JP2003026672A - New method of production for 3-aminooxetan and intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe and industrial advantageous method for producing 3-aminooxetan. SOLUTION: This method produces the 3-aminooxetan expressed by formula (I) or its salt by subjecting a 3-hydroxy or substituted alkoxyiminooxetan expressed by formula (II) or its salt to a catalytic reduction under a hydrated condition. (R<1> is H, a lower alkyl optionally having 1 to 3 (substituted)aryl substituents.).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a polymer raw material,
3-Aminooxetane (I) useful as a raw material for pharmaceuticals
Alternatively, the present invention relates to a novel production method of a salt thereof and a novel intermediate useful in the production method.

[0002]

2. Description of the Related Art Formula (I)

[Chemical 9] 3-aminooxetane represented by is a raw material for producing fibers and polymers useful as a coating agent (US 3449369,
US 3440231) and quinolone synthetic antibacterial agents, and other compounds useful as raw materials for producing pharmaceutical products (for example, JP-A-3-188074). As a method for producing 3-aminooxetane (I), as shown in the following reaction scheme, 3-oxetanone (VII) and hydroxyamine hydrochloride (VII) are used.
3-oxyiminooxetane (IIb) by reacting I)
Then, a catalytic reduction reaction is carried out using a 10% rhodium-alumina catalyst in a hydrogen gas atmosphere of 1000 psig in methanol in the presence of ammonia.

[Chemical 10] According to this method, 3-aminooxetane (I) can be produced in a yield of 55% (US 3449369).
However, it is difficult to obtain the starting material 3-oxetanone (VII) by the above method, and it is necessary to perform continuous extraction for 2 days as a post-treatment during the production of 3-oxyiminooxetane (IIb). It is not preferable as an industrial production method because it needs to be carried out under high pressure, and its improvement is desired. As another method for producing 3-aminooxetane (I), a ring-opening reaction with acetic acid, a hydroxyl group-protecting reaction, a hydrolysis reaction with a concentrated alkaline aqueous solution, and a ring-closing reaction with an oxetane ring using epichlorohydrin as a raw material , A deprotection reaction of a hydroxyl group, a conversion reaction of a hydroxyl group to an azide group, and a conversion reaction of an azide group to an amino group are known (J. Org. Chem., 1983, 48, 2953-29.
56). However, the method requires a total of 9 steps, the yield is only about 20%, and it is necessary to carry out the hydrolysis reaction and the oxetane ring closure reaction in a high temperature 50 wt% sodium hydroxide aqueous solution. Explosive, low-molecular-weight organic azide compound (chemical coterie
p9) has to be dealt with in an alkyl halide (Chem. Eng. News, 1993, Oct. 11, p2).

[0003]

That is, the above conventional production method is required to provide a safer and industrially advantageous production method as an industrial production method of 3-aminooxetane (I).

[0004]

As a result of intensive studies to solve the above problems, the present inventors have found that 3-hydroxy or substituted alkoxyiminooxetane compounds (II), especially novel 3-substituted alkoxyiminooxetane compounds ( II
When a) is used as a production intermediate and the intermediate is catalytically reduced under a water-containing condition, surprisingly, high-pressure conditions are not required, and 3-aminooxetane (I) is produced safely and industrially advantageously. I found that Furthermore, the present inventors
-Substituted alkoxyiminooxetane compound (IIa)
Is unstable due to deacetalization when a novel 3,3-dialkoxyoxetane derived from 1-acyloxy-3-haloacetone is used as a production intermediate.
The present invention has been completed by finding that oxetanone (VII) can be advantageously produced by simply reacting it with O-substituted hydroxyamine or a salt (IV) thereof without purification and oximation.

That is, the present invention has the general formula (II)

[Chemical 11] (Wherein R ¹ represents H or lower alkyl which may be substituted with 1 to 3 optionally substituted aryls) and a 3-hydroxy or substituted alkoxyiminooxetane compound or a salt thereof is hydrated. Formula (I) characterized by catalytic reduction under conditions

[Chemical 12] And a method for producing 3-aminooxetane or a salt thereof. Further, the present invention provides the following general formula (III)

[Chemical 13] (In the formula, R ² and R ³ are the same or different and mean lower alkyl.) The 3,3-dialkoxy oxetane compound represented by the formula ( ³ ) is deacetalized, and then an O-substituted hydroxyamine or a salt thereof (IV) is used. The following general formula (IIa)

