JPH0656806A - Morpholine derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a novel morpholine derivative or its acid adduct which is useful as an synthetic intermediate for a quinoline-carboxylic acid derivative having excellent antimicrobial activity. CONSTITUTION:A morpholine derivative of formula I (R is a 1 to 3C straight or branched lower alkyl) or its acid adduct, for example, 2- methoxymethylmorpholine. The compound of formula I is obtained by hydrolysis of a morpholine derivative of formula II (R<1> is a 1 to 4C straight or branched lower alkyl or an aralkyl) or hydrogenolysis of a morpholine derivative of formula III (R<2> is benzyl, substituted benzyl, benzyloxycarbonyl, substituted benzyloxycarbonyl) in the presence of a hydrogenation catalyst. The reaction of a compound of formula I with a fused tetracyclic ring compound of formula IV followed by hydrolysis gives a novel fused tetracyclic quinolinecarboxylic acid derivative of formula V.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel morpholine derivative and a method for producing the same. More specifically, the following formula (I), which is a novel intermediate useful for producing a quinolinecarboxylic acid derivative having excellent antibacterial activity,

[0002]

[Chemical 1] (In the formula, R represents a lower alkyl group having a straight or branched chain having 1 to 3 carbon atoms.), A morpholine derivative or an acid addition salt thereof, and a production method thereof.

[0003]

2. Description of the Related Art Since the discovery of nalidixic acid as a synthetic antibacterial agent, various quinolinecarboxylic acid derivatives have been studied with the aim of improving antibacterial activity, and condensed tricyclic compounds and condensed tetracyclic compounds have also been investigated. There is. That is, JP-A-5
No. 7-46986 discloses a fused tricyclic compound having a pyrido [1,2,3-de] [1,4] benzoxazine skeleton, for example, the following compound X, which is disclosed in European Patent Publication No. 286089 and Japanese Pharmaceutical Association. The 109th Annual Meeting Abstracts IV, p. 30 (1989), discloses a fused tetracyclic compound having a 9,1-epoxymethano-5H-thiazolo [3,2-a] quinoline skeleton, for example, the following compound Y. There is.

[0004]

[Chemical 4]

[0005]

An object of the present invention is to provide a novel intermediate useful for producing a quinolinecarboxylic acid derivative having excellent antibacterial activity and a method for producing the same.

[0006]

As a result of various studies, the present inventors have found that the following formula (I)

[0007]

[Chemical 1] (Wherein R is the same as above) and a novel morpholine derivative or acid addition salt thereof and the following formula (IV)

[0008]

[Chemical 5] Represented by the following formula (V) obtained by reacting with a fused tetracyclic compound represented by

[0009]

[Chemical 6] It was found that the novel fused tetracyclic quinolinecarboxylic acid derivative represented by the formula (wherein R is the same as above) has excellent antibacterial activity (Reference Examples 8 to 9 and Test Examples 1 and 2 described below).
reference). That is, it was found that the compound of the above formula (I) and its acid addition salt are useful intermediates for producing the quinolinecarboxylic acid derivative (V) having excellent antibacterial activity, and completed the present invention.

In the present specification, the aralkyl group means an aralkyl group having 7 to 10 carbon atoms such as a benzyl group, a substituted benzyl group, a phenylethyl group and a phenylpropyl group.

The substituted benzyl group means a benzyl group in which one or more chloro groups, nitro groups, methyl groups, methoxy groups and the like are substituted on the aromatic ring, and examples thereof include p-chlorobenzyl group and p-nitrobenzyl. Group, p-methylbenzyl group,
Examples thereof include p-methoxybenzyl group and 3,4,5-trimethoxybenzyl group.

The substituted benzyloxycarbonyl group means a benzyloxycarbonyl group in which one or more chloro groups, nitro groups, methyl groups, methoxy groups and the like are substituted on the aromatic ring, and for example, p-chlorobenzyloxycarbonyl group. Group, p-nitrobenzyloxycarbonyl group, p-methylbenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group and the like.

On the other hand, as the acid addition salt of the compound (I) of the present invention, inorganic acid salts such as hydrochloride and sulfate, or acetate,
There are addition salts of organic acids such as methane sulfonate and p-toluene sulfonate.

The compound (I) of the present invention can be produced by the following two methods (method a and method b). Method a is a method of hydrolyzing a morpholine derivative (II) as shown in the following formula.

[0015]

[Chemical 7] (In the formula, R is the same as above, and R ¹ represents a lower alkyl group having a straight or branched chain having 1 to 4 carbon atoms, or an aralkyl group.) Hydrolysis of the morpholine derivative (II) Preferably in an alkaline aqueous solution, for example in the presence of excess sodium hydroxide or potassium hydroxide, etc.
Heat for an hour.

When R ¹ is a morpholine derivative (II) in which R ¹ is a tert-butyl group, a benzyl group or a benzyl group having a substituent such as a methoxy group on the aromatic ring, the Invention compound (I) can be obtained.
Next, the method b will be described. Method b is a method of hydrolyzing a morpholine derivative (III) as shown in the following formula.

[0017]

[Chemical 8] (In the formula, R is the same as above, and R ² represents a benzyl group, a substituted benzyl group, a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group.) Hydrogenolysis is usually performed in acetic acid or in methanol or ethanol. It is carried out in a lower alcohol or in a lower alcohol in the presence of an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid in the presence of a catalyst for catalytic reduction. The reaction temperature is usually in the range of room temperature to 150 ° C., and the reaction is usually carried out under atmospheric pressure to hydrogen pressure of 50 kg / cm ² . In this case, as the catalyst for catalytic reduction, usual palladium black, palladium-carbon, platinum or the like can be used.

The compound (I) of the present invention and the acid addition salt thereof obtained by the above method a or method b are isolated and purified by a conventional purification means such as recrystallization, distillation or silica gel column chromatography. The compound (I) of the present invention can be converted into an acid addition salt by a conventional means.

Next, a method for producing the morpholine derivative (II) used in the method a will be described. Compound (II) is produced, for example, by the method shown below.

