a compound shown by the formula IV (X is Cl or Br).

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides 8-chloro-3°4-dihydro-5-
The present invention relates to a method for producing hydroxy-6-nidrocarpostyryl derivatives.

(Prior Art) The carbostyril derivative which is the object compound of the present invention has the general formula CI) α (wherein R1 and R2 represent a hydrogen atom or an aliphatic group,
).

The compound represented by the general formula (1) is a compound that has not been described in any literature, and therefore the method for its production has also not been published in any literature. is a special public official in 1974-39.
No. 694, Special Publication No. 1977-39695, Special Publication No. 1977-3
No. 8789, JP-A-57-146759, JP-A-57
-149270, Chemistry and φ Industry (London) (Chew, lnd, (London)
on), ) (1976) 1435. Pharmaceutical Journal 96,
571 (1976).

That is, JP-A-57-146759 and JP-A-57
The method of No. 149270 involves cyclization according to the following process formula (1), followed by dehydrogenation, and 3゜4-dihydro-5-
Hydroxycarbostyril is obtained.

Reaction process formula (1) Also, Tokuko No. 46-39694, Tokuko No. 46-3969
No. 5, Special Publication No. 46-38789, Chemistry and Industry (1976) 1435, the method is as follows:
This relates to the dehydrogenation reaction of reaction scheme (1).

(Problems to be Solved by the Invention) However, as an intermediate for a photographic cyan coloring agent, a nitro group at the 6-position and a chlorine group at the 8-position are further required, and the method of the above reaction scheme (1) Using 6-chloro-3,
When synthesizing 4-dihydro-8-hydroxycarbostyryl derivatives, nitro and chloro groups have to be introduced regioselectively later in 3,4-dihydro-5
-The nitration of hydroxycarbostyryl is described in JP-A-51-6971, but the following reaction process formula (
As shown in 2), the ratio between the 6th and 8th positions and the nitro body is approximately -2:1.
It is obtained as a mixture of 1-regioselectivity and cannot be said to be an efficient production method.

Reaction Scheme (2) Also, for chlorination at the 8-position, a production method with high regioselectivity has not yet been found.

Therefore, it is difficult to efficiently produce the carbostyril derivative represented by the general formula (r) by applying the conventional method for producing carbostyril derivatives.

Therefore, easily available compounds can be used as starting materials,
There is a need for the development of a method for producing carbostyril derivatives that can be applied industrially to stool.

An object of the present invention is to provide a method for producing easily and in high yield a carbostyryl derivative having a nitro group at the 6-position and a chlorine group at the 8-position, which is useful as an intermediate for a cyan coloring agent for color photography. be.

(Means for Solving the Problems) In order to develop a method for producing a novel carbostyril derivative represented by the above-mentioned general formula (r), the present inventors have conducted various studies and found that the known compound Using 2-chloro-5-methoxyaniline or 3-amino-4-chlorophenol derived from available 1-chloro-2-nitro-4-methoxybenzene by a conventional method as a starting material, one molecule is free. Carbostyryl derivatives can be efficiently produced by the Delu-Cluff reaction, and this method can completely solve the problem regarding the selectivity of the substitution positions of the nitro group and chlorine atom of 5-hydroxycarbostyryl derivatives. 8-chloro-3,4-dihydro-5 via chloro-3,4-dihydro-5-hydroxycarbostyryl derivative (general formula (■) below)
It has been found that -hydroxy-6-nitrocarpostyryl derivative (general formula (I)) can be produced in high yield.

That is, the present invention provides an 8-
In producing chloro-3,4-dihydro-5-hydroxy-6-nitrocarpostyryl derivatives, 8- represented by general formula (II) (wherein R and R2 have the same meanings as above) Provided is a method for producing an 8-chloro-3,4-dihydro-5-hydroxy-6-nitrocarpostyryl derivative, which comprises nitrating a chloro-3,4-dihydro-5-hydroxycarpostyril derivative. It is.

8 represented by the general formula (II) used in the present invention
The method for preparing the -chloro-3,4-dihydro-5-hydroxycarbostyryl derivative is not particularly limited. is a hydrogen atom or an aliphatic group, and is obtained by subjecting an acrylamide derivative represented by to a cyclization reaction.

