JP2978490B2 - 5-Substituted-4,7-dioxo-5-azaspiro [2.4] heptane derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate of an antibacterial spiro compound which is useful as a medicament, veterinary medicine, marine medicine and preservative.

[0002]

2. Description of the Related Art To date, various derivatives have been known as synthetic antibacterial compounds. However, it is known that some of those exhibiting high antibacterial activity often have poor (low) oral absorbability.

As a result of intensive studies, the present inventors have found that 7-amino-5-azaspiro [2.
4] It has been found that a quinolone derivative having a heptyl group has high antibacterial activity and is excellent in oral absorbability.

[0004]

The present invention relates to a compound of the general formula I

[0005]

Embedded image (Wherein, R represents a benzyl group or a 1-phenylethyl group) and a salt thereof.

The compound of the present invention is an intermediate for producing 7-amino-5-azaspiro [2.4] heptane. A compound derived from this compound and having a 7-amino-5-azaspiro [2.4] heptyl group at the “7-position equivalent” of the quinolone derivative has excellent properties. “7” of quinolone derivative
"Position equivalent" means the 7-position of 4-oxoquinoline-3-carboxylic acid or 4-oxo-1,8-naphthyridine-3-carboxylic acid having various substituents, or 7-oxopyrido [1,2 , 3-de] [1,
4] Benzoxazine-6-carboxylic acid 10-position, benzo [ij]
It means the 8-position of quinolidine-2-carboxylic acid and the like.

The compound of the present invention can be synthesized by the following method.

First, 1,2-ethyl acetoacetate is added in the presence of a base.
Dibromoethane is reacted to give ethyl 1-acetyl-1-cyclopropanecarboxylate. The acetyl group of this is then brominated with bromine, leading to ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. Next, this was reacted with benzylamine to close the ring, and 5-benzyl-4,7-
Dioxo-5-azaspiro [2.4] heptane can be produced.

When R-(+)-1-phenylethylamine is reacted with ethyl 1-bromoacetyl-1-cyclopropanecarboxylate, 5- [1- (R) -phenylethyl] -4,7- Dioxo-5-azaspiro [2.4] heptane can be produced.

Although an example using R-(+)-1-phenylethylamine has been described here, the same can be practiced with (S) -phenylethylamine. In addition, it is considered that the method can be carried out using optically active 1-phenylpropylamine, 1-phenylbutylamine, or the like.

Further, 5- [1- (R) -phenylethyl] -4,7-
Dioxo-5-azaspiro [2.4] heptane can also be synthesized by the following method. That is, after hydrolyzing an ester of ethyl 1-acetyl-1-cyclopropanecarboxylate to form a carboxylic acid, an amide derivative with R-(+)-1-phenylethylamine, N- [1- (R ) -Phenylethyl] -1-acetyl
-1- Cyclopropanecarboxamide. This compound converts the carbonyl group of the methyl ketone moiety into a ketal to give N- [1- (R) -phenylethyl] -1- (1,1-ethylenedioxyethyl) -1-cyclopropanecarboxamide.
After this, the methyl group adjacent to the ketal is halogenated,
For example, N- [1- (R) -phenylethyl] -1- (2-bromo-1,1-
Ethylenedioxyethyl) -1-cyclopropanecarboxamide. This halomethyl compound, when treated under basic conditions, is a pyrrolidinedione having a spiro ring and a ketal, 4,7-dioxo-5- [1- (R) -phenylethyl] -5-azaspiro [2.4] heptane-7 -Ethylene acetal. This is obtained by removing ketals under acidic conditions4,
7-dioxo-5- [1- (R) -phenylethyl] -5-azaspiro
[2.4] Converted to heptane.

7-amino-5 derived from the compound of the present invention
-Quinolone derivatives having an azaspiro [2.4] heptyl group have higher lipophilicity, higher oral absorbability and higher antibacterial activity than the corresponding quinolone derivatives having no spiro ring. You.

[0013]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1. 5-benzyl-4,7-dioxo-5-
Synthesis of azaspiro [2.4] heptane 1) Ethyl 1-acetyl-1-cyclopropanecarboxylate Ethyl acetoacetate, 10.4 g of 1,2-dibromoethane 15
g, potassium carbonate 23 g, N, N-dimethylformamide (D
MF) was mixed and stirred at room temperature for 2 days. The insoluble material was removed by filtration, the filtrate was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the pale yellow oil obtained was distilled under reduced pressure to give the title compound 2, 7.5 g as a fraction having a boiling point of 70-71 ° C / 2-3 mmHg. I got

¹ H-NMR (CDCl ₃ ) δ ppm: 1.30 (3H, t, J = 7
Hz), 1.48 (4H, s), 2.49 (3H, s), 4.24 (2H, q, J = 7H
z).

