JPS5922702B2 - Method for producing novel ortho-nitrobutylphenone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel ortho-nitrobutylphenone derivative.
is the general formula (a) (however, the dotted line indicates that the position between the 3 and 4 positions of the piperidine ring is a saturated bond or a double bond, and R1 exists only when the position between the 3 and 4 positions of the piperidine ring is a saturated bond). a hydrogen atom or a hydroxyl group, and R2 is a phenyl group substituted on the benzene ring with one or two substituents selected from a hydrogen atom, a halogen atom, a lower alkyl group, and a trifluoromethyl group. Hail.

) or general formula (b) (However, R3 is a phenyl group substituted with a lower alkoxy group.

) or formula (c) or formula (d) Or a morpholino group (-N(〉O)).

The present invention relates to a method for producing a novel ortho-nitrobutylphenone derivative and an acid addition salt thereof.
More specifically, the present invention is based on the general formula [] [wherein R is as described above and Y is a halogen atom or the general formula 0C0R1 (provided that RlO is a lower υ-class alkyl group).

)] and a rose-R monosubstituted-orthonitrobenzoic acid derivative represented by the general formula [I] (wherein Rll represents a lower alkyl group).

) is reacted with a lactone derivative of the general formula O] (wherein R and Rll are as described above) in the presence of a basic condensing agent.

) and/or a compound represented by the general formula [] (wherein R is as described above), and the compound represented by the above [] is subsequently prepared by:
By treating this with a dilute alkali, a compound having the general formula [] is obtained, and then a compound having the general formula [] obtained above and the general formula H-X (wherein, X represents a halogen atom) vinegar.

) is reacted with a hydrohalic acid obtained by the general formula u] (wherein R and X are as described above).

) by protecting the carbonyl group of the compound with the carbonyl protecting group as necessary, the general formula [](
In the formula, W represents an oxygen atom or a carbonyl group protected with a carbonyl group protecting group at C═W, and R and X are as described above.

), which is then converted into a compound of the general formula H-
Z (wherein Z is as described above.

), and when C═W is a protected carbonyl group, the protecting group is subsequently removed. This is a new method for producing orthonitrobutylphenone derivatives.

That is, the method of the present invention can be illustrated as follows.

(Note) The general formula [匍] is a formula containing the general formula [] and (4). The present inventors have continued intensive research on the synthesis of ortho-nitrophenyl ketone derivatives, and as a result, they were able to synthesize this by method 1 of the present invention, and the The present invention was completed by discovering that the compound has an excellent central nervous system depressing effect.

In addition, since the object compound [1] of the present application can be further converted into another useful medicine, it also has utility as an intermediate.
It is something that Therefore, an object of the present invention is to provide an industrially advantageous method for producing a series of novel compounds of high pharmaceutical value.

In the above general formula, a halogen atom means a difluorine, chlorine, bromine or iodine atom, and the halogen atom represented by R is preferably a fluorine atom.

The lower alkyl group and lower alkoxy group are linear or branched hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. and an alkoxy group consisting of these. From the reaction between general formula [] and general formula [], which is the first step of the method of the present invention,
The step of obtaining the 5-ortho-nitrobenzoyl lactone compound represented by the general formula [] is carried out in an inert solvent using a basic condensing agent, but various changes are possible in the embodiment.

First, as the basic condensing agent, metal lower alkoxides (for example, sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide, potassium tert-butoxide, magnesium ethoxide, magnesium methoxide, etc.) are used. .

), alkali metal hydrides (for example, sodium hydride, lithium hydride, etc.), alkali metal amides (for example, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, etc.), Examples include triphenylmethane metal salts (for example, sodium or lithium salts of triphenylmethyl) and sodium, potassium, or lithium salts of methylsulfinyl carbanion.

Among these, lower alkoxides of metals, especially magnesium alkoxides, can be mentioned as one of the most advantageous methods. This is carried out by bringing the compound into contact with an agent and then reacting the compound of the general formula [].

