JP2978491B2 - 7-Amino-5-substituted-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 diligent studies, the present inventors have found that a quinolone derivative having a 7-amino-5-azaspiro [2.4] heptyl group derived from the compound of the present invention has high antibacterial activity and excellent oral absorbability. I found that.

[0004]

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

[0005]

Embedded image (Wherein R ¹ represents a hydrogen atom or an amino-protecting group, and R ² represents a benzyl group or a 1-phenylethyl group) and a salt thereof.

The protecting group is an alkoxycarbonyl group,
An aralkyloxycarbonyl group, an acyl group, an alkyl group, an aralkyl group, a compound that is an ether or a silyl group and a salt thereof,

Further, the present invention relates to a compound wherein the protecting group is an alkoxycarbonyl group, an aralkyloxycarbonyl group or an acyl group, and a salt thereof.

A compound wherein the protecting group is a tertiary butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group or an acetyl group; It relates to its salts and to compounds of the general formula I which consist of the pure optical isomers.

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 protecting group for the amino group may be appropriately selected from those generally used. Examples thereof include alkoxycarbonyl groups such as tertiary butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, and benzyloxy group. Aralkyloxycarbonyl groups such as carbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group, etc. Acyl groups,
Tertiary butyl group, benzyl group, paranitrobenzyl group,
Alkyl groups such as paramethoxybenzyl group and triphenylmethyl group or aralkyl groups, methoxymethyl group, tert-butoxymethyl group, tethydropyranyl group, 2,2,2-
Examples thereof include ethers such as trichloroethoxymethyl group, and silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group and tertiary butyldiphenylsilyl group.

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

First, in ethyl acetoacetate 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-
Converts to dioxo-5-azaspiro [2.4] heptane. When this is reacted with hydroxylamine hydrochloride, the ketone at the 7-position becomes an oxime to give 5-benzyl-7- (hydroxyimino) -4-oxo-5-azaspiro [2.4] heptane. This oxime compound is reduced with lithium aluminum hydride to produce an aminopyrrolidine compound having a spiro ring, 7-amino-5-benzyl-5-azaspiro [2.4] heptane.

Further, R-(+)-1-phenylethylamine is reacted with ethyl 1-bromoacetyl-1-cyclopropanecarboxylate to give 5- [1- (R) -phenylethyl] -4,7-dioxo. -Five
-Azaspiro [2.4] heptane. This compound is reacted with hydroxylamine hydrochloride to convert the carbonyl group at the 4-position into an oxime. 5- [1- (R) thus obtained
-Phenylethyl] -7-hydroxyimino-4-oxo-5-
Azaspiro [2.4] heptane is catalytically reduced to convert a hydroxyimino group to an amino group, and to give 7-amino-4-oxo-5- [1-
(R) -Phenylethyl] -5-azaspiro [2.4] heptane. In this compound, the carbon atom at the 7-position is an asymmetric carbon and the (R) -phenylethyl group is present at the 5-position,
It is a mixture of two diastereomers. It has been found that the separation of this mixture can be carried out by silica gel column chromatography, and the separation of the optically active substance does not need to use HPLC. Further, if various crystalline acid addition salts of this compound are synthesized, separation can be performed by fractional recrystallization.

This 7-amino-4-oxo-5- [1- (R) -phenylethyl] -5-azaspiro [2.4] heptane is reduced with a metal hydride such as lithium aluminum hydride to give 7-amino-5. -[1- (R) -Phenylethyl]-
5-Azaspiro [2.4] heptane can be produced.
Then, when the amino group of this was treated with BOC-ON, it was converted to a tertiary butoxycarbonylamino group and the optically active 7-
Tertiary butoxycarbonylamino-5- [1- (R) -phenylethyl] -5-azaspiro [2.4] heptane is obtained.

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

Incidentally, 5- [1- (R) -phenylethyl] -4,7-dioxo-5-azaspiro [2.4] heptane may 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. Thereafter, the conversion may be performed in the same manner as described above.

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.

[0018]

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. 7-Amino-5-benzyl-5-azas
Synthesis of pyro [2.4] heptane 1) Ethyl 1-acetyl-1-cyclopropanecarboxylate Ethyl acetoacetate, 1,4-dibromoethane in 10.4 g
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).