[Chemical 14] (Wherein R ^1a means lower alkyl which may be substituted with 1 to 3 optionally substituted aryl), and a 3-substituted alkoxyiminooxetane compound or a salt thereof is prepared, and then water-containing conditions are used. The present invention relates to a process for producing 3-aminooxetane (I) or a salt thereof, which is characterized by performing catalytic reduction below. Further, the present invention provides the compound represented by the general formula (V)

[Chemical 15] (In the formula, R ⁴ represents an acyl group and X represents halogen.) 1-acyloxy-3-haloacetone or a salt thereof is acetalized with a trialkyl orthoformate (VI), and then hydrolyzed. Subsequent cyclization provides the compound represented by the general formula (III) according to claim 2,
A method for producing 3-aminooxetane (I) or a salt thereof, which comprises producing a 3-dialkoxyoxetane compound and then subjecting it to the method according to claim 2. Also,
The present invention relates to the above-mentioned 3-substituted alkoxyiminooxetane compound useful as an intermediate or a salt thereof (IIa). Furthermore, the present invention relates to the 3,3-dialkoxy oxetane compound (III). In intermediate (II), particularly preferably a lower alkyl which may R ¹ is 1 to 3 substituents at aryl which may be substituted, 1 to more preferably aryl optionally R ¹ is substituted Three
It is a compound that is individually substituted methyl. ; Intermediate (I
In II), a compound in which R ² and R ³ are both a methyl group or an ethyl group is more preferable, and a compound in which an ethyl group is more preferable.

The present invention will be described in more detail. In the definition of the general formulas in the present specification, the term “lower” means a linear or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. The "lower alkyl" is C1-6 alkyl, preferably C1-4 alkyl such as methyl, ethyl, propyl, isopropyl and t-butyl, and more preferably methyl. "Aryl" as a whole is 6-1.
It is a 4-membered aromatic hydrocarbon ring group, preferably phenyl, naphthyl and the like, which may have one or more substituents. Examples of the substituent of “aryl which may be substituted” include lower alkyl, halogen, nitro, lower alkyl-O—, and amine which may be substituted by 1 to 2 lower alkyl. “Halogen” means a fluorine, chlorine, bromine or iodine atom, and “halo” means a negative group of halogen. “Acyl” means lower alkylcarbonyl or arylcarbonyl optionally substituted with formyl, aryl. These aryls may be substituted by the substituents mentioned in the above “aryl which may be substituted”. Preferred is lower alkylcarbonyl.

To carry out the production method of the present invention, the reaction is carried out according to the following reaction scheme.

[Chemical 16] (The symbols in the formula are as described above.) Step A In this step, 1-acyloxy-3-haloacetone compound (V) is used as a raw material, and trialkyl orthoformate (V
I) is reacted and acetalized to give 1-acyloxy-
In this step, 3-halo-2,2-dialkoxypropane is produced, and further hydrolyzed and cyclized to produce a novel 3,3-disubstituted alkoxyoxetane (III).
Acetalization is advantageously performed by reacting in the presence of an acidic catalyst, and the acidic catalyst that can be used in this reaction is
p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid, etc., preferably p-toluenesulfonic acid,
This acidic catalyst is used in an amount of 0.01 to 1 equivalent, preferably 0.05 to 0.1 equivalent, per equivalent of compound (V). Examples of the trialkyl orthoformate (VI) include triethyl orthoformate, trimethyl orthoformate and tripropyl orthoformate, and the compound (VI) is used in 1 to 5 equivalents, preferably 1.5 to 2 equivalents, relative to the compound (V). . The reaction is carried out at room temperature to reflux, preferably 25 to 50 ° C. In this step, a solvent such as methanol, ethanol, benzene, dimethoxyethane, chloroform or methylene chloride may be used if necessary. The obtained 1-acyloxy-3-halo-2,2-dialkoxypropane can be directly subjected to the reaction step without further isolation and purification. The 1-acyloxy-3-halo-2,2-dialkoxypropane obtained by the acetalization reaction is then subjected to a hydrolysis reaction. This hydrolysis reaction is preferably carried out under alkaline conditions. Examples of the alkaline aqueous solution that can be used include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like, and the concentration of the alkaline aqueous solution used is
It is 10 to 50% by weight. This reaction is preferably carried out in the presence of a phase transfer catalyst, and examples of the phase transfer catalyst include tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, benzyltriethylammonium chloride, trioctylmethylammonium chloride. And the like, quaternary ammonium salts such as, tetrabutylphosphonium bromide, phosphonium salts such as trioctylethylphosphonium chloride, tetraphenylphosphonium chloride, and the like can be used. This hydrolysis reaction solution can also be subjected to the next cyclization reaction without particular isolation and purification. The cyclization reaction is preferably carried out in the presence of a phase transfer catalyst, and as the phase transfer catalyst, the above-mentioned quaternary ammonium salt, phosphonium salt or the like can be used. The cyclization reaction is preferably carried out at room temperature to reflux, preferably 50 ° C. to reflux, more preferably reflux.