[0020]

[Chemical 9] (In the formula, R and R ¹ are the same as above, and R ³ represents a lower alkyl group having a straight or branched chain having 1 to 4 carbon atoms or an aralkyl group.) That is, first, 1,2-epoxy -3-lower alkyloxypropane (VI) and N-substituted ethanolamine (VII) were used in the absence of solvent or in lower alcohols such as methanol and ethanol, organic solvents such as benzene, toluene, dioxane, etc. The reaction is usually performed at room temperature to 100 ° C at the boiling point. The amount of 1,2-epoxy-3-methoxypropane used is usually 1 to 3 mol with respect to 1 mol of N-substituted ethanolamine (VII),
It is preferably 1.0 to 2.2 mol and the reaction time is 1 to 10
It's 0 hours.

Next, the reaction product obtained by the above reaction and a sulfonyl chloride such as p-toluenesulfonyl chloride or methanesulfonyl chloride are placed in an aprotic organic solvent such as 1,4-dioxane, tetrahydrofuran, benzene or toluene. Tris (3,6-dioxaheptyl) amine, 18-crown-6 or tetra-n-
The compound of the formula (VIII) is reacted at 10 ° C to the boiling point of the solvent in the presence of a phase transfer catalyst such as butylammonium bromide and an inorganic base such as potassium hydroxide or sodium hydroxide.
A morpholine derivative represented by

When tetra-n-butylammonium bromide is used as the phase transfer catalyst, it is usually a two-layer structure comprising a water-insoluble organic solvent such as benzene or toluene and an aqueous solution of an inorganic base such as potassium hydroxide or sodium hydroxide. The reaction is carried out in the system.

The amount of sulfonyl chloride such as p-toluenesulfonyl chloride or methanesulfonyl chloride used is usually 1.0 to 2.0 mol, preferably 1.0 to 2.0 mol, per 1 mol of N-substituted ethanolamine (VII). 1.5
The amount of the inorganic base such as potassium hydroxide or sodium hydroxide used is usually 2.0 to 7.0 mol, preferably 3.0 to 7.0 mol, relative to 1 mol of N-substituted ethanolamine (VII). It is 4.0 mol.

The amount of the phase transfer catalyst such as tris (3,6-dioxaheptyl) amine, 18-crown-6 or tetra-n-butylammonium used is 1 mol of N-substituted ethanolamine (VII). Normally 0.00
It is 1 to 0.05 mol, preferably 0.005 to 0.02 mol. The reaction is usually completed in 1 to 30 hours. In addition,
The target compound (VIII) can be obtained without using a phase transfer catalyst, but the yield thereof is lower than when using a catalyst.

Then, the morpholine derivative (VIII) is reacted with the chlorocarbonic acid ester in an organic solvent such as benzene or toluene at room temperature to the boiling temperature of the solvent to obtain the morpholine derivative (II). In this case, the amount of chlorocarbonic acid ester used is usually 1 to 10 mol and the reaction time is 1 to 10 hours with respect to 1 mol of the compound (VIII).

The compound (VIII) also contains N as shown below.
It can also be derived from a substituted morpholine derivative (IX).

[0027]

[Chemical 10] (In the formula, R and R ³ are as described above, and X represents a halogen atom or a p-toluenesulfonyloxy group.)
For example, 4-benzyl-2-lower alkyloxymethylmorpholine is 4-benzyl-2-chloromethylmorpholine [see Synthetic Communication, 10 (1), 59 (1980)] or 4-benzyl-2- (p-toluenesulfonyl). (Oxymethyl) morpholine {4-benzyl-2-hydroxymethylmorpholine [Synthetic Communication, 10 (1), 59 (1
980)]]. } And sodium lower alkoxide.

Next, the morpholine derivative (III) used in the method b will be described. The compound (III) in which R ² is a benzyl group or a substituted benzyl group is a substituted ethanolamine (VII) in which the substituent R ³ is a benzyl group or a substituted benzyl group in the production of the compound (VIII) and an epoxy compound. It is obtained by reacting with (VI) in the same manner.

In the compound (III), R ² is a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group, and the compound (VIII) and R ¹ are a benzyl group or a substituted benzyl group in the production of the compound (II). It is obtained by reacting with a chlorocarbonic acid ester which is a group.

[0030]

INDUSTRIAL APPLICABILITY The compound of the present invention is important and useful for producing a novel fused tetracyclic quinolinecarboxylic acid derivative showing excellent antibacterial activity. That is, the compound (I) of the present invention or an acid addition salt thereof is added to the following formula (IV)

[0031]

[Chemical 5] In a polar solvent such as dimethyl sulfoxide or N, N-dimethylformamide, a fused tetracyclic compound represented by
In the presence of an acid scavenger, the temperature is usually 1 to 30 at room temperature to 150 ° C.
By reacting for a time and hydrolyzing the resulting compound to remove the boryl group, the following formula (V)

[0032]

[Chemical 6] (In the formula, R is the same as above.) The novel quinolinecarboxylic acid derivative can be easily produced (see Reference Examples 8 to 9 below). As the above-mentioned acid scavenger, a tertiary amine such as triethylamine or an excess amount of the morpholine derivative (I) which is the compound of the present invention can be used.

Hydrolysis of the compound produced by the reaction of the compound (I) of the present invention or an acid addition salt thereof with the compound (IV) is carried out by using a water-soluble organic solvent such as acetone, methanol or ethanol and water. In a mixed solvent of 1) under alkaline conditions. Compound (V) is isolated and purified by a conventional purification means such as silica gel column chromatography or recrystallization. In addition, compound (V) can be converted into a pharmaceutically acceptable salt according to a conventional method.

The compound (V) produced from the compound (I) of the present invention or an acid addition salt thereof and a pharmaceutically acceptable salt thereof have a broad antibacterial spectrum and a strong antibacterial activity (see Test Example 1 below). ). In particular, it has excellent antibacterial activity against Gram-positive bacteria and also shows strong antibacterial activity against clinically isolated bacteria (see Test Example 2 below).

On the other hand, the toxicity of compound (V) and its pharmaceutically acceptable salts is low. Therefore, compound (V) and its pharmaceutically acceptable salts can be excellent preventive and therapeutic agents for various infectious diseases, particularly various infectious diseases caused by Gram-positive bacteria. The fused tetracyclic compound represented by the formula (IV) can be produced, for example, by the method shown below (see Reference Examples 1 to 7 below).

[0036]

[Chemical 11] (In the formula, R ⁴ represents a lower alkyl group having a straight or branched chain having 1 to ⁴ carbon atoms.) The test examples are described below. [Test Example 1] Antibacterial activity (minimum inhibitory concentration: MIC) Test Compound The antibacterial activity of the fused tetracyclic compounds (V-1) and (V-2) synthesized from the compound (I) of the present invention was tested. For reference, the known compounds X and Y were also tested for antibacterial activity.