2) 5-benzyl-4,7-dioxo-5-azas
Pyro [2.4] heptane 4 Dissolve 2, 7 g of compound in 50 ml of ethanol, and add bromine 8.0
g was added dropwise with stirring at room temperature. After stirring at room temperature for 2 hours,
Excess bromine and the solvent were distilled off under reduced pressure to give 1-bromoacetyl-1-.
Ethyl cyclopropanecarboxylate 3, was obtained. This was dissolved in 50 ml of ethanol without purification, and 12 g of benzylamine was added dropwise under ice-cooling and stirring. After returning to room temperature and stirring for 24 hours, the solvent was distilled off under reduced pressure.
The resultant was dissolved in 00 ml, washed with 1N hydrochloric acid and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel chromatography and eluted with 2% methanol-chloroform to elute the title compound (4, 2.3 g).
Was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.6-1.8 (4H, m),
3.78 (2H, s), 4.68 (2H, s), 7.2-7.45 (5H, br s).

Reference Example 1. 7-amino-5-azaspiro [2.4]
Synthesis 1) 5-Benzyl-7- heptane (hydroxyimino) -4-oxo-5-A
Zaspiro [2.4] heptane 5 compound 4, 670 mg in hydroxylamine hydrochloride 700 mg,
Add 200 mg of triethylamine and 10 ml of ethanol,
Stirred overnight at room temperature. The solvent was distilled off under reduced pressure.
An aqueous citric acid solution was added for dissolution, and the mixture was extracted with chloroform. The chloroform extract was back-extracted with a 1N aqueous sodium hydroxide solution, and the aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. After the extract was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (5, 490 mg) as white crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.3-1.7 (4H, m),
3.80 ^* & 4.10 ^* (2H, s), 4.60 ^** & 4.70 ^** (2H, s), 7.38 (5
H, arm.) (*, **: mixture of sin and anti)

2) 7-amino-5-azaspiro [2.4] hepta
490 mg of Compound 7 was dissolved in 80 ml of anhydrous tetrahydrofuran, 500 mg of lithium aluminum hydride was added, and the mixture was heated under reflux for 8 hours. After returning to room temperature, 0.5 ml of water,
0.5 ml of 15% aqueous sodium hydroxide solution and 1.5 ml of water were added in this order, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give 7-amino-5.
-Benzyl-5-azaspiro [2.4] heptane 6, was obtained.
This was dissolved in ethanol (20 ml) without purification, 10% palladium-carbon was added thereto, and the mixture was catalytically hydrogenated at 4.5 kg / cm ² and 50 ° C. After 6 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure at room temperature or lower to obtain a crude product of the title compound 7.
This compound 7 was used for various reactions without purification.

3) 7-[(R) -Np-toluenesulfonylproly
L] amino-5-benzyl-5-azaspiro [2.4] heptane
8 compound 6, 2.8 g, triethylamine 1.5 g,
Mix 50 ml of methylene chloride, and stir under ice-cooling and stir separately prepared acid chloride of (R) -Np-toluenesulfonylproline (Note: Use 4 g of (R) -Np-toluenesulfonylproline and excess thionyl chloride 10 ml of methylene chloride was added dropwise over 10 minutes, and the mixture was returned to room temperature and stirred for 3 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to flash column chromatography (silica gel 80 g) to give the titled compound 8 (3.5 g) as a candy substance from the fraction eluted with ethyl acetate.

4) 7-[(R) -Np-toluenesulfonylproly
Ru] amino-5-benzyloxycarbonyl-5-azaspire
B [2.4] Heptane 9, optically active compounds 9a and 9b , 8, 3.5 g of compound and 2.5 ml of benzyl chlorocarbonate were added to 4 ml of dry methylene chloride and stirred at room temperature for 12 hours.
After adding 4 ml of benzyl chlorocarbonate and stirring for 5 hours,
Chloroform was added, and a saturated aqueous solution of sodium hydrogen carbonate was added,
Washed sequentially with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to flash column chromatography (silica gel, 85 g), eluting with ethyl acetate-n-hexane (2: 1 to 4: 1, v / v). Part of the title compound
9.3 g were obtained as a pale yellow oil, which was immediately subjected to HPLC to obtain 1.40 g and 1.45 g of optically active compounds 9a and 9b, respectively.