Step B In this step, the 3,3-disubstituted alkoxyoxetane (III) obtained in the step A is used as a raw material for deacetalization, and then an O-substituted hydroxyamine or a salt (IV) thereof is used. Oxime to 3-hydroxy or 3
It is a step of producing a -substituted alkoxyiminooxetane compound (II). The deacetalization reaction is advantageously carried out in the presence of a carbonyl compound. Specific examples of the carbonyl compound to be used include 4-methylcyclohexanone, 4-t-butylcyclohexanone, acetone and the like, preferably 4-methylcyclohexanone and 4-methylcyclohexanone.
It is t-butylcyclohexanone. The reaction can be carried out at room temperature to reflux, preferably 50 to 100 ° C., and normal pressure to reduced pressure, preferably reduced pressure. In this step, a solvent can be used if necessary, and the solvent used is tetrahydrofuran, alcohol, acetonitrile, water or the like. The 3-oxetanone produced by deacetalization is subjected to the next oxime-forming reaction without purification. The O-substituted hydroxyamine or its salt (IV) used in the oximation means a substituted hydroxyamine or a salt thereof in which oxygen may be substituted, such as O-benzylhydroxyamine and O- (4-nitrobenzyl). Examples thereof include O-substituted benzylhydroxyamines such as hydroxyamine, O-tritylhydroxyamine and the like, and salts thereof with hydrochloric acid, acetic acid and the like, and O-benzylhydroxyamine hydrochloride is preferable. The reaction can be carried out in a solvent such as pyridine, ethanol or water. Further, depending on the reaction conditions, the reaction can be carried out in the presence of a basic salt such as ammonium acetate, sodium acetate or ammonium formate.

Step C In this step, the 3-hydroxy- or 3-substituted alkoxyiminooxetane compound (II) obtained in Step B is catalytically reduced under a hydrogen atmosphere under a water-containing condition to give 3-aminooxetane (I) or a compound thereof. This is a process of producing salt. This process is
It is performed under hydrous conditions. Here, the water-containing condition is water,
It means the reaction conditions in which a solvent containing water such as hydrochloric acid water, aqueous ammonia solution, hydrous alcohol, hydrous acetic acid is used for the reaction. Examples of the catalyst that can be used in the catalytic reduction in this step include palladium catalysts such as palladium, palladium-carbon and palladium hydroxide, and metal catalysts such as Raney nickel, platinum oxide and rhodium-carbon. Preferred is a palladium catalyst. This reaction can be carried out at room temperature to reflux temperature, preferably at room temperature, under hydrogen atmosphere at atmospheric pressure. In the above-mentioned production method, isolation / purification is carried out by applying usual chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various chromatographies. In the method of the present invention, the salt of 3-aminooxetane can also be produced by selecting the reaction solvent in step C and subjecting the obtained free 3-aminooxetane to a salt-forming reaction by a conventional method. Specifically, it is an acid addition salt with an inorganic acid or an organic acid. Specific examples of these salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid. Acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid,
Examples thereof include organic acids such as ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid, and addition salts with acidic amino acids such as aspartic acid and glutamic acid. The present invention includes the inventions relating to Compounds (IIa) and (III) which are novel intermediates for production of the above-mentioned 3-aminooxetane (I) or a salt thereof. These compounds of the present invention may be optical isomers (optically active substances, diastereomers, etc.) depending on the type of group.
And geometric isomers (E-form, Z-form, etc.) exist. In the present invention,
It includes a separated form or a mixture of these isomers. The compounds represented by the general formulas (II) and (IIa) form a salt when the optionally substituted aryl substituent is a basic group or an acidic group. Specifically, it is an acid addition salt with an inorganic acid or an organic acid, or a salt with an inorganic or organic base. Specific examples of these salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid. Acid, maleic acid,
Lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or
Organic acid such as toluenesulfonic acid or addition salt with acidic amino acid such as aspartic acid or glutamic acid, inorganic base such as sodium, potassium, magnesium, calcium, aluminum and lithium, organic base such as methylamine, ethylamine and ethanolamine, lysine ，
Examples thereof include salts with basic amino acids such as ornithine.