Compound (V-1) ... 9,1-
(Methylimino) methano-7-fluoro-8- (2-methoxymethylmorpholino) -5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid [Reference Example 8
Compound of] -Compound (V-2) --- 9,1- (methylimino) methano-7-fluoro-8- (2-ethoxymethylmorpholino) -5-oxo-5H-thiazolo [3,2-
a] Quinoline-4-carboxylic acid [Compound of Reference Example 9] Known compound X ... 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-dihydro-7H-pyrido [1,2,3-
de] [1,4] benzoxazine-6-carboxylic acid-known compound Y ... 9,1-epoxymethano-7-fluoro-8- (4-methyl-1-piperazinyl) -5-oxo- 5H-thiazolo [3,2-a] quinoline-4-carboxylic acid hydrochloride

2. Test Method Compounds (V-1) and (V-2) were dissolved in dimethylsulfoxide, and the known compound X was dissolved in 0.1N sodium hydroxide aqueous solution to prepare a 5000 μg / ml solution. The known compound Y was dissolved in sterile purified water to prepare a 5000 μg / ml solution. Next, each of the above-mentioned solutions was diluted with sterile purified water to prepare a standard solution having a concentration of each test compound of 1000 μg / ml. After that, the method specified by the Japanese Society of Chemotherapy [Ch
emotherapy, 29 , 76-79 (1981), TOKYO].

The medium for pre-culture of Streptococcus pneumoniae and Streptococcus pyogenes is Brain Heart Infusion Medium (DIFCO).
Manufactured by Nissui Pharmaceutical Co., Ltd.) was used as the medium for measuring the minimum inhibitory concentration. A broth for sensitivity measurement (manufactured by Nissui Pharmaceutical Co., Ltd.) is used as a medium for preculturing other bacteria, and an agar medium for sensitivity measurement (manufactured by Nissui Pharmaceutical Co., Ltd.) is used as a medium for measuring the minimum inhibitory concentration. used. 3. Test results are shown in Table 1.

[0040]

[Table 1]

[0041]

[Table 2]

Test Example 2 Antibacterial activity against clinical isolates 1. Test compound Same as in Test Example 1 (compound (V-1), compound (V-
2), known compound X and known compound Y).

2. Test method Known compound X is 0.1N sodium hydroxide aqueous solution, compounds (V-1) and (V-2) are dimethyl sulfoxide,
The known compound Y was dissolved in sterilized purified water to give 50
A solution of 00 μg / ml was prepared. Next, each of the above-mentioned solutions is diluted with sterile purified water so that the concentration of each test compound is 1000 μm.
A standard solution of g / ml was prepared. After that, 25 strains of Staphylococcus aureus (staphylococcus aureus) were clinically isolated according to the method specified by the Japanese Society of Chemotherapy [Chemotherapy, 29 , 76-79 (1981), TOKYO] (of which, the minimum for methicillin Minimum inhibitory concentration for methicillin-resistant Staphylococcus aureus strains having a growth inhibitory concentration of 6.25 μg / ml or more, 25 strains of Staphylococcus epidermidis, 25 strains of Enterococcus faecalis and 25 strains of Enterococcus faecium (MIC) ) Of the test compound against these strains (MI
C _range ), the minimum concentration (MI) that prevents the growth of 50% of the strains.
C ₅₀ ), and the minimum concentration (MIC ₉₀ ) that inhibits the growth of 90% of the strain was determined.

A broth for sensitivity measurement (manufactured by Nissui Pharmaceutical Co., Ltd.) was used as a medium for preculture of each strain, and an agar medium for sensitivity measurement (Nissui Pharmaceutical Co., Ltd.) was used as a medium for measuring the minimum inhibitory concentration. Manufactured) was used.

Further, the above-mentioned clinically isolated bacteria are 1988 11
It was isolated from the clinic during the month from June to June 1989, and was obtained from the Tokyo Laboratory. 3. Test results are shown in Tables 2 to 5.

[0046]

[Table 3]

[0047]

[Table 4]

[0048]

[Table 5]

[0049]

[Table 6]

[0050]

EXAMPLES The present invention will be described below with reference to examples and reference examples. Example 1 2-methoxymethylmorpholine [in the formula (I), R is
Methyl group compound] : produced in the following two steps. (1) N-benzyl-2-methoxymethylmorpholine N-benzylethanolamine 459 g and 1,2-
Epoxy-3-methoxypropane (422 g) at 50 ° C.
After stirring for 6 hours, excess 1,2-epoxy-3-methoxypropane was distilled off under reduced pressure. The residue was dissolved in 3000 ml of 1,4-dioxane and powdery potassium hydroxide 692.
5 g and 11.4 g of tris (3,6-dioxaheptyl) amine were added, and a solution of 809.4 g of p-toluenesulfonyl chloride in 2000 ml of 1,4-dioxane was stirred for 1.5 hours. Was dropped. At this time, the temperature of the reaction solution increased and reflux of the solvent was observed. After completion of dropping, the mixture was stirred for 2 hours, and then insoluble matter was filtered off.
The filtrate and a washing liquid obtained by washing the insoluble matter with ethyl acetate were combined, and the solvent was distilled off under reduced pressure. 600 ml of water and 300 ml of concentrated hydrochloric acid were added to the residue to make it strongly acidic and then washed with ethyl acetate. Next, 160 g of sodium hydroxide was added to the aqueous layer to make it strongly alkaline under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was distilled under reduced pressure to obtain 391.3 g of the title compound as a colorless liquid.

Boiling point: 103 ° C./0.25 mmHg. NMR (CDCl ₃ ) δ: 2.0 (1H, t, J = 11Hz), 2.2 (1H, dt, J = 3H)
z, J = 11Hz), 2.6 ~ 2.8 (2H, m), 3.4 (3H, s), 3.3 ~ 3.5 (2H, m),
3.5 (2H, s), 3.7 ~ 3.8 (2H, m), 3.9 ~ 4.0 (1H, m), 7.2 ~ 7.4 (5
H, m). Elemental analysis value (as C ₁₃ H ₁₉ NO ₂ ): Calculated value (%) C, 70.56; H, 8.65; N,
6.33. Analytical value (%) C, 70.53; H, 8.70; N,
6.19.