Further, the 8-chloro-3,4-dihydro-5-hydroxycarbostyryl derivative represented by the general formula CH) in n17 used in the present invention is the general formula (IT), (V) or (V
I) (rV) (V) cVI) (R
, R and R3 have the same meanings as above.

R4 represents a hydrogen atom or an aliphatic group, and X represents a chlorine atom or an atom.

A method for producing a carbostyril derivative to which the method of the present invention is applied can be represented by the following formula (3).

Reaction process formula (3) (In the formula, R1, R2, R3, R4.

Hydrogen atom or aliphatic group R5: -CH=C-R'! X: chlorine atom or bromine atom) Next, each step will be explained in detail. The amidation reaction in Step 1 can be carried out by a commonly known method. That is, the reaction is carried out using the corresponding carboxylic acid or its acid halide. When a carboxylic acid is used, a known dehydrating agent is used at the same time. As the dehydrating agent, for example, thionyl chloride, phosphorus pentachloride, dicyclohexylcarbodiimide, acetic anhydride, polyphosphoric acid, etc. are used, and thionyl chloride is particularly preferred. The solvent is preferably an aprotic polar solvent, such as acetonitrile, N, N
-Dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethylsulfoxide or a mixed solvent thereof can be used, but particularly preferred is a combination of acetonitrile and N,N-dimethylformamide or N,N-dimethylacetamide. It is a mixed solvent, and its mixing ratio can be determined arbitrarily.

In step 2, cyclization can be carried out by a Friedel-Crach reaction using aluminum chloride. A solvent may or may not be used. As a solvent, a halogenated hydrocarbon (for example, methylene chloride, ditaloloethane, etc.) or nitrobenzene can be used.9 The reaction temperature is 90°C to 160°C in the case of no solvent. When a solvent is used, the boiling point range of the solvent used is preferably selected from 25°C. In general formula (II), R1,
When synthesizing a compound in which neither R2 is a hydrogen atom, it is preferable to use a precursor represented by the general formula (m), and in this case, the amount of aluminum chloride used is
) is preferably 2.5 to 3 times molar. When synthesizing a compound in which R1 and/or R2 are hydrogen atoms in general formula (II), general formula (■)
.

It is preferred to use a precursor represented by (V) or (Vl), and in this case the amount of aluminum chloride used is 3.5% relative to (IV), (V), (VT).
The other reaction conditions, which are preferably 5 to 4 times the mole, can be appropriately determined according to the general Friedel-Krach reaction conditions.

The nitration reaction in step 3 can be carried out using a known nitration agent. Examples of nitrating agents that can be used include concentrated nitric acid, nitric anhydride, nitric acid and concentrated sulfuric acid, acetic anhydride,
Alternatively, examples include a mixture with glacial acetic acid, a mixture of sulfuric acid and a nitrate such as potassium nitrate or sodium nitrate, and the like. Among these, preferred is a mixture of nitric acid and concentrated sulfuric acid or glacial acetic acid. The amount of nitric acid used is 1 to 2 times the mole of (II), preferably 1.1 times to 1.3 times the mole.

(Effects of the Invention) According to the present invention, carbostyril derivatives (general formulas (1) and (I)
I)) can be obtained. For example, the reaction formula (0
As shown in , after two steps from the compound of general formula (I),
Color Photography - A cyan coloring agent with excellent heat fastness and light fastness, which are important properties, can be produced.

Reaction scheme (4) (R, R2 dihydrogen atom or aliphatic group R6: oil-solubilizing group) Furthermore, according to the production method of the present invention, the above-mentioned useful
The known compounds 2-chloro-5-methoxyaniline or 3-amino-4-chlorophenol (
These can be easily synthesized from available 1-chloro-2-nitro-4-methoxybenzene by conventional methods. ), it can be obtained in high yield, and since there are few by-products in each step, it can be extracted as crystals with good purity, so it is suitable as an industrially implemented method.

(Examples) Next, the present invention will be described in more detail based on Examples.