Examples of inert solvents include ethers (for example, diethyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (
Solvents that do not participate in the reaction are widely used, such as benzene, toluene, xylene, etc.). In addition, the halogen atom represented by Y in the above general formula [] is preferably a base or bromine, and the group -0C00R
As 10, a group in which RlO is methyl or ethyl is suitable. Furthermore, in the general formula [], Rll
Methyl is preferred because of its ease of availability.

The reaction was carried out in the range of about equivalent to 3 times the equivalent of compound [] to the basic condensing agent, and the amount of compound [] was 0 to that of compound [].
．． It can be used in a range of 2 to 2.0 times the equivalent, and the progress of the reaction can be adjusted by promoting or suppressing the reaction by heating or cooling as appropriate depending on the ease of reaction. .

After the completion of the reaction, the product can be isolated and purified by conventional chemical means, but depending on the generally used reaction and post-treatment conditions, the product may be a mixture of the target compound, general formula [], and intermediate products. It is a mixture of various compositions of compounds represented by the general formula [], and either one can be obtained almost as a single product.

Therefore, in general, when intermediate products [ ] are obtained as main products and when they are present to a significant extent, the resulting products are subsequently treated with dilute alkalis (e.g. ammonia, alkali metal hydroxides, alkali metal carbonates). It is advisable to deacylate the compound by treating it with a solution or suspension in water, alcohol, or an inert organic solvent (such as a solution or suspension in water, alcohol, or an inert organic solvent) to lead to the target compound of the general formula.

Next, the reaction between the lactone derivative of general formula [v] and hydrogen halide (HX), which is the second step of the method of the present invention, is generally carried out easily and in high yield by simply heating an aqueous solution of hydrohalic acid. A γ-halobutylophenone skeleton of the formula [] can be produced.

In addition, in the above HX, chlorine, bromine or iodine is used as halogen X. This step can be carried out in various embodiments, i.e., with at least an equivalent amount of hydrochloric acid, hydrobromic acid or hydriodic acid, directly or with a solvent that does not participate in the reaction (e.g. selected from ethers, aromatic hydrocarbons, ketones, etc.). This can be carried out by heating the mixture to room temperature or higher; however, for the purpose of promoting the reaction, it may be heated to 50°C or higher directly with 3 or more equivalents of hydrogen halide or in the coexistence of a solvent that does not participate in the reaction. This can be carried out suitably. After the completion of the reaction, the target product can be isolated and purified by ordinary chemical means, but in general, the γ-halogen of the general formula -4-Fluoro-2-nitrobutylphenone can be obtained.

Finally, the γ-halogen 4 of the general formula [] obtained in this way
-Fluoro-2-nitrobutylphenone with the general formula H-Z
It can be condensed with a secondary amine formed by 2 to lead to ortho-nitrobutylphenone [1], which is the target compound of the present invention.
It can be carried out by two synthetic routes.

That is, either the γ-halogenobutyrophenone represented by the general formula u] and the secondary amine H-Z are directly condensed, or the carbonyl group in the general formula [] is protected in advance (
4), and then condensed with a secondary amine H-Z, followed by removal of the protective group to produce the γ-(orthonitro-substituted butylphenone derivative of general formula [1]). Any protecting group for the carbonyl group mentioned above may be used as long as it can be easily removed by hydrolysis etc.
For example, dimethyl ketal, diethyl ketal, hemithioketal, cyclic thioketal, Schiff's base, enol esters, etc. "Advance in Organic Chemistry Volume 1, pp. 258-268 (19
(Published by John Willy End Sons in 1963)
Among these, cyclic ketal-protected groups such as ethylenedioxy are preferred from the viewpoint of ease of handling and availability of raw materials.