(2) 2-Methoxymethylmorpholine N-benzyl-2-methoxymethylmorpholine 412.
3 g was dissolved in 2000 ml of methanol, 33 g of 10% palladium-carbon was added, and 100 ° C. under a hydrogen pressure of 9 kg / cm ^2.
It was stirred at. After completion of the reaction, palladium-carbon was filtered off, and the solvent was distilled off under normal pressure to obtain a pale yellow oily substance. The oily substances were combined and then distilled under reduced pressure to obtain 212.3 g of the title compound as a colorless liquid. Boiling point: 90 ° C./19 mmHg. NMR (CDCl ₃ ) δ: 2.0 (1H, bs), 2.6 (1H, dd, J = 12Hz, J = 1
0.5Hz), 2.8 ~ 3.0 (3H, m), 3.4 (3H, s), 3.3 ~ 3.5 (2H, m), 3.6
~ 3.7 (2H, m), 3.9 ~ 4.0 (1H, m).

Example 2 2-methoxymethylmorpholine [in the formula (I), R is
Methyl group compound] : produced in the following two steps. (1) N-benzyl-2-methoxymethylmorpholine 12.5 g of N-benzylethanolamine and 15.4 g of 1,2-epoxy-3-methoxypropane at 50 ° C.
After stirring for 5 hours, excess 1,2-epoxy-3-methoxypropane was distilled off under reduced pressure. The obtained residue is 1,
Dissolved in 150 ml of 4-dioxane, 16.2 g of powdered potassium hydroxide and 270 mg of tris (3,6-dioxaheptyl) amine were added, and 11.4 g of methanesulfonyl chloride 11.4 g while stirring at 70 ° C. A solution dissolved in 50 ml dioxane was added dropwise. After completion of dropping, the mixture was stirred at the same temperature for 16 hours, and then the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, the ethyl acetate layer was separated, washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure to obtain 7.3 g of the title compound as a colorless liquid. The physical analysis values of the compound obtained here were in agreement with those of N-benzyl-2-methoxymethylmorpholine obtained in Example 1 (1).

(2) 2-Methoxymethylmorpholine The title compound was obtained in the same manner as in Example 1 (2). The analysis values of the physical properties of the compound obtained here were in agreement with those of the 2-methoxymethylmorpholine obtained in Example 1 (2).

Example 3 2-methoxymethylmorpholine hydrochloride [in formula (I)
And hydrochloride of a compound in which R is a methyl group] : Prepared in the following two steps. (1) N-benzyl-2-methoxymethylmorpholine N-benzylethanolamine (2.83 g) and 1,2-epoxy-3-methoxypropane (2.61 g) at 50 ° C.
After stirring for 7 hours, excess 1,2-epoxy-3-methoxypropane was distilled off under reduced pressure. The obtained residue is 1,
Dissolve in 60 ml of 4-dioxane, add 3.7 g of powdered potassium hydroxide and 50 mg of 18-crown-6, and add 50
P-toluenesulfonyl chloride with stirring at 4.degree.
A solution of 6 g dissolved in 20 ml of 1,4-dioxane was added dropwise. After completion of dropping, the mixture was stirred at the same temperature for 3 hours, then the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. 2N hydrochloric acid 2 in the residue
The mixture was made strongly acidic by adding 0 ml and washed with ethyl acetate. Then add sodium hydroxide aqueous solution to make it strong alkaline,
It was extracted with ethyl acetate. The ethyl acetate layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol = 100:
1) and the title compound 2.1 as a colorless liquid.
6 g was obtained. The physical analysis values of the compound obtained here were in agreement with those of N-benzyl-2-methoxymethylmorpholine obtained in Example 1 (1).

(2) 2-Methoxymethylmorpholine-hydrochloride N-benzyl-2-methoxymethylmorpholine was hydrolyzed in ethanol containing hydrochloric acid according to the procedure of Example 1 (2) to give 2-methoxymethylmorpholine. -Hydrochloride was obtained. NMR (D ₂ O) δ: 3.0 to 3.3 (2H, m), 3.3 to 3.4 (2H, m), 3.4
(3H, s), 3.5 to 3.7 (2H, m), 3.8 to 4.2 (3H, m).

Example 42-methoxymethylmorpholine hydrochloride [in formula (I)
And R A hydrochloride of a compound in which is a methyl group] : 2 below
2-methoxymethylmorpholine hydrochloride was obtained in the process. (1) 4-benzyl-2-methoxymethylmorpholy
N: From 0.58 g of sodium and 28 ml of anhydrous methanol
To the prepared sodium methoxide solution, N-benzyl-
2-Chloromethylmorpholine (Synthetic Communicatio
n Volume 10, pages 59-73, 1980
Therefore synthesized. ) 2.9 g and sodium iodide
After adding 2.8 g and heating under reflux for 24 hours, in a pressure vessel
The mixture was stirred at 165-170 ° C for 23 hours. Depressurize the solvent
Distill off underneath and add chloroform to the resulting residue to make it insoluble.
The product was filtered off. After the filtrate was evaporated to dryness under reduced pressure, the residue was filtered over silica gel.
Column chromatography (solvent, chloroform: me
The title compound 1.05 after purification with tanol = 100: 1)
g was obtained. The physical property analysis values of the compound obtained here are
N-benzyl-2-methoxymethyi obtained in Example 1 (1)
Matched that of Lemorpholine.

(2) 2-methoxymethylmorpholine
Hydrochloride N-Benzyl-2-methoxymethylmorpholine was hydrogenolyzed according to the procedure of Example 3 (2) to obtain 2-methoxymethylmorpholine.hydrochloride. The physical analysis values of the compound thus obtained were in agreement with those of 2-methoxymethylmorpholine.hydrochloride obtained in Example 3 (2).