3) 5-benzyl-7- (hydroxyimino) -4-
Oxo-5-azaspiro [2.4] heptane 5 compound 4, 670 mg to 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)

[0025]4) 7-amino-5-benzyl-5-azaspiro
[2.4] Heptane 6 Dissolve 490 mg of Compound 5 in 80 ml of anhydrous tetrahydrofuran
And add 500 mg of lithium aluminum hydride.
And refluxed 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
The insoluble material was 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.Reference Example 1.7-amino-5-azaspiro [2.4] hep
Synthesis of Tan 7 20 ml of ethanol was obtained without purifying the compound 6 obtained in Example 1.
And add 10% palladium-carbon, 4.5 kg / cm^Two, 50
It was catalytically hydrogenated under the condition of ° C. After 6 hours, the catalyst is removed by filtration.
The filtrate was concentrated under reduced pressure at a temperature lower than room temperature to give the title compound.
 Seven crude products were obtained. This compound 7 can be used without purification
Used for various reactions.

[0026]Reference Example 2.7-Amino-5-azaspiro
[2.4] Synthesis of heptane 1) 7-[(R) -Np-toluenesulfonylprolyl] amino-5
-Benzyl-5-azaspiro [2.4] heptane 8 Compound 6, 2.8 g, triethylamine 1.5 g, methylene chloride
(R)
-N-p- Toluenesulfonylproline acid chloride (Note,
(R) -N-p-toluenesulfonylproline 4 g and excess chloride
Prepared using thionyl. ) Methylene chloride 1
After 0 ml of the solution was added dropwise in 10 minutes, the temperature was returned to room temperature and stirred for 3 hours.
did. The reaction mixture was saturated aqueous sodium hydrogen carbonate and
After washing with saturated saline, it was dried over anhydrous sodium sulfate.
After evaporating the solvent under reduced pressure, the residue was purified by flash column chromatography.
Graphite (silica gel 80 g) and eluted with ethyl acetate
From the obtained part, 3.5 g of the title compound 8 as a candy substance was obtained.

2) 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)

[0029]3) 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.

Example 2.7 7-tert-butoxycarbonyl
Amino-5-benzyl-5-azaspiro [2.4] heptane 10
The compound (6, 800 mg) was dissolved in tetrahydrofuran (30 ml), 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (BOC-ON) (1.2 g) was added at room temperature, and the mixture was reacted for 2 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. Reference Example 3.7-tert-butoxycarbonylamino-5-
Synthesis of azaspiro [2.4] heptane 11 This compound 10, 870 mg was dissolved in ethanol 15 ml, and
% -Palladium on carbon 500 mg and pressurized (4.5 kg / c
m ² ) at 40 ° C. for catalytic hydrogenation. After 2 hours, the catalyst was filtered off,
The filtrate was concentrated under reduced pressure to obtain the title compound 11, which was used for a substitution reaction without purification.

Embodiment 3 FIG . Optically active 7-amino-5- [1- (R)
Synthesis of 1 -phenylethyl] -5-azaspiro [2.4] heptane 1) 5- [1- (R) -phenylethyl] -4,7-dioxo-5-azas
Pyro [2.4] heptane 12 Compound 2 Dissolve 35.7 g of compound 2 in 200 ml of ethanol
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).

2) 5- [1- (R) -phenylethyl] -7-hydroxy
Simino-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)

3) 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)

4) 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)

[0042]Embodiment 4. FIG. 7- (tert-butoxycarbonyl
Amino) -5- [1- (R) -phenylethyl] -5-azaspiro [2.
4] Synthesis of heptane 16a, 16b Compound 15b, 764 mg in 20 ml of anhydrous tetrahydrofuran
And BOC-ON, 1.3 g, and stirred at room temperature for 4 hours.
Was. Ethyl acetate was added to the reaction solution, and 1N sodium hydroxide was added.
After washing twice with aqueous solution and once with water, extract with 10% citric acid aqueous solution.
Issued. After washing the aqueous layer once with ethyl acetate, 15%
After adding an aqueous solution of thorium under cooling to make it alkaline,
Extract three times with chloroform, and wash the organic layer with saturated saline.
Washed and dried. After evaporation of the solvent, the residue
Chromatography (silica gel, 20 g, chloroform
(Methanol: methanol = 20: 1, eluted with 10: 1)
Compound 690 mg was obtained as Compound 16b. This crystallizes after standing
Was. Washed with n-hexane. Compound 16a is prepared in a similar manner.
Obtained.