When protecting with ethylenedioxy, in addition to the usual ketalization method in which the water produced under acid catalyst is azeotropically dehydrated, ethylene sulfide, orthoesters, or molecular sieves can be used as a water remover. It can also be done using General formula [] (i.e. general formula [] or C
The condensation reaction between the compound VU)) and the secondary amine H-Z is
For example, it can be carried out without a solvent or using an inert solvent in the presence of an alkali carbonate, an alkali bicarbonate, a caustic alkali, or a suitable basic condensing agent such as pyridine, triethylamine, dimethylaniline. Solvents that do not participate in the reaction are widely used as solvents, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), ether solvents (tetrahydrofuran, dioxane, etc.)
, lower alkanones (acetone, methyl ethyl ketone, 4
-methyl-2-pentanone, etc.), lower alcohols (
(ethanol, propanol, etc.), dimethylformamide, etc. In general, starting materials [ ] and secondary amines (
H-Z) is reacted in approximately equivalent amounts, but it can also be carried out using approximately 2 equivalents of secondary amine without using the above-mentioned basic condensing agent, and it is generally preferable to use starting material (4) in slight excess. Can be implemented. The progress of the reaction can be adjusted as appropriate in the temperature range from room temperature to the boiling point of the solvent depending on the ease of reaction, but generally when using the ketone body u], the reaction is carried out at a low temperature from room temperature to 9. It is preferable to do so. General formula [V
] is used as a starting material, the protecting group for the carbonyl group of the resulting condensation product (general formula []) is subsequently hydrolyzed by a method depending on the protecting group to obtain the general formula [1].
] can be obtained.

Although the protective group can be removed by a conventional method, for example, hydrolysis of ethylenedioxy or the like can usually be achieved by heating for a short time in the presence of a mineral acid such as hydrochloric acid or sulfuric acid. The novel orthonitrobutylphenone derivative of the general formula [1] thus obtained can be converted into a pharmaceutically acceptable acid addition salt with an inorganic acid or a strong organic acid.

The acid may be any pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, citric acid, malic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, succinic acid, glycolic acid, and benzoic acid. , cinnamic acid, salicylic acid, etc. The most closely related known compound to the ortho-nitrobutylphenone derivative produced by the present invention is a γ-piperazine-ortho-nitrobutylphenone derivative described in U.S. Pat. No. 3,562,277. Specifically, γ-(4-phenylpiperazino)-2-nitro-
4,5-dimethoxybutylphenone is only mentioned as the only compound.

The patent also states that these orthonitrobutylphenone derivatives were inactive on the central nervous system.
However, the present inventors have discovered that the general formula [
It was discovered that the ortho-nitrobutylphenone derivative (1) has a surprisingly excellent central nervous system depressing effect,
This completes the present invention.

The compounds of the present invention demonstrate activity in animal experiments by applying various pharmacological tests classified as central nervous system depressants. Therefore, due to these actions, the compounds of the present invention are useful as medicines, and have value as, for example, depressants, psychotic drugs, tranquilizers, sedatives, or analgesics. Preferred examples of psychosis therapeutic agents include compounds in which R in the general formula [1] is a hydrogen atom or a halogen atom (more preferably a fluorine atom); It has shown in animal experiments that it has a stronger and superior central nervous system depressing effect than chloropromacine, which is commonly used as a drug. Furthermore, although the above-mentioned US patent describes that ortho-nitrobutylphenone derivatives are produced by nitration, it is difficult to apply this to the compounds of the present invention if the nitro group is introduced at a different position. It would be expected to give a mixture of two nitro compounds, making industrial implementation difficult or impossible.

However, the production method of the present invention is not only a new method for industrially producing the compound of the present invention, which is difficult to produce, but also a butyrophenone derivative having various substituents on the benzene ring that are difficult to synthesize by conventional known methods for producing butyrophenone derivatives. It also provides a general synthetic method for producing . That is, as long as benzoic acid derivatives corresponding to the above general formula [] having various substituents are available, various butyrophenone skeletons can be synthesized using the γ-butyrolactone ring. The ortho-nitrobutylphenone derivatives obtained according to the present invention are also useful as pharmaceutical intermediates, and for example, by reducing the nitro group, ortho-aminobutylphenone derivatives, which are known central nervous system depressants, can be obtained. can be manufactured.