Example 5 2-methoxymethylmorpholine [in the formula (I), R is
Methyl group compound] : The compound was produced by the following three steps. (1) N-benzyl-2-methoxymethylmorpholine 60 g of N-benzylethanolamine and 55 g of 1,2-epoxy-3-methoxypropane were stirred at 50 ° C. for 16 hours, and then excess 1,2-epoxy-3 was added. -Methoxypropane was distilled off under reduced pressure. 2 out of 98 g of the residue obtained
0 g was dissolved in 50 ml of toluene, and sodium hydroxide 12
A solution of 40 g of water in 40 ml of water and 0.25 g of tetra-n-butylammonium bromide were added, and p-toluenesulfonyl chloride 1 was added thereto while stirring at room temperature.
A solution of 6.8 g dissolved in 30 ml of toluene was added dropwise.
After completion of dropping, the mixture was stirred for 2 hours, and 100 ml of water was added. The toluene layer was separated and washed with water, 150 ml of 2N hydrochloric acid was added, and the aqueous layer was separated. Aqueous sodium hydroxide solution was added to the aqueous layer to make it strongly alkaline, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was distilled under reduced pressure to obtain 11 g of the title compound as a colorless liquid.
The physical property analysis values of the compound thus obtained are shown in Example 1 (1).
Consistent with that of N-benzyl-2-methoxymethylmorpholine obtained in.

(2) 4-ethoxycarbonyl-2-methoxymethylmorpholine 4-benzyl-2-methoxymethylmorpholine 10.6
g was dissolved in 20 ml of toluene, and 10.6 g of ethyl chlorocarbonate was added dropwise while stirring at 90 ° C. 90 after the dropping
After stirring at 2 ° C. for 2 hours and at 120 ° C. for 3 hours, the insoluble material was filtered off, and the mixture was concentrated under reduced pressure. The concentrated liquid was distilled under reduced pressure to obtain 8.2 g of the title compound as a colorless liquid.

Boiling point: 92 to 94 ° C./1 mmHg. NMR (CDCl ₃ ) δ: 1.2 to 1.3 (3H, t, J = 7Hz), 2.8 (1H, bt,
J = 11.5Hz), 3.0 (1H, bt, J = 11.5Hz), 3.4 (3H, s), 3.4 (2H, dd,
J = 2Hz, J = 5Hz), 3.5 to 3.6 (2H, m), 3.9 (2H, dd, J = 3Hz, J = 11.5
Hz), 4.0 (1H, bs), 4.1 to 4.2 (2H, q, J = 7Hz). Mass spectrum (m / e): 203 (M ⁺ ). Elemental analysis value (as C ₉ H ₁₇ NO ₄ ): Calculated value (%) C, 53.19; H, 8.43; N,
6.91. Analytical value (%) C, 52.94; H, 8.20; N,
6.79.

(3) 2-Methoxymethylmorpholine 4-ethoxycarbonyl-2-methoxymethylmorpholine (5.0 g) was mixed with 37 ml of a 2N aqueous sodium hydroxide solution, and the mixture was heated under reflux at 110 ° C. for 3 hours. Concentrated hydrochloric acid 1 in the reaction solution
2.5 ml was added. The reaction solution was evaporated to dryness under reduced pressure, 35 ml of ethanol was added to the residue, and the insoluble material was filtered off. The filtrate was evaporated to dryness under reduced pressure, 28 g (w / w) sodium methylate-methanol solution 6 g was added to the residue, and the mixture was stirred for 15 hours.
The insoluble material was filtered off, and the filtrate was concentrated under normal pressure. The concentrate was distilled under reduced pressure to obtain 1.89 g of the title compound as a colorless liquid. The physical property analysis values of the compound thus obtained are shown in Example 1.
This coincided with that of 2-methoxymethylmorpholine obtained in (2).

Example 6 2-methoxymethylmorpholine [in the formula (I), R is
Methyl group compound] : produced in the following two steps. (1) 4-Methyl-2-methoxymethylmorpholine N-methylethanolamine (20.0 g) was stirred at 57 ° C., and 1,2-epoxy-3-methoxypropane (26.1 g) was added dropwise thereto over 30 minutes. At this time, the temperature of the reaction solution rose to 95 ° C. After completion of dropping, the mixture was stirred for 3 hours. Then, with stirring at room temperature, 200 ml of dioxane, 59.3 g of potassium hydroxide and 0.87 g of tris (3,6-dioxaheptyl) amine were added, and then p-
60.9 g of toluenesulfonyl chloride in 1 of dioxane
The solution dissolved in 25 ml was added dropwise over 3 hours. After completion of dropping, the reaction solution was filtered after stirring at room temperature for 6 hours. The filtrate was concentrated under normal pressure, and the concentrated liquid was distilled under reduced pressure to obtain 17.2 g of the title compound as a colorless liquid.

Boiling point: 78 to 85 ° C./34 mmHg. NMR (CDCl ₃ ) δ: 1.9 (1H, t, J = 11Hz), 2.1 to 2.2 (1H, d)
t, J = 3.5Hz, J = 11.5Hz), 2.3 (3H, s), 2.6〜2.7 (2H, m), 3.4 (3
H, s), 3.3-3.5 (2H, m), 3.6-3.8 (2H, m), 3.9 (1H, m). Mass spectrum (m / e): 145 (M ⁺ ).

(2) 2-Methoxymethylmorpholine 20.0 g of 4-methyl-2-methoxymethylmorpholine obtained in the same manner as above was dissolved in 50 ml of benzene,
A reflux apparatus was attached, and 45.2 g of ethyl chlorocarbonate was added dropwise thereto while stirring at 90 ° C. After completion of dropping, the mixture was stirred at the same temperature for 100 minutes. A reddish brown viscous substance was precipitated on the way. After cooling, the supernatant was separated, and the remaining viscous substance was washed with a small amount of benzene. The supernatant and washings were combined and dried under reduced pressure. 200 ml of 2N sodium hydroxide solution in the residue
Was added, and the mixture was heated under reflux at 110 ° C. for 2 hours and then cooled with ice 6
100 ml of N hydrochloric acid was added. After the reaction solution was dried under reduced pressure, 200 ml of a saturated solution of potassium hydroxide in methanol was added to the residue. The insoluble material was filtered off, and the filtrate was concentrated under normal pressure. The concentrate was distilled under reduced pressure to give the title compound 8.8 as a colorless liquid.
g was obtained. The analysis values of the physical properties of the compound obtained here were in agreement with those of the 2-methoxymethylmorpholine obtained in Example 1 (2).