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

Reference Example 4. 7-tert-butoxycarbonyla
Mino-5-azaspiro [2.4] heptane 11a, 11b Synthetic compound 16b, 650 mg, 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)

Reference Example 5. 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
De 60 Compound 59, was dissolved 248.4 g of benzene 800 ml, ethylene glycol 230 ml, p-toluenesulfonic acid monohydrate
10.0 g was added, and the mixture was heated and refluxed for 24 hours while dehydrating. 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
The mixture was dissolved in 00 ml and 43.0 g of 60% sodium hydride was added in three portions at room temperature in small portions over 1.5 hours. Internal temperature is 28 ℃
Since the mixture generates heat up to about 35 ° C., the reaction was cooled with ice water, the reaction was continued at an internal temperature of about 30 ° C., and the reaction was carried out 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 each)
= 17.7 Hz), 5.81 (1H, q, J = 7.2 Hz), 7.34 (5H, s)

Reference Example 6. 7-amino-5-azaspiro [2.4]
Synthetic compound of heptane dihydrochloride 68b 15b, 630 mg, 1N hydrochloric acid 10 ml, ethanol 20 ml
The solution was added with 800 mg of 5% palladium-carbon, and reduced under a hydrogen atmosphere at 4 atm while heating with a tungsten lamp. After 3.5 hours, the catalyst was removed, and the solvent in the filtrate was distilled off under reduced pressure to obtain 350 mg of the title compound.

[0059] mp: 230 - 240 ℃ (decomposition begins to decompose at around _{190 ℃) [α] D -41.5} ° (c = 1.616, H 2 O) Elemental _{analysis: C 6 H 14 N 2 Cl} 2 · 1 Calculated as / 2H ₂ O C 37.13 H 7.79 N 14.43 Found C 37.49 H 7.32 N 14.59 MS: m / z = 149 (M ⁺ -HCl) ¹ H-NMR (CDCl ₃ ) δppm ： 0.79-1.60 (4H, m), 3.08 (1H,
d, J = 12 Hz), 3.48-3.67 (3H, m), 3.93 (1H, dd, J
= 7 & 13.5 Hz)

Reference Example 7. 7-tert-butoxycarbonyla
Synthetic compound of mino-5-azaspiro [2.4] heptane 11b 16b, 50% in a solution of 11.8 g of ethanol in 200 ml
11 g of water-containing 5% palladium-carbon was added and subjected to catalytic reduction while heating with a tungsten lamp. After 6 hours, the catalyst was removed and the solvent of the filtrate was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the mixture was extracted with a 10% aqueous citric acid solution. The aqueous layer was washed with ethyl acetate, made alkaline with a 15 to 20% aqueous sodium hydroxide solution, and extracted with chloroform. The extract was dried and the solvent was distilled off under reduced pressure to obtain 7.6 g of the title compound.

Melting point: 56-59 ° C. [α] _D -68.54 ° (c = 1.742, CHCl ₃ )

[0062]

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[0063]

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──────────────────────────────────────────────────続 き Continued on the front page (31) Priority claim number Japanese Patent Application No. 1-156316 (32) Priority date Hei 1 (1989) June 19 (33) Priority claim country Japan (JP) (58) Field (Int. Cl. ⁶ , DB name) C07D 209/54 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the general formula I (Wherein, R ¹ represents a hydrogen atom or an amino-protecting group, and R ² represents a benzyl group or a 1-phenylethyl group) and salts thereof. 2. The protecting group is an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group, an alkyl group, an aralkyl group, an ether or a silyl group.
And the salts thereof 3. The compound according to claim 1, wherein the protecting group is an alkoxycarbonyl group, an aralkyloxycarbonyl group or an acyl group, and a salt thereof. 4. The protecting group is a tertiary butoxycarbonyl group,
The compound according to claim 1, which is a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, or an acetyl group, and a salt thereof. 5. The compound according to claim 1, 2, 3 or 4 and a salt thereof, wherein the compound of the general formula is a compound comprising a pure optically active form.