The compounds of the present invention can be applied as pharmaceuticals by preparing butyrophenone derivatives of the general formula [1] or their acid addition salts in various formulations such as tablets, sugar-coated tablets, granule capsules, suppositories, injection ampoules, etc. natural or synthetic carriers, diluents, lubricants, stabilizers such as glucose, sucrose, lactose,
It can be administered orally, rectally, parenterally, or locally in combination with starch, talc, magnesium stearate, casein, calcium phosphate, methylcellulose, ethylcellulose, gum arabic, polyglycol, tragacanth, distilled water, and the like. The active therapeutic dose varies as a function of the severity of symptoms, but approximately 0.001 in humans.
It is administered orally in the range of ~0.59.

Examples are given below to explain the present invention in more detail, but the embodiments of the present invention are not limited to these.

Example 1 (4) 0.8 g of metallic magnesium, anhydrous ethanol 3.
When 39 and 0.3 ml of carbon tetrachloride were mixed and allowed to stand, a violent exothermic reaction started several minutes later.

When the reaction has almost subsided, add 25wL1 of dry toluene.
was slowly added dropwise with stirring, and stirring was continued for further 3 hours at room temperature. Then α-acetyl-γ-butyrolactone 8.46
A solution of 9 in dry toluene (10 m0) was added dropwise at 0°C under ice cooling, and the mixture was further stirred at room temperature for 1 hour. To the resulting reaction solution, 5.559 g of 4-fluoro-2-nitrobenzoic acid and 17 m1 of thionyl chloride were refluxed for 2 hours. Then, a dry toluene (10mj) solution of 4-fluoro-2-nitrobenzoic acid chloride obtained by distilling off excess thionyl chloride under reduced pressure was added dropwise, and the mixture was further stirred at room temperature for 3 hours. Sulfuric acid water 70ml
was added dropwise under ice-cooling, and extracted with toluene. After washing the toluene extract layer with water, extract and separate the layers three times with cold 5% ammonia water, combine the resulting ammonia water layers, wash with toluene, and cool for 15 minutes.
% sulfuric acid water and cooled, the precipitated crystals were obtained by suction and filtration. By washing with water and drying under reduced pressure, α-(4-fluoro-2-nitrobenzoino(c)-1γ-butyrolactone) was obtained as crystals with a melting point of 87 to 89°C. (B) In the above example, metallic magnesium , ethanol, carbon tetrachloride instead of using ethoxymagnesium ((EtO)
The same compound was obtained by carrying out the same procedure using 2Mg) powder 3.439.

Melting point 86.5-89.0C Example 2 Magnesium metal 1.5f11 Absolute ethanol 8.5m
1. After 0.6 ml of carbon tetrachloride was allowed to stand for 10 minutes, stirring was started, and 45 ml of anhydrous ether was added dropwise.

After further stirring for 3 hours, a solution of 7.69 g of α-acetyl-γ-butyrolactone in anhydrous ether (5d) was added dropwise while cooling at 0'C, and the mixture was further stirred for 30 minutes. Next, anhydrous ether (12 m0 liquid) of 4-fluoro-2-nitrobenzoic acid chloride synthesized from 4-fluoro-2-nitrobenzoic acid of 13.149 using thionyl chloride was added dropwise at room temperature, and the mixture was further stirred for 3 hours.

70 ml of 10% sulfuric acid was added dropwise to the resulting reaction solution under cooling to decompose it, and a large amount of water was further added under cooling and stirred, and the precipitated crystals were collected in a suction furnace. After thorough washing with water and drying under reduced pressure, α-(4-fluoro-2-nitrobenzoyl)-γ
-Butyrolactone was obtained as crystals. Melting point 85-8
7℃. According to Example 1 or 2 above, α-(2-nitrobenzoino(c)-1γ-butyrolactone) was obtained. Melting point: 75
~77 (C0 Example 3 (4) α-(4-fluoro-2-nitrobenzoyl)
Mono-γ-butyrolactone 209 and hydrobromic acid (specific gravity 1.4
8) 66.69 was added, heated and stirred at 85° C. until no gas generation was observed, and further heated for 30 minutes.