Example 7 2-methoxymethylmorpholine [in the formula (I), R is
Methyl group compound] : produced in the following two steps. (1) 4-Ethyl-2-methoxymethylmorpholine N-ethylethanolamine 46.0 g was added to dioxane 3
Dissolve in 50 ml and stir at room temperature while adding 1,2
A solution of 47.8 g of -epoxy-3-methoxypropane in 50 ml of dioxane was added dropwise. 70 after dropping
Stirred at 4 ° C for 4 days. Next, with stirring at room temperature, 115.8 g of potassium hydroxide and 1.69 g of tris (3,6-dioxaheptyl) amine were added, and then a solution of 118.1 g of p-toluenesulfonyl chloride dissolved in 250 ml of dioxane was added dropwise. . After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours and then the reaction solution was filtered. After concentrating the filtrate at atmospheric pressure,
The concentrate was distilled under reduced pressure to obtain 29.8 g of the title compound as a colorless liquid.

Boiling point: 100 to 102 ° C./29 mmHg. NMR (CDCl ₃ ) δ: 1.1 (3H, t, J = 7Hz), 1.9 (1H, t, J = 11H)
z), 2.1 to 2.2 (1H, dt, J = 3.5Hz, J = 11.5Hz), 2.4 to 2.5 (2H, q,
J = 7.5Hz), 2.7 to 2.8 (2H, m), 3.4 (3H, s), 3.4 to 3.5 (2H, m),
3.7〜3.8 (2H, m), 3.9 (1H, m). Mass spectrum (m / e): 159 (M ⁺ ).

(2) 2-Methoxymethylmorpholine 4-ethyl-2-methoxymethylmorpholine 20.0 g
Was dissolved in 60 ml of toluene, a reflux apparatus was attached, and 60.0 ml of ethyl chlorocarbonate was added dropwise thereto while stirring at 90 ° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for 6 hours, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the concentrated solution were added 50 ml of ethanol and 100 ml of 2N aqueous sodium hydroxide solution, and the mixture was stirred at 60 ° C. for 18 hours and 100 ° C. for 4.5 hours, 220 ml of 2N hydrochloric acid was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure, 300 ml of ethanol was added, the insoluble material was filtered off, and the filtrate was dried again under reduced pressure.
Dissolve the residue in 30 ml of methanol, and under ice cooling 28% (w /
w) Sodium methylate-methanol solution 32.0 ml
Was added and stirred for 20 minutes. The insoluble material was filtered off, and the filtrate was concentrated under normal pressure. The concentrate was distilled under reduced pressure to obtain 11.2 g of the title compound as a colorless liquid. The analysis values of the physical properties of the compound obtained here were in agreement with those of the 2-methoxymethylmorpholine obtained in Example 1 (2).

Example 8 2-Ethoxymethylmorpholine [in the formula (I), R
Is an ethyl group] : 2-ethoxymethylmorpholine was obtained by the following three steps. (1) 4-benzyl-2- (p-toluenesulfonyloxymethyl) morpholine: 4-benzyl-2-hydroxymethylmorpholine (Synthetic Communication, 1
51 g (synthesized according to the method described in Vol. 0, pp. 59-73, 1980) was dissolved in 100 ml of pyridine, 51.7 g of p-toluenesulfonyl chloride was added while cooling with ice, and the mixture was stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to give 70 g of the hydrochloride of the title compound. 50 g of this was suspended in 200 ml of water, adjusted to pH 10 with 2N sodium hydroxide, and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 43 g of the title compound. NMR (CDCl ₃ ) δ: 1.7 to 2.9 (4H, m), 2.4 (3H, s), 3.4 to
4.1 (5H, m), 3.5 (2H, s), 7.2〜7.5 (7H, m), 7.8 (2H, d, J = 9H
z).

(2) 4-Benzyl-2-ethoxymethylmorpholine: 4-benzyl-2- (p-toluenesulfonyloxymethyl) morpholine.hydrochloride (3 g) and sodium ethoxide (2 g) were added to ethanol (150 ml) to give 70
Stir at 24 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After distilling off the solvent under reduced pressure,
The residue was purified by silica gel column chromatography [eluted with a mixed solvent of chloroform-methanol (40: 1)] and further subjected to bulb-to-bulb distillation to obtain 0.9 g of the title compound as a colorless liquid.

Boiling point: 162 ° C./0.4 mmHg. NMR (CDCl ₃ ) δ: 1.2 (3H, t, J = 7Hz), 1.9 (1H, dd, J = 11H)
z, J = 10.5Hz), 2.2 (1H, td, J = 11Hz, J = 3Hz), 2.6-2.7 (1H,
m), 2.8 (1H, dt, J = 11Hz, J = 2Hz), 3.3〜3.5 (6H, m), 3.6〜3.8
(2H, m), 3.8 to 3.9 (1H, m), 7.2 to 7.4 (5H, m).

(3) 2-Ethoxymethylmorpholine:
200% of 10% palladium-carbon and 4-benzyl-2-
Ethoxymethylmorpholine 1.6g ethanol 30ml
In addition, the mixture was stirred for 24 hours under a hydrogen pressure of 5 kg / cm ² . Palladium-carbon was filtered off and the solvent was distilled off under reduced pressure to obtain 0.7 g of the title compound as a colorless liquid. NMR (CDCl ₃ ) δ: 1.2 (3H, t, J = 7Hz), 3.0 to 3.2 (2H, m),
3.4 ~ 3.6 (6H, m), 4.0 ~ 4.2 (3H, m), 8.2 (1H, br).

Reference Example 1 N- (2,3,4-trifluorophenyl) dithiocar
Vamidic acid 3-chloro-2-oxopropyl ester [formula
Compound of (X)] : 2.0 g of 1,3-dichloroacetone
Is added to 100 ml of methylene chloride and stirred at 2-5 ° C.
Then, 5.0 g of triethylammonium N- (2,3,4-trifluorophenyl) dithiocarbamate (see European Patent Publication No. 286089) was added. Then, the mixture was stirred for 60 minutes and washed with 3N hydrochloric acid and then with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solvent of hexane-ethyl acetate-ether to give 4.2 g of the title compound. Mass spectrum (m / e): 313 (M ⁺ ).

Reference Example 2 4-chloromethyl-3- (2,3,4-trifluorophenyl)
Phenyl) -2 (3H) -thiazolthione [of the formula (XI)
Compound] : N- (2,3,4-trifluorophenyl)
Dithiocarbamic acid 3-chloro-2-oxopropyl ester 4.0 g was added to a 30% hydrogen chloride / methanol solution 15
The mixture was added to ml and heated under reflux for 3 hours. Then, the solvent was distilled off under reduced pressure, cold water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine and dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was recrystallized from cyclohexane to obtain 2.6 g of the title compound as pale yellow crystals.