Column used: Nucleosyl 50-5 (20 × 2
50 mm) Developing solvent: ethyl acetate 9a: [α] _D +133.6 ° (c = 0.75, chloroform) 9b: [α] _D + 76.0 ° (c = 0.85, chloroform)

[0024]5) Optically active 7-amino-5-azaspiro
[2.4] Heptane 7a and 7b Dissolve 1.4 g of compound 9a in 20 ml of ethanol and add 2N
An aqueous sodium chloride solution (15 ml) was added, and the mixture was refluxed for 19 hours. Anti
The reaction solution was acidified with concentrated hydrochloric acid, and then added twice with chloroform and ethyl acetate.
After washing once with water, the aqueous layer was concentrated under reduced pressure to give a colorless solid as a residue.
As obtained. 50% aqueous solution of sodium hydroxide in this colorless solid
Add 10 ml of the solution, perform vacuum distillation, and add an aqueous solution containing compound 7a.
Was obtained as a distillate and used as it was in the next reaction.

The other compound 7b is compound 9
The same operation was obtained from b.

6) 7-tert-butoxycarbonylamino-5
-Dissolve 6 mg of azaspiro [2.4] heptane 11 compound in 800 ml of tetrahydrofuran and add 1.2 g of 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (BOC-ON) at room temperature. Allowed to react for hours. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the mixture was extracted with a 10% aqueous citric acid solution. The citric acid extract was adjusted to pH 10 with 1N aqueous sodium hydroxide solution.
As described above, extraction was performed with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 7-tert-butoxycarbonylamino-5-benzyl-5-azaspiro [2.4]
Heptane 10, 900 mg was obtained. 10, 870 mg of this compound
Was dissolved in 15 ml of ethanol and 10% -palladium carbon 500
The resulting mixture was subjected to catalytic hydrogenation at 40 ° C. under pressure (4.5 kg / cm ² ). After 2 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound 11, which was used for the substitution reaction without purification.

Embodiment 2 FIG . 5- [1- (R) -phenylethyl] -4,
Dissolve 35.7 g of 7-dioxo-5-azaspiro [2.4] heptane 12 synthesized compound in 200 ml of ethanol and obtain bromine.
40 g were added dropwise at room temperature with stirring. After stirring at room temperature for 2 hours, excess bromine and the solvent were distilled off under reduced pressure to obtain ethyl 1-bromoacetyl-1-cyclopropanecarboxylate 3. This was dissolved in 200 ml of ethanol without purification, and 33 g of R-(+)-1-phenylethylamine and 27 g of triethylamine were simultaneously added dropwise over 1 hour under ice-cooling and stirring, and then returned to room temperature and stirred for 2 days. went. After filtering off the insoluble matter, the ethanol was distilled off under reduced pressure, and the residue was treated with ethyl acetate 300 m
The resultant was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated saline solution in this order, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to 200 g of silica gel column chromatography, and chloroform to 2% methanol /
Elution with chloroform gave the title compound 12 as colorless crystals.

Melting point: 98-103 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.62 (3H, d, J = 7.2 Hz), 1.4
-1.8 (4H, m), 3.5 (1H, d, J = 18 Hz), 3.9 (1H, d, J
= 18 Hz), 5.82 (1H, q, J = 7.2 Hz), 7.36 (5H, s).

Reference Example 2. Optically active 7-amino-5-azas
Synthesis of pyro [2.4] heptane 1) 5- [1- (R) -phenylethyl] -7-hydroxyimino-4-
Oxo-5-azaspiro [2.4] heptane 13 Compound 12, 3.35 g to hydroxylamine hydrochloride 1.6
g, triethylamine 2.3 g, and ethanol 80 ml, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, chloroform was added to the residue, and the mixture was washed with a 10% aqueous citric acid solution and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound 13,
3.5 g were obtained as colorless crystals.