[0010]

EXAMPLES The present invention will be described in more detail with reference to the following examples. The invention is in no way limited to these examples. ¹ H-NMR: Proton nuclear magnetic resonance spectrum (measured at 400 MHz using DMSO-d ₆ or CDCl ₃ as a measurement solvent and tetramethylsilane as an internal standard) MS: Mass spectrometry (FAB: fast atom bombardment mass spectrometry, EI : Electron impact mass spectrometry, M: molecular weight) Example (1) 1-acetoxy-3-chloroacetone (186.5
g), triethyl orthoformate (275.4 g) and p-toluenesulfonic acid monohydrate (11.8 g) at room temperature for 6 times.
Stir for 3 hours. The reaction mixture was concentrated under reduced pressure to give a brown oily substance. This oily substance contains 1-acetoxy-3
Since -chloroacetone remained, triethyl orthoformate (183.8 g) and p-toluenesulfonic acid monohydrate (11.8 g) were added to this oily substance, and the mixture was stirred at 35 ° C for 14 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 1-acetoxy-3-chloro-2,2-diethoxypropane. A 20 wt% sodium hydroxide aqueous solution (744 g) and tetrabutylammonium bromide (20.0 g) were added to the obtained crudely purified product, and the mixture was stirred at 95-100 ° C for 18 hr. After completion, the reaction mixture was cooled to room temperature and then diluted with diisopropyl ether (600 ml). Separate the organic layer and add it to water (600
ml) and saturated brine (600 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a slightly yellow oily substance (199.7 g). The obtained oily substance was distilled under reduced pressure to obtain a fraction containing 3,3-diethoxyoxetane (42-60 ° C, 10-12 mmHg, 107.5 g). 3,3-Diethoxyoxetane ¹ H-NMR (CDCl ₃ ); 1.24 (t, 6H), 3.45 (q, 4H), 4.59 (s, 4H) Boiling point; 64-66 ℃ / 12-14 mmHg (colorless liquid )

(2) 4-methylcyclohexanone (410
g) and p-toluenesulfonic acid monohydrate (70.4 g)
The mixture was decompressed to 140 mmHg and further heated to 75 ° C., and then the fraction (107.0 g) containing 3,3-diethoxyoxetane obtained above was added dropwise to the mixture over 60 minutes.
By collecting the distillate from the reaction system in an ice bath, an oily substance (14
2.4g) was obtained. The obtained oily substance was dissolved in pyridine (284 g), O-benzylhydroxyamine monohydrochloride (116.5 g) was further added, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and 0.5M aqueous hydrochloric acid were added to the obtained residue. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 0.5 M aqueous hydrochloric acid, 0.5 M aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in chloroform, silica gel (300 g) was added thereto, and the mixture was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =
The product was purified by 7: 1) to obtain 3-benzyloxyiminooxetane (45.7 g). ¹ H-NMR (CDCl ₃ ); 5.06 (s, 2H), 5.24-5.27 (m, 2H), 5.27-
5.30 (m, 2H), 7.29-7.39 (m, 5H) MS (EI); 177 (M)

(3) 3-Benzyloxyiminooxetane (45.7 g) was dissolved in acetic acid (774 ml), 1 M hydrochloric acid water (258 ml) and 53.7% water-containing 10% palladium-carbon were added, and the atmosphere was hydrogen atmosphere. The mixture was stirred at room temperature for 12 hours. The insoluble matter was removed from the reaction mixture by filtration using Celite, and the insoluble matter was washed with water. The filtrate and the washing solution were collected and concentrated under reduced pressure. The residue was azeotropically distilled with ethanol to distill off excess water, thereby obtaining dark brown crude crystals (20.4 g). The obtained crude crystals were heated with ethyl acetate / ethanol (3/1)
By washing in a mixed solvent of 3-aminooxetane
The hydrochloride salt (16.9g) was obtained. ¹ H-NMR (DMSO-d ₆ ); 4.26-4.34 (m, 1H), 4.61 (t, 2H), 4.6
9 (t, 2H), 7.59 (br) MS (FAB +); 74 (M + 1)

