JP2002338574A - Method for producing piperidylidene derivative having physiological activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing the piperidylidene derivative, remarkably improved in the number of production steps and yield. SOLUTION: This invention relates to a new method for producing a benzoxepino-11-piperidylidene represented by the general formula (wherein X is CH or N; X' is CH2 or O; X" is a group which does not participate in reaction; R represents an alkyl group substituted with an esterified or amidated carboxy group, a carboxyalkyl group, an unsubstituted alkyl group, an esterified or amidated carboxy group or carboxy group) and useful as an antiallergic agent. The method is characterized by reacting a benzoxepino compound with a piperidin-4-one compound in the presence of titanium having low valence.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a benzoxepino-11-piperidylidene compound or an intermediate thereof useful as an antiallergic agent.

[0002]

BACKGROUND OF THE INVENTION One of the compounds targeted by the present invention is Jo
urnal of Medicinal Chemistry Vol.38 No.3 p496〜507
And 3- [4- (8-fluoro-5,5) described in JP-A-06-192263.
11-dihydro [1] benzoxepino [4,3-b] pyridine-11-
(Ylidene) piperidino] propionic acid, which is an amphoteric antiallergic agent and exhibits selective histamine H1 receptor antagonism. The compound is disclosed in the above-mentioned publications as 2-cyano-3-bromomethylpyridine starting from 2-cyano-3-methylpyridine,
After producing 8-fluoro-5,11-dihydrobenz [b] oxepino [4,3-b] pyridin-11-one via 2-cyano-3- (3-fluorophenoxymethyl) pyridine, the 11-position Grignard reaction to the ketone group, followed by dehydration to produce 1-methylpiperidylidene, further liberating piperidylidene via 1-ethoxycarbonylpiperidylidene, and acrylate to form propionate, and further sodium hydroxide or It is manufactured by removing the ester group with an acid.

[0003]

The above-mentioned compounds exhibit excellent medicinal properties, maintain good stability, and have desirable properties as drugs. However, the number of steps from the benzoxepino compound to the final target product is low. In many cases, the yield is also a problem, and this has been a major obstacle to making it into a pharmaceutical product.

[0004]

Means for Solving the Problems The present inventors have known that the conventional production method has a large number of steps and the yield is also a problem. Therefore, first, the following steps after the tricyclic compound as the benzooxepino compound are considered. As a result of intensive studies, the present inventors have succeeded in developing a production method for obtaining a propionate and a free propionate in high yield directly from the tricyclic compound, and completed the present invention.

That is, the present invention provides a compound represented by the following general formula (1):

[0006]

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(Wherein X is CH or N; X ′ is CH ₂ or O; X ″ is a group not participating in the reaction), in the presence of low-valent titanium, General formula (2):

[0008]

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(Wherein R ′ represents an esterified or amidated carboxyl-substituted alkyl group, an unsubstituted alkyl group, or an esterified or amidated carboxyl group) Piperidine-
Reacting a 4-one compound, and optionally decomposing an ester bond or an amide bond, wherein the general formula (1):

[0010]

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(Wherein R represents an esterified or amidated carboxyl-substituted alkyl group, a carboxyalkyl group, an unsubstituted alkyl group, an esterified or amidated carboxyl group, or a carboxyl group. X, X ′ and X ″ are as defined above), a process for producing a benzoxepino-11-piperidylidene compound, a salt thereof or a hydrate thereof.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the compounds of the formulas (1) and (3), the group not participating in the reaction represented by X ″ includes a hydrogen atom, a halogen atom, an alkyl group and the like. Here, the alkyl group usually includes an alkyl group having 1 to 5 carbon atoms. Also, in the compounds of formulas (1) and (3), X is preferably nitrogen;
X ′ is preferably oxygen and X ″ is preferably a halogen atom. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom, and a fluorine atom is particularly preferable. In the compound of the formula (2), R ′
Is preferably substituted or unsubstituted with an esterified carboxyl group, having 1 to 5 carbon atoms, particularly 1 carbon atom.
Or 2 alkyl groups or esterified carboxyl groups. As the ester, methyl, ethyl, t-
Groups that are hydrolyzed under acid or alkaline conditions, such as alkyl groups such as butyl, and esters of alkoxyalkyl such as methoxymethyl and methoxyethoxymethyl, are preferred. In the compound of the formula (3), R is preferably an alkyl group having 1 to 5 carbon atoms, particularly an alkyl group having 1 to 2 carbon atoms, which is substituted or unsubstituted with an esterified carboxyl group, an esterified carboxyl group, Or a carboxyl group.
Here, the ester is preferably the ester described for R ′. Examples of the salt of the benzoxepino-11-piperidylidene compound of the formula (3) include halogen salts such as hydrochloride and bromate; and organic acid salts such as tartrate, methanesulfonate and citrate. , Preferably halogenates, especially hydrochlorides or bromates. The hydrates thereof (that is, the hydrates of the above-mentioned pyridylidene compounds and the hydrates of the salts of the above-mentioned pyridylidene compounds, in particular, the hydrates of the salts of the above-mentioned compounds) are mono- to di-hydrates. Things are typically illustrated.