Melting point: 188-194 ° C. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.2-1.4 (2H, m), 1.53 (3H, d,
J = 7.2 Hz, & 2H, m), 3.8 (1H, d, J = 18 Hz), 4.16 (1
H, d, J = 18 Hz), 5.63 (1H, q, J = 7.2 Hz), 7.32 (5H,
s)

2) 7-amino-4-oxo-5- [1- (R) -phenyl
Ruethyl] -5-azaspiro [2.4] heptane 14a, 14b Compound 13 (3.5 g) and Raney nickel 7.5 ml were added to methanol 150 ml and subjected to catalytic reduction at room temperature for 12 hours.
After removing the catalyst by filtration, the solvent was evaporated under reduced pressure, and the residue was subjected to 100 g of silica gel column chromatography, and eluted with 5% methanol / chloroform to give compound 14b.
(Fraction eluted first) and 1.0 g and 0.8 g of compound 14a were obtained as colorless oils, respectively.

14b; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.8-1.4 (4
H, m), 1.52 (3H, d, J = 7 Hz), 2.87 (1H, dd, J = 10.
3Hz), 3.3-3.9 (2H, m), 4.27 (2H, br s), 5.42 (1H, q,
J = 7 Hz), 7.29 (5H, s)

14a; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.6-1.3 (4
H, m), 1.40 (2H, s), 1.53 (3H, d, J = 7.2 Hz), 2.99 (1
H, dd, J = 12.8, 7.2 Hz), 3.15-3.45 (2H, m), 5.52
(1H, q, J = 7.2 Hz), 7.30 (5H, s)

3) 7-amino-5- [1- (R) -phenylethyl]-
5-Azspiro [2.4] heptane 15a, 15b To 50 ml of anhydrous tetrahydrofuran was added 1.0 g of compound 14b and 500 mg of lithium aluminum hydride.
Reflux for 17 hours. After cooling, add 0.5 ml of water and 15%
An aqueous sodium hydroxide solution (0.5 ml) and water (1.5 ml) were sequentially added, followed by stirring at room temperature for another 30 minutes. After filtering the insolubles, the residue was thoroughly washed with tetrahydrofuran, and the filtrate and the washing were combined and dried. After evaporating the solvent under reduced pressure, the title compound 1 as a pale yellow oil was obtained.
5b, 940 mg were obtained. Similarly, 755 mg of compound 15a was obtained from 800 mg of compound 14a.

15b; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.2-0.8 (4
H, m), 1.35 (3H, d, J = 6.6 Hz), 1.6-2.0 (2H, br
m), 2.2-3.1 (4H, m), 3.24 (1H, q, J = 6.6 Hz), 3.5-
3.9 (1H, m), 7.28 (5H, br s)

15a; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.3-0.9 (4
H, m), 1.36 (3H, d, J = 6.7 Hz), 1.8-2.2 (2H, m),
2.2-3.2 (4H, m), 3.24 (1H, q, J = 6.7 Hz), 3.6-
3.9 (1H, m), 7.28 (5H, br s)

4) 7- (tert-butoxycarbonylamino)-
5- [1- (R) -phenylethyl] -5-azaspiro [2.4] hepta
16a, 16b Compound 15b, 764 mg in 20 ml of anhydrous tetrahydrofuran
And 1.3 g of BOC-ON, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, washed twice with a 1N aqueous sodium hydroxide solution and once with water, and then extracted with a 10% aqueous citric acid solution. The aqueous layer was washed once with ethyl acetate, and made alkaline by adding a 15% aqueous sodium hydroxide solution under cooling.
Extraction was performed three times with chloroform, and the organic layer was washed with saturated saline and dried. After evaporating the solvent, the residue was subjected to silica gel column chromatography (silica gel, 20 g, eluted with chloroform: methanol = 20: 1, 10: 1) to obtain 690 mg of the title compound 16b. This crystallized after standing. Washed with n-hexane. Compound 16a was obtained in a similar manner.

16b: colorless crystal Melting point: 103-105 ° C. [α] _D -15.2 ° (c = 1.475, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-0.9 (4H, m), 1.36 (3H,
d, J = 7.2 Hz), 1.44 (9H, s), 2.42 (2H, AB q, J = 10.
2 Hz), 2.79 (2H, d, J = 5.6 Hz), 3.24 (1H, q, J = 7.2
Hz), 3.6-4.0 (1H, m), 4.6-5.1 (1H, br d), 7.28 (5
H, s) Elemental analysis: C ₁₉ H ₂₈ N ₂ O ₂ Calculated: C 72.12, H 8.92, N 8.85 Analytical values: C 71.63, H 9.07, N 8.64