Melting point: 127-130 ° C. NMR (CDCl ₃ ) δ: 4.1 (1H, d, J = 13Hz), 4.2 (1H, d, J = 13H
z), 6.8 (1H, s), 7.2 (2H, m) .IR (KBr) ν _max cm ^-1 : 3072,1516,1504,1314,1260,11
02. Elemental analysis value (as C ₁₀ H ₅ NS ₂ F ₃ Cl): Calculated value (%) C, 40.61; H, 1.70; N,
4.74. Analytical value (%) C, 40.59; H, 1.80; N,
4.71.

Reference Example 3 5-Methyl-6,7-difluoro-1H, 4H-thiazo
[3,4-a] quinoxaline-1-thione [formula (XI
Compound of I)] : 4-chloromethyl-3- (2,3,4
2.5 g of -trifluorophenyl) -2 (3H) -thiazolthione was dissolved in 25 ml of acetonitrile, and 3.3 g of 40% methanol solution of methylamine was added to this solution.
The mixture was stirred at 0 ° C for 16 hours. The reaction mixture was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a mixed solvent of cyclohexane-ethyl acetate to obtain 2.0 g of the title compound as pale yellow crystals.

Melting point: 165 to 167 ° C. NMR (CDCl ₃ ) δ: 3.0 (3H, d, J = 2.5Hz), 4.0 (2H, d, J = 1H
z), 6.4 (1H, t, J = 1Hz), 6.9 (1H, dt, J = 8Hz, J = 9Hz), 9.3 (1H, d
dd, J = 2.5Hz, J = 5Hz, J = 9.5Hz). IR (KBr) ν _max cm ^-1 : 1502,1492,1306,1290,1032. Elemental analysis value (C ₁₁ H ₈ N ₂ S ₂ F _{As 2} ): Calculated value (%) C, 48.87; H, 2.98; N, 1
0.36. Analytical value (%) C, 49.04; H, 2.96; N, 1
0.41.

Reference Example 4 5-Methyl-6,7-difluoro-1-methylthio-4
H-quinoxalino [1,2-c] thiazolium iodide
[Compound of Formula (XIII) in which R ⁴ is a Methyl Group] : 5-
0.4 g of methyl-6,7-difluoro-1H, 4H-thiazolo [3,4-a] quinoxaline-1-thione and 0.4 g of methyl iodide were dissolved in 3 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature. It was left in the dark for 40 hours. The precipitate was collected by filtration and washed successively with acetonitrile and ether to give 0.5 g of the title compound as yellow crystals. NMR (DMSO-d ₆ ) δ: 3.0 (3H, d, J = 4Hz), 3.1 (3H, s), 4.4
(2H, s), 7.3 (1H, dt, J = 8Hz, 9.5Hz), 7.9 (1H, ddd, J = 2Hz, J = 5
Hz, J = 9.5Hz), 8.0 (1H, s).

Reference Example 5 (5-Methyl-6,7-difluoro-1H, 4H-thia
Zoro [3,4-a] quinoxaline-1-ylidene) malo
Diethyl acid ester [in the formula (XIV), R ⁴ is ethyl
Group compound] : Oily sodium hydride [content rate about 60
(W / w)%] 54 mg was suspended in tetrahydrofuran 3 ml, and diethyl malonate 0.2 g was added dropwise at 20 ° C.
Stir for minutes. Next, the above-mentioned 5-methyl-6,7-difluoro-1-methylthio-4H-quinoxalino [1,2
-C] 0.5 g of thiazolium iodide was added at 10 ° C,
Stir for 30 minutes at room temperature. The reaction mixture was dried under reduced pressure, cold water was added, the insoluble matter was collected by filtration, washed with water, dried and recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 0.34 g of the title compound as a yellow crystal. .

Melting point: 146-148 ° C. NMR (CDCl ₃ ) δ: 1.2 (6H, t, J = 7Hz), 3.1 (3H, d, J = 4.5H
z), 3.9 (4H, q, J = 7Hz), 4.0 (2H, s), 6.5 (1H, t, J = 1Hz), 6.8 (1
H, dt, J = 8Hz, J = 9Hz), 7.3 (1H, ddd, J = 2Hz, J = 5Hz, J = 9Hz) .IR (KBr) ν _max cm ^-1 : 1700,1642,1506,1426, 1294,118
. 8,1082 Elemental analysis (as _{C 18 H 18 N 2 O 4} SF 2): Calculated: C, 54.54; H, 4.58 ; N, 7.0
7. Analytical values: C, 54.45; H, 4.61; N, 6.8
9.

Reference Example 6 9,1- (methylimino) methano-7,8-difluoro
-5-oxo-5H-thiazolo [3,2-a] quinoline
-4-carboxylic acid ethyl ester [in the formula (XV), R
Compound in which ⁴ is an ethyl group] :: (5-methyl-6,7-difluoro-1H, 4H-thiazolo [3,4-a] quinoxaline-1-ylidene) malonic acid diethyl ester (see Reference Example 5) 1.2 g 100 g of a mixture of 10 g of polyphosphoric acid and
The mixture was stirred at 0 ° C for 5 hours. Cold water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of chloroform-ethanol to obtain 0.6 g of the title compound as pale yellow crystals.

Melting point: Decomposition around 285 ° C. NMR (DMSO-d ₆ ) δ: 1.3 (3H, t, J = 7Hz), 3.2 (3H, d, J = 5.
5Hz), 4.3 (2H, q, J = 7Hz), 4.5 (2H, d, J = 1Hz), 7.3 (1H, s), 7.4
(1H, dd, J = 7.5Hz, J = 10.5Hz) .IR (KBr) ν _max cm ^-1 : 3060,1708,1574,1496,1478,145
6,1050. Elemental analysis value (as C ₁₆ H ₁₂ N ₂ O ₃ SF ₂ ): Calculated value (%) C, 54.85; H, 3.45; N,
8.00. Analytical value (%) C, 54.65; H, 3.59; N,
7.97.