The compounding molar ratio of the benzoxepino compound of the formula (1) to the piperidin-4-one compound of the formula (2) is usually 2: 1 to 1: 2, preferably about 1: 1.

The low-valent titanium refers to titanium having a valence of less than trivalent, and is generally one or two types of commercially available trivalent or tetravalent titanium halides such as titanium chloride and titanium bromide.
It can be generated in the reaction system using a reducing agent more than one kind. Specific examples of the titanium halide include titanium tetrachloride and titanium trichloride. As the reducing agent, zinc, zinc-copper alloy, magnesium, lithium,
Examples thereof include lithium aluminum hydride and potassium graphite. Preferred reducing agents are zinc or zinc-copper alloys. The amount of the low-valent titanium to be used is generally 2 to 4 moles, preferably about 2 moles, per mole of the compound of the formula (1). Therefore, the blending amount of the titanium halide is substantially the same as or more than the amount of the low-valent titanium used. The amount of the reducing agent varies depending on the valence of the titanium halide used, and is preferably approximately equimolar or more than the amount of the titanium halide. The presence of trimethylsilyl chloride in this reaction system saves titanium halide, and is also effective in recovering products and treating solvents and the like.

The reaction time in the present invention is several minutes to several tens of minutes. The reaction is preferably carried out at a temperature from room temperature to 120 ° C., preferably around the boiling point of the solvent used.

The solvent which can be used for the reaction is preferably an ether solvent, for example, tetrahydrofuran, dioxane,
Dimethoxyethane, diisopropyl ether and the like can be used. Preferred solvents are tetrahydrofuran and 1,1
4-dioxane.

After the reaction of the benzoxepino compound of the formula (1) with the piperidin-4-one compound of the formula (2),
If desired, the ester bond or the amide bond can be decomposed by a conventional method to obtain a compound in which R in Formula (3) is a carboxyalkyl group or a carboxyl group. An acid or alkali is used for the ester decomposition reaction, and it is preferable to use an acid, for example, a mineral acid such as hydrochloric acid, sulfuric acid, or bromic acid, or an organic acid solution or an alcohol solution of such an acid.
Examples of the alkali include caustic soda, KOH, K ₂ C
Hydrolysis may be performed using an alkali such as O ₃ or LiOH. In order to isolate the compound of the formula (3) in the form of a salt, for example, an acid such as hydrochloric acid or bromic acid may be added to a solution of the compound of the formula (3) in an organic solvent after completion of the reaction. To isolate the target substance from the reaction mixture, a conventional method, for example, filtration, washing,
Extraction, recrystallization, various types of chromatography and the like may be used.

[0018]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 3- [4- (8-fluoro-11H-10-oxa-4-aza-dibenzo [a,
Preparation of d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid t-butyl ester (3)

[0019]

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Under an argon stream, anhydrous tetrahydrofuran
443.7 mg (90%) of zinc was added to 5.6 mL, and then 0.22 mL of titanium tetrachloride was added dropwise in an ice bath, and the mixture was heated under reflux for 30 minutes. 228.7 mg of 8-fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cyclohepten-5-one (1)
And 3- (4-oxo-piperidin-1-yl) -propionic acid t-butyl ester (2) 226.7 mg of anhydrous tetrahydrofuran
A 4.0 mL solution was quickly added dropwise, and the mixture was heated under reflux for 20 minutes. After cooling, 15 mL of 10% aqueous potassium carbonate solution and 15 mL of ethyl acetate
Was added and the mixture was stirred at room temperature for 20 minutes, and the insoluble matter was filtered through celite. 20 mL of water was added to the filtrate, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to NH silica gel column chromatography (chloroform: n-hexane = 2: 1) to give 269.2 mg of the title compound (3) as a pale yellow oil. In this reaction solution, a free form in which the t-Bu ester group of compound (3) was decomposed was confirmed by HPLC. ¹ H-NMR (270 MHz, CDCl ₃ ); δ (ppm) 8.55 (1H, dd,
J = 4.9, 1.7 Hz), 7.68 (1H, dd, J = 7.5, 1.5 Hz),
7.23 (1H, dd, J = 7.6, 5.1 Hz), 7.05 (1H, dd, J =
8.7, 6.8 Hz), 6.59 (1H, ddd, J = 8.2, 7.9, 2.6 H
z), 6.50 (1H, dd, J = 10.3, 2.5 Hz), 5.64 (1H, d, J
= 12.4 Hz), 4.83 (1H, d, J = 12.4 Hz), 2.83-2.17
(11H, m), 2.06 (1H, ddd, J = 10.4, 10.3, 3.3 Hz),
1.44 (9H, s).