16a: colorless crystal Melting point: 94-97 ° C. [α] _D + 47.6 ° (c = 0.89, chloroform) ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-0.9 (4H, m), 1.33 (3H, d,
J = 6.6 Hz), 1.40 (9H, s), 2.29 (1H, d, J = 9 Hz), 2.
44 (1H, dd, J = 10.8, 3.6 Hz), 2.77 (1H, d, J = 9 H
z), 2.88 (1H, dd, J = 10.8, 5.3 Hz), 3.22 (1H, q, J =
6.6 Hz), 3.6-3.9 (1H, m), 4.7-5.2 (1H, br d), 7.
27 (5H, s) Elementary _{analysis: C 19 H 28 N 2 O} 2 Calculated: C 72.12, H 8.92, N 8.85 Analytical values: C 71.86, H 9.36, N 8.68

5) 7-tert-butoxycarbonylamino-5
-Azaspiro [2.4] heptane 11a, 11b Compound 16b, 650 mg and 50% aqueous palladium-carbon 500 m
g was added to 30 ml of ethanol and subjected to catalytic reduction at 4.2 atm under heating. Six hours later, the catalyst was removed by filtration and the mother liquor was distilled off under reduced pressure. Ethyl acetate was added to the resulting oily residue, and the mixture was extracted twice with a 10% aqueous citric acid solution. Then, this was extracted three times with chloroform, and the chloroform layer was washed with water and dried.
After evaporating the solvent, 440 mg of the title compound 11b was obtained as a crude product.
Obtained. Compound 11a was obtained in the same manner. Compounds 11b and 11a
^{The 1} H-NMR spectra were completely consistent.

17b; ¹ H-NMR (CDCl ₃ ) δ ppm: 0.4-1.0 (4
H, m), 1.42 (9H, s), 2.71 (1H, d, J = 10.2 Hz), 2.92
(1H, dd, J = 10.8, 3.6 Hz), 3.01 (1H, d, J = 10.2 H
z), 3.33 (1H, dd, J = 10.8, 5.4 Hz), 3.5-3.9 (1H,
m), 5.0-5.4 (1H, br d)

Example 3 4,7-Dioxo-5- [1- (R) -phenyl
Separate synthesis of ruethyl-5-azaspiro [2.4] heptane 12 1) Dissolve 268.6 g of 1-acetylcyclopropane-1-carboxylic acid 58 compound 2 in 400 ml of ethanol and add 75.67 g of sodium hydroxide to 200 ml of water. The aqueous solution was added dropwise at room temperature for 20 minutes (the internal temperature was 21 to 41 ° C.), and the mixture was stirred at room temperature for 2 hours. 1,500 ml of dichloromethane
And 1,500 ml of water were added. The mixture was shaken and separated, and the aqueous layer was washed twice with 500 ml of dichloromethane. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid under water cooling, and extracted with 1,500 ml of dichloromethane. The aqueous layer was extracted again with 500 ml of dichloromethane, and the dichloromethane layer was collected, washed with 500 ml of water, and dried over anhydrous sodium sulfate. The dichloromethane was distilled off under reduced pressure to obtain 232 g of the title compound which was colorless and transparent.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.6-2.0 (4H,
m), 2.21 (3H, s)

2) N- [1- (R) -phenylethyl] -1-acetyl
1-Cyclopropanecarboxamide 59 Compound 58, 232.0 g was dissolved in chloroform 1,500 ml, triethylamine 250.8 ml was added, and the mixture was cooled to an internal temperature of -40 ° C in a dry ice-acetone bath, and ethyl chloroformate 215.9 g was added. Dropped in 20 minutes (internal temperature -40 to -30
° C). After stirring at around -30 ° C for 40 minutes, the mixture was cooled again to -40 ° C, and 241.1 g of R-(+)-1-phenylethylamine was added dropwise over 20 minutes (internal temperature: -25 ° C). Stir for 1.5 hours, 1N
Hydrochloric acid was added for washing. After washing again with 1N hydrochloric acid, washing with water and a saturated aqueous solution of sodium hydrogencarbonate was followed by washing with water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was distilled off under reduced pressure to give the title compound as a colorless oil (489.3 g).
Obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.50 (3H, d, J =
7.2 Hz), 1.4-1.6 & 1.7 -1.9 (2H, m each), 1.95 (3H,
s), 5.10 (1H, q, J = 7.2Hz), 7.30 (5H, s)