Reference Example 7 Diacetoxy [9,1- (methylimino) methano-
7,8-Difluoro-5-oxo-5H-thiazolo
[3,2-a] quinoline-4-carboxy] borane [formula
Compound of (IV)] : 0.27 g of boric acid and 3 of acetic anhydride
The mixture of g was stirred at 75-80 ° C for 50 minutes to obtain a solution of triacetoxyborane, to which 9,1- (methylimino) was added.
1.0 g of methano-7,8-difluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxylic acid ethyl ester was added, and the mixture was stirred at 100 ° C for 40 minutes.
The reaction mixture was allowed to cool to room temperature and the resulting crystals were collected by filtration and washed with isopropyl ether to give the title compound (1.26 g). The title compound recrystallized from acetonitrile showed the following physical properties.

Melting point: 285 ° C. or higher NMR (DMSO-d ₆ ) δ: 1.9 (6H, s), 3.3 (3H, d, J = 6Hz), 4.8
(2H, d, J = 1Hz), 7.6 (1H, dd, J = 7Hz, 10Hz), 7.9 (1H, t, J = 1H
z). IR (KBr) ν _max cm ⁻¹ : 1718,1697. Elemental analysis value (as C ₁₈ H ₁₃ N ₂ O ₇ SF ₂ B): Calculated value (%) C, 48.02; H, 2. 91; N,
6.22. Analytical value (%) C, 47.92; H, 3.02; N,
6.21.

Reference Example 8 9,1- (Methylimino) methano-7-fluoro-8-
(2-Methoxymethylmorpholino) -5-oxo-5H
-Thiazolo [3,2-a] quinoline-4-carboxylic acid
[Compound of Formula (V-1)] : Diacetoxy [9,1-
0.9 g of (methylimino) methano-7,8-difluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxy] borane (see Reference Example 7) was added to 20 ml of dimethyl sulfoxide and 2-methoxy. A mixture of 0.8 g of methylmorpholine hydrochloride (see Example 3) and 5.1 g of triethylamine was added, and the mixture was stirred at 60 ° C. for 22 hours. Dimethyl sulfoxide was distilled off under reduced pressure, 15 ml of acetone, 5 ml of concentrated hydrochloric acid and 40 ml of water were added to the residue, and the mixture was stirred at room temperature for 1 hour. The obtained solid was washed successively with water and acetone. This was recrystallized from acetonitrile to obtain 0.54 g of the title compound.

Melting point: Decomposition around 224 ° C. NMR (CDCl ₃ ) δ: 2.9 (3H, s), 3.3 (1H, ddd, J = 2.5Hz, J =
10.5Hz, J = 12.5Hz), 3.4 (3H, s), 3.4〜3.6 (5H, m), 3.8〜4.0
(2H, m), 4.0 (1H, dt, J = 2Hz, J = 11Hz), 4.4 (2H, s), 7.0 (1H,
s), 7.6 (1H, d, J = 12.5Hz), 15.4 (1H, bs). IR (KBr) ν _max cm ^-1 : 1696,1616,1490. Elemental analysis value (C ₂₀ H ₂₀ N ₃ O ₅ SF · ¼H ₂ O): Calculated value (%) C, 54.85; H, 4.72; N,
9.59. Analytical value (%) C, 54.90; H, 4.73; N,
9.59.

Reference Example 9 9,1- (methylimino) methano-7-fluoro-8-
(2-Ethoxymethylmorpholino) -5-oxo-5H
-Thiazolo [3,2-a] quinoline-4-carboxylic acid
[Compound of Formula (V-2)] : Diacetoxy [9,1-
(Methylimino) methano-7,8-difluoro-5-oxo-5H-thiazolo [3,2-a] quinoline-4-carboxy] borane (see Reference Example 7) 1.4 g, 2-ethoxymethylmorpholine (Example) 8) 0.7 g, triethylamine 1.6 g and dimethyl sulfoxide 40
The ml mixture was stirred at 65 ° C. for 16 hours. Water was added to the reaction solution, and the insoluble material was collected by filtration. To this, 25 ml of acetone, 8 ml of concentrated hydrochloric acid and 60 ml of water were added, and the mixture was stirred at room temperature for 3 hours.
The insoluble material was collected by filtration, washed with acetonitrile, and recrystallized from dimethyl sulfoxide to obtain 0.5 g of the title compound.

Melting point: Decomposed near 231 ° C. NMR (DMSO-d ₆ ) δ: 1.1 (3H, t, J = 7Hz), 2.8 (3H, s), 3.0
~ 3.1 (1H, m), 3.2 ~ 3.5 (7H, m), 3.7 ~ 3.8 (2H, m), 3.9 ~ 4.0
(1H, m), 4.5 (2H, s), 7.6 (1H, s), 7.6 (1H, d, J = 12.5Hz), 15.8
(1H, s). IR (KBr) ν _max cm ^-1 : 1706,1614,1494,1464. Elemental analysis value (as C ₂₁ H ₂₂ N ₃ O ₅ SF · 1 / 2H ₂ O): Calculated value (% ) C, 55.25; H, 5.08; N,
9.20. Analytical value (%) C, 55.29; H, 5.05; N,
9.23.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomohiro Miyasaka 2-12-21-102, Tomobuchi-cho, Miyakojima-ku, Osaka (72) Inventor Toshio Achiha Kasuga, Kasuga, Taiko-cho, Minamikawachi-gun, Osaka Prefecture

Claims (3)

[Claims] 1. The following formula (I): (In the formula, R represents a lower alkyl group having a straight or branched chain having 1 to 3 carbon atoms.) A morpholine derivative or an acid addition salt thereof. 2. The following formula (II): (In the formula, R represents a lower alkyl group having a straight or branched chain having ¹ to 3 carbon atoms, and R ¹ is a lower alkyl group having a straight chain or branched chain having 1 to 4 carbon atoms, or an aralkyl group. The following formula (I) is characterized by hydrolyzing a morpholine derivative represented by the formula: (In the formula, R represents a lower alkyl group having a straight or branched chain having 1 to 3 carbon atoms.) A method for producing a morpholine derivative or an acid addition salt thereof. 3. The following formula (III): (In the formula, R represents a lower alkyl group having a straight or branched chain having 1 to 3 carbon atoms, and R ² represents a benzyl group, a substituted benzyl group, a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group.) A morpholine derivative represented by the formula (I): wherein hydrogenolysis is carried out in the presence of a catalyst for catalytic reduction. (In the formula, R represents a lower alkyl group having a straight or branched chain having 1 to 3 carbon atoms.) A method for producing a morpholine derivative or an acid addition salt thereof.