[0013]

INDUSTRIAL APPLICABILITY According to the present invention, as a method for producing 3-aminooxetane or a salt thereof, a compound represented by the general formula (II), preferably (IIa) is used and subjected to catalytic reduction under hydrous conditions, The conventional catalytic reduction under high pressure can be performed at normal pressure. The production method of the present invention has fewer reaction steps than the conventional method via 3-azidooxetane,
The reaction can be carried out without using an azide compound which has a risk of explosion. The general formulas (IIa) and (II of the present invention
The compound represented by I) is a production raw material for the synthesis of 1-oxetane-3-yl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivative useful as an antibacterial agent. It is useful as an intermediate. That is, using 3-aminooxetane which can be produced by the method of the present invention, a benzoylacetic acid derivative represented by the general formula (A) as 1) of reaction formula- (1) described on page 10 of JP-A-3-188074, and Orthoformate ester (B) is reacted, and then 2) 3-aminooxetane is reacted to obtain an oxetan-3-yl-amino-substituted acrylic acid derivative represented by general formula (C), and then general formula (C) The target product can be obtained by cyclizing. The compounds represented by the general formulas (III) and (IIa) of the present invention are 1-acetoxy-3-, in the production of 3-aminooxetane useful as a raw material for the production of the above-mentioned antibacterial agent.
By using chloroacetone as a starting material and passing through the compounds represented by the general formulas (III) and (IIa), the reaction time can be shortened and the use of a high concentration reagent at a high temperature can be avoided. It is an industrially useful intermediate that can be obtained.

Continued front page    (72) Inventor Takashi Kamikubo             21 Yamanouchi Pharmaceutical Co., Ltd. Miyukigaoka, Tsukuba City, Ibaraki Prefecture             Inside the company (72) Inventor Hideki Karai             21 Yamanouchi Pharmaceutical Co., Ltd. Miyukigaoka, Tsukuba City, Ibaraki Prefecture             Inside the company (72) Inventor Makoto Oku             21 Yamanouchi Pharmaceutical Co., Ltd. Miyukigaoka, Tsukuba City, Ibaraki Prefecture             Inside the company (72) Inventor Toshihiro Watanabe             21 Yamanouchi Pharmaceutical Co., Ltd. Miyukigaoka, Tsukuba City, Ibaraki Prefecture             Inside the company F-term (reference) 4C048 TT01 TT03 TT04 UU03 XX02                       XX04

Claims (5)

[Claims] 1. The following general formula (II): (In the formulae, R ¹ is H, or optionally substituted aryl is 1
To 3 to 3 lower alkyl which may be substituted. )
A 3-hydroxy or substituted alkoxyiminooxetane compound represented by or a salt thereof is subjected to catalytic reduction under water-containing conditions. A method for producing 3-aminooxetane or a salt thereof represented by: 2. The following general formula (III): (In the formula, R ² and R ³ are the same or different and mean lower alkyl.) The 3,3-dialkoxy oxetane compound represented by the formula ( ³ ) is deacetalized, and then an O-substituted hydroxyamine or a salt thereof (IV ) Is converted to an oxime by the following general formula (IIa) (Wherein R ^1a means lower alkyl which may be substituted with 1 to 3 optionally substituted aryl), and a 3-substituted alkoxyiminooxetane compound or a salt thereof is prepared, and then water-containing conditions are used. Formula (I) characterized by catalytic reduction under A method for producing 3-aminooxetane or a salt thereof represented by: 3. A compound represented by the general formula (V): (In the formula, R ⁴ represents an acyl group and X represents halogen.) 1-acyloxy-3-haloacetone or a salt thereof is acetalized with a trialkyl orthoformate (VI), and then hydrolyzed. Subsequent cyclization provides the compound represented by the general formula (III) according to claim 2,
A method for producing 3-aminooxetane (I) or a salt thereof, which comprises producing a 3-dialkoxyoxetane compound and then subjecting it to the method according to claim 2. 4. The following general formula (IIa): (In the formula, R ^1a represents lower alkyl which may be substituted with 1 to 3 optionally substituted aryl.) 3
-Substituted alkoxyiminooxetane compounds or salts thereof. 5. The following general formula (III): (In the formula, R ² and R ³ are the same or different and mean lower alkyl.) 3,3-dialkoxy oxetane compound.