Example 2 3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a,
Preparation of d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5)

[0022]

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Instead of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate, ethyl 3- (4-oxo-piperidin-1-yl) -propionate (4) 19
The reaction was carried out in the same manner as in Example 1 using 9.6 mg to obtain 286.3 mg of the title compound (5) as a pale yellow oil. ¹ H-NMR (270 MHz, CDCl ₃ ); δ (ppm) 8.55 (1H, dd,
J = 5.1, 1.7 Hz), 7.68 (1H, dd, J = 7.6, 1.6 Hz),
7.22 (1H, dd, J = 7.6, 5.1 Hz), 7.06 (1H, dd, J =
8.6, 6.8 Hz), 6.59 (1H, ddd, J = 8.2, 7.9, 2.6 H
z), 6.50 (1H, dd, J = 10.4, 2.6 Hz), 5.64 (1H, d, J
= 12.4 Hz), 4.83 (1H, d, J = 12.4 Hz), 4.14 (2H,
dd, J = 14.2, 7.1 Hz), 2.85-2.47 (9H, m), 2.37-2.2
3 (2H, m), 2.09 (1H, ddd, J = 10.4, 9.9, 3.3 Hz),
1.25 (3H, t, J = 7.1 Hz).

Example 3 3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a,
d] Cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) A reaction was carried out in the same manner as in Example 2 except that 714.4 mg of a zinc-copper alloy was used instead of zinc. 271.5 mg of compound (5) was obtained.

Example 4 3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a,
Preparation of d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) As in Example 2, 5.6 mL of 1,4-dioxane was used instead of tetrohydrofuran as the reaction solvent. The reaction was performed to obtain 120.0 mg of the desired title compound (5).

Example 5 3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a,
Preparation of d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid ethyl ester (5) The title compound (5)
218.0 mg were obtained.

Example 6 8-Fluoro-5- (1-methyl-piperidine-4-ylidene) -5,11
Of 7-dihydro-10-oxa-4-aza-dibenzo [a, d] cycloheptene (7)

[0028]

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Reaction was carried out in the same manner as in Example 1 except that 109.7 mg of 1-methyl-piperidin-4-one (6) was used instead of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate. The title compound (7) 182.2 mg as a pale yellow oil
I got ¹ H-NMR (270 MHz, CDCl ₃ ); δ (ppm) 8.56 (1H, dd,
J = 4.9, 1.7 Hz), 7.68 (1H, dd, J = 7.6, 1.7 Hz),
7.23 (1H, dd, J = 7.6, 5.1 Hz), 7.07 (1H, dd, J =
8.6, 6.8 Hz), 6.59 (1H, ddd, J = 8.2, 7.8, 2.6 H
z), 6.51 (1H, dd, J = 10.4, 2.6 Hz), 5.65 (1H, d, J
= 12.4 Hz), 4.83 (1H, d, J = 12.4 Hz), 2.81-2.51
(4H, m), 2.39-2.16 (3H, m), 2.28 (3H, s), 2.01 (1
H, ddd, J = 10.4, 10.3, 3.3 Hz).

Example 7 4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a, d] cycloepten-5-ylidene) -piperidine-1-carboxylic acid
Production of ethyl ester (9)

[0031]

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Example 1 was repeated using 184.7 mg of ethyl 4-oxo-piperidine-1-carboxylate (8) instead of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate. The reaction was carried out in the same manner to obtain 270.8 mg of the title compound (9) as a pale yellow oil. ¹ H-NMR (270 MHz, CDCl ₃ ); δ (ppm) 8.56 (1H, dd,
J = 4.9, 1.7 Hz), 7.69 (1H, dd, J = 7.6, 1.7 Hz),
7.25 (1H, dd, J = 7.7, 5.1 Hz), 7.04 (1H, dd, J =
8.6, 6.4 Hz), 6.60 (1H, ddd, J = 8.2, 7.8, 2.6 H
z), 6.52 (1H, dd, J = 10.3, 2.6 Hz), 5.61 (1H, d, J
= 12.4 Hz), 4.84 (1H, d, J = 12.4 Hz), 4.15 (2H,
dd, J = 14.2, 7.1 Hz), 3.83 (2H, m), 3.26 (1H, dd
d, J = 13.1, 9.0, 4.3 Hz), 3.10 (1H, ddd, J = 13.
0, 9.3, 4.0 Hz), 2.67-2.44 (3H, m), 2.29 (1H, m),
1.26 (3H, t, J = 7.1 Hz).