After cooling, it was diluted with 300 ml of water and extracted with toluene. The toluene layer was washed with water, dried (sodium sulfate), and concentrated under reduced pressure to obtain γ-bromo-4-fluoro-2-nitrobutylphenone. Yield: 21.79 (yield: 95%)
). This product contains only a very small amount of impurity at the origin on the thin layer chromatogram (silica gel-benzene development). When vacuum distillation is performed to find out the physical properties, the boiling point is 139-148℃ (0
．． 18 to 0.2011 Hg). (B) α-
Add 20 grams of concentrated hydrochloric acid to 5.069 grams of (4-fluoro-2-nitrobenzoinole)-γ-butyrolactone,
The mixture was heated and stirred at ~9'C).

After no gas generation was observed, the mixture was further heated for 30 minutes, cooled, and treated in the same manner as the diluted mixture with water to obtain γ-chloro-4-fluoro-2-nitrobutyphenone.
Yield 4.49 (yield 90 (F6)) When this product is distilled under reduced pressure, the boiling point is 132.0-132.5℃ (0.17-0.197
1&7! LHg).

The procedure was carried out in substantially the same manner as in Example 3 above to obtain γ-bromo-2-nitrobutylphenone as an oil. It solidified on cooling and had a melting point of 45-46°C. Example 4 (4) γ-Bromo-4-fluoro-2-nitrobutylphenone 1179, ethylene glycol 50f! , balatoluenesulfonic acid (hydrate) 7.7g and benzene 5
00ml was refluxed for 60 hours, during which time the water formed was separated in a Dean-Sta-Rke trap.

After cooling, the reaction solution was washed with water, diluted sodium bicarbonate solution, dried (mirabilite), and concentrated under reduced pressure to produce 4-bromo-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxybutane as an oil. obtained as. Yield: 1359 (yield quantitative) Nuclear magnetic resonance vector analysis of this product showed that the raw material content was extremely low and it was highly pure.

When this product is vacuum distilled, the boiling point is 0.171!1Hg and 135
The temperature was ~140°C. (B) γ-bromo-4-fluoro-2-nitrobutylphenone 2.99%, ethylene glycol 1.259%, ethylene sulfide 2.29%, valatoluenesulfonic acid hydrate 0.389%, and toluene 20%
m1 was heated under reflux for 9 hours.

After cooling, the mixture was diluted with 40 ml of 5% caustic soda water, the toluene layer was separated, and the aqueous layer was further extracted with toluene. The toluene extract layers were combined, washed with water, dried (with Glauber's salt), and then concentrated under reduced pressure to obtain 4-bromo-1-(4-fluoro- 2-nitrophenyl)1,1-ethylenedioxybutane was obtained as an oil. Yield 3.19 (yield 93
%) In the same manner as in the above example, 4-bromo-1-(2nitrophenyl)-1,1-ethylenedioxybutane was obtained as an oil.

Example 5 (A) 4-bromo-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxybutane 3.79
A catalytic amount of potassium iodide was added to 2.59 ml of 4-(3-trifluoromethylphenyl)-4-hydroxypiperidine, 1.49 potassium carbonate, and 20 ml of methyl isobutyl ketone, and the mixture was heated at 80 to 90°C for 2 hours. .

After cooling, the reaction solution was poured into 100 ml of water and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain 4-[4-(3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl].
-1-(4-fluoro-2nitrophenyl)-1,1-
Ethylenedioxybutane was obtained as a crude product (viscous syrup). (B) To the above crude product were added 27.59 g of isoprobanol and 27.59 g. of 20% hydrochloric acid water, and the mixture was heated under reflux for 1 hour.

By drying the reaction solution under reduced pressure and recrystallizing the resulting solid residue from isoprobanol (treated with activated carbon)
2.89 [4-(3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl]-4-fluoro-2-nitrobutyphenone hydrochloride was obtained. Melting point: 209-210.5°C;
59 crystals were obtained. Melting point: 205-209°C (two-step total yield: 70 (Ff)) When this product is made into a free base using a conventional method and reconstituted with aqueous ethanol, it has a melting point of 109-1.
It showed 12°C. Example 6 γ-bromo-4-fluoro-2-nitrobutylphenone 9.49, 4-(3-trifluoromethylpheno(ha)-4-hydroxypiperidine 7.19, potassium carbonate 4.09 and toluene) 60 ml of the solution was stirred at room temperature for 10 hours.