3) N- [1- (R) -phenylethyl] -1- (1,1-d
(Tylenedioxyethyl) -1-cyclopropanecarboxami
248.4 g of Compound 60 (59, 248.4 g) was dissolved in 800 ml of benzene, 230 ml of ethylene glycol and 10.0 g of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed for 24 hours while being dehydrated. After cooling, 500 ml of water and 500 ml of benzene were added to carry out liquid separation, followed by washing with a saturated aqueous solution of sodium hydrogen carbonate and water, and the benzene layer was dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure to obtain 227.8 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 0.7-0.95 & 1.0
-1.2 (2H, m each), 1.48 (3H, s), 1.47 (3H, d, J = 7.
2 Hz), 3.98 (4H, s), 5.11 (1H, q, J = 7.2 Hz), 7.31 (5
H, s), 7.75 (1H, bs)

4) N- [1- (R) -phenylethyl] -1- (2-bromo
(Mo-1,1-ethylenedioxyethyl) -1-cyclopropaneca
At room temperature, 145.4 g of bromine was added dropwise to 436 ml of ruboxamide 61 dioxane over 30 minutes (the internal temperature increased to 35 degrees). Partly, a dioxane bromine complex was precipitated. The mixture was stirred at the same temperature for 30 minutes, and a solution of compound 60, 227.8 g of dichloromethane and 2,000 ml of dichloromethane was added at once (the internal temperature was lowered from 35 ° C to 25 ° C.
Rises to about 35 ° C). The mixture was stirred for 2 hours, an aqueous solution of sodium thiosulfate was added, and after liquid separation, the organic layer was washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate, and dichloromethane was distilled off under reduced pressure to obtain 326.0 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm: 0.7-1.0 & 1.0
-1.25 (2H, m each), 1.49 (3H, d, J = 7.2 Hz), 3.69 (2
H, s), 3.8-4.3 (4H, m), 5.08 (1H, q, J = 7.2 Hz),
7.30 (5H, s), 7.6 (1H, bs)

5) 4,7-dioxo-5- [1- (R) -phenylethyl
Le] -5-Azaspiro [2.4] heptane-7-ethylene acetate
62 Compound 61, 293.0 g with N, N-dimethylformamide 1,5
Dissolved in 100 ml, 60% sodium hydride 43.0
g was added in three portions at room temperature in small portions over 1.5 hours.
Since the internal temperature generates heat from 28 ℃ to about 35 ℃, cool with ice water,
The reaction was continued at an internal temperature of about 30 ° C., and reacted at room temperature for 18 hours. The reaction solution was poured into ice, extracted with 3,000 ml of ethyl acetate, washed several times with water, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After concentrating the solvent and treating with activated carbon, the solvent was distilled off under reduced pressure to obtain 203.3 g of the title compound as a black oil. ¹ H-NMR (CDCl ₃ ) δ ppm: 0.98-1.38 (4H, m), 1.50 (3H,
d, J = 7.2 Hz), 3.07 & 3.41 (1H, d, J = 10.2 H each)
z), 3.83 (4H, s), 5.61 (1H, q, J = 7.2 Hz), 7.30 (5H,
s)

6) 4,7-dioxo-5- [1- (R) -phenylethyl
L] -5-azaspiro [2.4] heptane 12 compound 62, 203.3 g in 1,000 ml of acetone and 1N hydrochloric acid 3
Then, the mixture was heated and refluxed for 1.5 hours. Acetone was distilled off under reduced pressure, and ethyl acetate (1,500 ml) was added to the residue. After washing with water, the ethyl acetate layer was dried over anhydrous sodium sulfate. After activated carbon treatment, ethyl acetate was distilled off under reduced pressure to obtain 160.0 g of the crude compound of the title. The residue was subjected to silica gel column chromatography (silica gel 1.3 kg), and eluted with chloroform containing 0-10% ethyl acetate to obtain 65.7 g of the title compound as white crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.61 (3H, d, J =
7.2 Hz), 1.4-1.75 (4H, m), 3.48 & 3.88 (1H,
d, J = 17.7 Hz), 5.81 (1
H, q, J = 7.2 Hz), 7.34 (5
H, s)

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Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 401/04 209 C07D 401/04 209 C07M 7:00 (31) Priority claim number Japanese Patent Application No. 1-156316 (32) Priority Date 1 ( (1989) June 19 (33) Countries claiming priority Japan (JP) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 209/54 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula I (Wherein, R represents a benzyl group or a 1-phenylethyl group) and salts thereof.