Example 8 3- [4- (8-Fluoro-11H-10-oxa-4-aza-dibenzo [a,
Production of d] cycloheptene-5-ylidene) -piperidin-1-yl] -propionic acid (10) hydrochloride

[0034]

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3- [4- (8-fluoro-11H-10-oxa-4-aza-
Dibenzo [a, d] cycloheptene-5-ylidene) -piperidine
1-yl] -propionic acid ethyl ester (5) 2 in 2.9 g
6.4 mL of caustic soda was added to carry out an esterolysis reaction by a conventional method, and hydrochloric acid was added dropwise to obtain 2.7 g of the title compound (10) hydrochloride as pale yellow crystals. ¹ H-NMR (270 MHz, DMSO-d ₆ ); δ (ppm) 8.55 (1H,
d, J = 4.8 Hz), 7.97 (1H, d, J = 7.6 Hz), 7.40 (1
H, dd, J = 7.3, 5.3 Hz), 7.14 (1H, t, J = 8.1Hz),
6.77 (1H, t, J = 8.2 Hz), 6.67 (1H, dd, J = 10.6,
2.3 Hz), 5.67 (1H, d, J = 12.4 Hz), 5.03 (1H, d, J
= 12.5 Hz), 3.50-3.15 (8H, m), 2.90-2.65 (3H, m),
2.51-2.40 (1H, m).

Reference Example 1 Preparation of ethyl 3- (4-oxo-piperidin-1-yl) -propionate (4)

[0037]

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25.3 g of 4-piperidone hydrochloride monohydrate (12) and 21.4 mL of ethyl acrylate in 60 mL of isopropanol solution
To the mixture was added 60 mL of 20% K ₂ CO _{3 while} stirring at room temperature, and the mixture was heated under reflux for 6.5 hours. After cooling, the solvent and excess ethyl acrylate were distilled off under reduced pressure, and the residue was extracted with ethyl acetate (150 mL × 2). The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30.8 g of the title compound (4) as a yellow oil. ¹ H-NMR (270 MHz, CDCl ₃ ); δ (ppm) 4.17 (2H, dd, J
= 14.2, 7.1 Hz), 2.83 (2H, t, J = 7.3 Hz), 2.78 (4
H, t, J = 5.9 Hz), 2.53 (2H, t, J = 7.1 Hz), 2.44
(4H, t, J = 6.1 Hz), 1.27 (3H, t, J = 7.1 Hz).

Reference Example 2 Preparation of t-butyl 3- (4-oxo-piperidin-1-yl) -propionate (2) 2.13 g of 4-piperidone hydrochloride monohydrate and t-acrylic acid
2.94 g of the title compound (2) was obtained in the same manner as in Reference Example 1 using 1.78 g of butyl. ¹ H-NMR (270 MHz, CDCl ₃ ); δ (ppm) 2.82 to 2.72 (6H,
m), 2.50-2.40 (6H, m), 1.46 (9H, s).

[0040]

According to the production method of the present invention, a benzoxepino-11-pyridylidene compound can be produced from a benzoxepino compound in a small number of steps and in a high yield.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Junichiro Amada 3936-2 Sashigi, Saitama-shi, Saitama Pref. F-term at Fuji Omiya Daiichi Laboratory (Reference) 4C050 AA01 AA07 BB03 CC19 EE01 FF10 GG01 HH04 4C086 AA04 CB22 MA01 MA04 NA14 ZB13 4H039 CA42 CD40

Claims (3)

[Claims] 1. General formula (1): (Wherein X is CH or N; X ′ is CH ₂ or O; X ″ represents a group that does not participate in the reaction) to a benzoxepino compound represented by a general formula ( 2): embedded image Wherein R ′ represents an esterified or amidated carboxyl-substituted alkyl group, an unsubstituted alkyl group, or an esterified or amidated carboxyl group. A compound of the general formula (3), characterized by reacting an -one compound and, if desired, decomposing an ester bond or an amide bond. (Wherein, R represents an esterified or amidated carboxyl-substituted alkyl group, a carboxyalkyl group, an unsubstituted alkyl group, an esterified or amidated carboxyl group, or a carboxyl group; , X ′ and X ″ are as defined above), a method for producing a benzoxepino-11-piperidylidene compound, a salt thereof, or a hydrate thereof. 2. The method according to claim 1, wherein X ″ in formulas (1) and (3) is a hydrogen atom, a halogen atom or an alkyl group.
Manufacturing method. 3. The method according to claim 1, wherein the low-valent titanium is generated in a reaction system using a trivalent and / or tetravalent titanium halide and a reducing agent.