The reaction solution was poured into water and extracted with toluene monoethyl acetate (1:1), and then this organic layer was extracted with 30% aqueous hydrochloric acid. γ-[4-(3-
Trifluoromethylphenyl)-4-hydroxypiperidin-1-yl]-4-fluoro-2-nitrobutylphenone was obtained as a crude candy-like substance. (Confirmed from thin layer chromatogram and instrumental data) Yield: 6.49 This was converted into a hydrochloride by a conventional method, and crystals completely matching the hydrochloride obtained in Example 5 were obtained in infrared absorption spectrum.

Melting point: 200-202°C Example 7 According to Example 5 or 6, 4-(3-trifluoromethylphenyl)-4-
By applying a suitable secondary amine in place of hydroxypiperidine, the following ortho-nitrobutylphenones were obtained in almost similar yields.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R represents a hydrogen atom or a halogen atom. ] The general formula obtained by reacting a compound represented by the formula H-X with a hydrohalic acid represented by the general formula H-X (wherein, X represents a halogen atom) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R and In the formula, W represents an oxygen atom or a carbonyl group protected with a carbonyl group protecting group at C═W, and R and
is as described above. ) was obtained, and then converted into a compound represented by the general formula H-
Z [In the formula, Z is represented by the following various general formulas, namely, general formula (a) ▲ Numerical formulas, chemical formulas, tables, etc. It represents a double bond, R^1 exists only when the 3rd and 4th positions of the piperidine ring are saturated bonds and represents a hydrogen atom or a hydroxyl group, and R^2 represents a hydrogen atom or halogen on the benzene ring. Represents a phenyl or benzyl group substituted with one or two substituents selected from atoms, lower alkyl groups, and trifluoromethyl groups. ) or general formula (b) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 represents a phenyl group substituted with a lower alkoxy group.) or formula (c) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or formula (d) ▲ mathematical formulas, chemical formulas, tables, etc. etc. ▼ Or represents a morpholino group (▲ There are mathematical formulas, chemical formulas, tables, etc. ▼). ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ which are characterized by reacting with a compound represented by the formula and then removing the protecting group when C=W is a protected carbonyl group ▼ In the formula, R and Z are as described above.) A method for producing an ortho-nitrobutyrophenone derivative and an acid addition salt thereof. 2 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents a hydrogen atom or a halogen atom,
Y is a halogen atom or the general formula OCOOR^1^0(
However, R^1^0 represents a lower alkyl group. ) represents. ] A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1^1 represents a lower alkyl group) is reacted with a compound represented by the general formula (A)
There are mathematical formulas, chemical formulas, tables, etc. ▼ Compounds represented by (A) (in the formula, R and R^1^1 are as described above) and/or general formula (B) ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Obtain the compound represented by (B) (in the formula, R is as described above), and then obtain the compound represented by (A) above by subjecting it to dilute alkali treatment. By doing so, a compound represented by the general formula (B) is obtained, and then a compound represented by the general formula (B) obtained above and a general formula H-X (wherein, X represents a halogen atom) is obtained. The carbonyl group of the compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R and X are as described above.) By protecting the carbonyl group with a protecting group, the general formula ▲mathematical formula, chemical formula, table, etc.▼ (In the formula, W is an oxygen atom or C=W represents a carbonyl group protected with a carbonyl group protecting group, R and X
is as described above. ) was obtained, and then converted into a compound represented by the general formula H-
When C═W is a protected carbonyl group, the protecting group is subsequently removed by reacting with a compound represented by Z (wherein Z has the same meaning as in claim 1). A method for producing an ortho-nitrobutyrophenone derivative and its acid addition salt represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R and Z are as described above.) .