8-chloro-3,4-dihydro-5-hydroxy-4,
Synthesis of 4-dimethyl-6-nitrocarpostyryl (1) N-(2-chloro-5-methoxyphenyl)-3
, Synthesis of 3-dimethylacrylic acid amide 3. 16.2 g of 3-dimethylacrylic acid was mixed with 30 mjl of acetonitrile and 10 mJ of N,N-dimethylacetamide.
1 of a mixed solvent, and 13 mM of thionyl chloride was added dropwise while cooling with water. After stirring for 1 hour, a solution of 30.0 g of 2-chloro-5-methoxyaniline in 0 mft of acetonitrile was added. IO min t11 N Stir, 32 ml of pyridine
was added. After stirring for 40 minutes at a temperature ranging from 30°C to 40°C, the mixture was poured into water and extracted with ethyl acetate. The product 11 obtained by evaporation of the solvent was purified by silica gel chromatography (eluted with n-hexane/ethyl acetate = 10) to give N-(2-chloro-5-methoxyphenyl)-3, 32.8 g of 3-dimethylacrylic acid 7amide was obtained as a white solid.

NMI'? δ (C00 sentence,): 8.12 (d, J=3.0Hz, IH) 7.53
(s, 18) 7.13 (d, J=9.0Hz, IH) 6.53
(d, d, j=9.0.3.0Hz, IH)5.
87~5.57 (ts, IH) 3.75 (s,
3H) 2.22 (s, 3H) 1.90 (s, 3H) (2) Synthesis of 8-chloro-3,4-dihydro-5-hydroxy-4,4-dimethylcarbostyryl N-(2-chloro -5-methoxyphenyl)-3,3-
Dimethyl acid amide 22.3g dichloroethane 67mJ
37.2 g of aluminum chloride was added little by little at room temperature. The reaction temperature in the is hot bath was set to 60°C,
The 0 reaction solution reacted for 1 hour was poured onto ice and extracted with methylene chloride. After washing the organic layer with water and drying, the solvent was evaporated, and ethyl acetate was added to the obtained brown solid to perform re-crystallization. The precipitated crystals were collected by filtration, washed with a small amount of ethyl acetate, and then dried to obtain 10.5 g of the title compound (colorless crystals with a melting point of 185-186°C).

NMRδ (COO view.) Near, 88 (s, IH) 7.00 (d, J=9.0Hz, IH) 6.87
(s, IH) 6.38 (d, J”1.OHz, IH) 2.50
(s, 2H) 1.47 (s, 6H) Elemental analysis Measured value H: 5.33 C: 58
．． 39N: 6.55 CKL: 15.87 Calculated value H: 5.38 C: 58.54N: 6.2
1G: 15.71 (3) Synthesis of 8-chloro-3,4-dihydro-5-hydroxy-6-nitro-4,4-dimethylcarbostyryl 8-chloro-5-hydroxy-4,4-dimethylcarbo Styryl IO,Og was dissolved in 100 mJ1 of glacial acetic acid, and 4.85 g of concentrated nitric acid was added dropwise over 20 minutes while stirring at room temperature.

The mixture was cooled with ice water, and the precipitated yellow crystals were collected by filtration, washed with acetonitrile, and then dried. 11.0 g of yellow crystals with a melting point of 217-218°C were obtained.

NMR (DMSO-d6) δ: 11.10 Cs,
IH) 9.93 (s, 1H) 8.08 (s, IH) 2.50 (s, 2H) 1.42 (s, 8H)

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 and R^2 represent a hydrogen atom or an aliphatic group.) 8-chloro-3,4-dihydro In producing -5-hydroxy-6-nitrocarbostyryl derivatives, there are general formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ (wherein, R^1 and R^2 have the same meanings as above). A method for producing an 8-chloro-3,4-dihydro-5-hydroxy-6-nitrocarbostyryl derivative, which comprises nitrating an 8-chloro-3,4-dihydro-5-hydroxycarbostyryl derivative. (2) 8-chloro-3,4-dihydro-5-hydroxycarbostyryl derivative has the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^1, R^2 and R^3 are hydrogen 8-chloro-3,4-dihydro-5- according to claim 1, which is obtained by a cyclization reaction of an acrylamide derivative represented by (representing an atom or an aliphatic group) Hydroxy-6-
Method for producing nitrocarbostyryl derivatives. (3) 8-chloro-3,4-dihydro-5-hydroxycarbostyryl derivative has the general formula ▲ mathematical formula, chemical formula, table, etc. ▼, ▲ mathematical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3 and R^4 represent hydrogen atoms or aliphatic groups, and X represents chlorine atoms or , representing a bromine atom. −
Method for producing nitrocarbostyryl derivatives.