JP3185946B2 - γ, δ-unsaturated-β-amino acid derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a .gamma.,. Delta.-unsaturated .beta.-amino acid derivative useful as an intermediate for .beta.-lactam antibiotics and a method for producing the same.

[0002]

2. Description of the Related Art Various β-lactam antibiotics have been developed, and some methods for their production have been proposed. However, there are problems such as a large number of steps, low optical purity, etc. Has not been established.

[0003]

Means for Solving the Problems The present inventors have studied various reactions of lithium diamide copper compounds, and found that α,
By reacting with a β, γ, δ-unsaturated carboxylic acid derivative and then with acetaldehyde, α- (1
-Hydroxyethyl) -γ, δ-unsaturated-β-amino acid derivative was produced, and it was found that a 2-azetidinone derivative could be produced from the β-amino acid derivative in good yield.
The present invention has been completed. That is, the present invention relates to (1)

Embedded image (Wherein, R 1 represents lower alkyl or phenyl, and X represents optically active bornansultam), and (2) a compound represented by the general formula:

Embedded image (Wherein, R1 and X have the same meanings as described above) and the formula {C6 H5 CH2 N [Si (CH3) 3]} 2 CuLi
[III] or {C6 H5 CH2 N [Si (CH3) 3
] 2 A method for producing a compound represented by the general formula [I], comprising reacting a lithium diamide copper compound represented by Cu (CN) Li2 [III '], followed by reacting with acetaldehyde.

The reaction is carried out in an organic solvent such as THF at -100 °
Perform at ０0 ° C. for 10 minutes to several hours. After completion of the reaction, the desired product can be obtained by performing ordinary post-treatment.
Further, the hydroxyl group of the compound represented by the general formula [I] is t-
It can also be isolated as a compound protected with a butyldimethylsilyloxy group (TBDMS) or the like. Formula [III
] Or [III '] can be easily prepared by reacting N- (trimethylsilyl) benzylamine with n-butyllithium and copper iodide or copper cyanide in an organic solvent such as THF. It can be produced and usually reacted with the compound represented by the general formula [II] without isolation. The compound of the present invention represented by the general formula [I] can be produced from the azetidinone derivative in good yield, for example, according to the following reaction formula. In this case, by using the optically active bornansultam represented by X, the desired optically active compound can be obtained. it can.

Embedded image

[0005]

Next, the present invention will be described in more detail with reference to Examples and Reference Examples. Example 1 N-{(E)-(2S, 3S) -3-benzylamino-
2-[(1'S) -tert-butyldimethylsilyloxyethyl] -5-phenyl-4-pentenoyl {bornane-
10,2-Saltam:

Embedded image N- (trimethylsilyl) benzylamine 6.08 ml
Was dissolved in 40 ml of THF, and 18.6 ml (30.0 mmol) of an n-butyllithium hexane solution was slowly added at -78 ° C. After stirring for 25 minutes, 1.34 g of copper cyanide was added, and the mixture was further stirred for 30 minutes. To this mixture was added 1.86 g of compound (2) in 15 ml of THF.
The solution was added at -100 C over 20 minutes. After 40 minutes 10 ml (50 mmol) of acetaldehyde THF solution were added and the mixture was gradually warmed to -70 ° C over 1 hour. The reaction mixture was combined with a saturated aqueous ammonium chloride solution at 28%
The mixture was poured into a mixed solution with aqueous ammonia (1: 1, 50 ml), stirred vigorously, and diethyl ether was added. The organic layer was separated, washed twice with a mixed solution of a saturated ammonium chloride solution and 28% aqueous ammonia (1: 1 50 ml) with brine, and dried over potassium carbonate. The solvent was distilled off to obtain a crude product (3). This crude product (3) was dissolved in 100 ml of methylene chloride, and 3.4 g of imidazole and 5.7 g of t-butyldimethylsilyl chloride were added to the solution.
Was added at 0 ° C. The mixture was stirred overnight at room temperature and then mixed with water. The organic layer was separated, washed with brine, and dried over potassium carbonate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 5: 1) to obtain 2.26 g of compound (4) as a sticky oil. [Α] _D ²² = -27.02 ° (c1.02, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ 7.50-7.17 (m, 10H), 6.46 (d, J = 15.3H)
z, 1H), 6.23 (br, 1H), 4.30 (br, 1H), 3.92-3.32 (m, 7H),
2.10-1.80 (m, 6H), 1.45-1.22 (m, 3H), 1.13 (s, 3H), 0.94
(s, 3H), 0.83 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H); IR (CCl ₄ ) 2960, 1335, 1115 cm ^-1 ; HRMS calcd for C ₃₆ H ₅₂ N ₂ SSiO ₄ 636.3417, found 636.
3389.

Reference Example 1 (1S, 2R, 3S) -N-benzyl-N- [3-t-
Butyldimethylsilyloxy- (E) -1-styryl-
2-triethylsiloxymethylbutyl] -t-butoxycarbonylamine:

Embedded image To a solution in which 1.7 g of the compound (4) was dissolved in 40 ml of diethyl ether, 150 mg of lithium aluminum hydride was slowly added at 0 ° C. After stirring for 1 hour, water was added in the order of 0.15 ml of water, 15% NaOH, and 0.45 ml of water, followed by vigorous stirring for 30 minutes. The reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure from the filtrate, and the remaining oil was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1) to give 686 mg of compound (5) as a colorless oil. I got (60% yield)

[0007] Compound (5) (638 mg) was treated with methylene chloride (4).
204 mg of imidazole at 0 ° C in a solution dissolved in 0 ml
And 0.504 ml of triethylsilyl chloride were added, and the mixture was stirred at room temperature for 1 hour and mixed with water. Separate the organic layer,
After washing with saline, it was dried over potassium carbonate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1) to obtain 793 mg of the compound (6) as a colorless oil. (Yield 98
%)

Compound (6) 793m in DMF10ml
g, triethylamine _{2ml, (t-C 4 H} 9 OCO)
₂ g of ₂ O was dissolved and stirred at 50 ° C. for 4.5 hours. Water and diethyl ether were added to the mixture at 0 ° C., and the organic layer was separated. After washing with brine, the extract was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7: 1) to obtain 574 mg of compound (7) as a colorless oil.
(Yield 61%) Compound (7) ¹ H NMR (CDCl ₃ ) δ0.06 (s, 3H), 0.11 (s, 3H), 0.50 (q, J =
7.5Hz, 6H), 0.88 (t, J = 7.5Hz, 9H), 0.92 (s, 9H), 1.06 (br
d, J = 6.0Hz, 3H), 1.39 (br, 9H), 1.99 (m, 1H), 3.56 (m, 1
H), 3.68 (m, 1H), 4.03 (m, 1H), 4.38 (m, 1H), 6.17-6.28
(m, 2H), 7.15-7.30 (m, 10H); IR (neat) 2955, 1695, 1250 cm ^-1 ; HRMS calcd for C ₃₇ H ₆₁ NO ₄ Si ₂ 639.4139, found 639.4
155.

Reference Example 2 (E)-(2R, 3S) -2-[(1'S) -1'-t
-Butyldimethylsilyloxyethyl] -3- (N-benzyl-t-butyloxycarbonylamino) -5-phenyl-4-pentenoic acid:

Embedded image 189 mg of compound (7) in 0.5 ml of THF, 0.5 m of water
and 0.5 ml of acetic acid were dissolved and stirred at room temperature for 24 hours. 0.3 ml of acetic acid was added to the mixture, and after stirring for 2 days, diethyl ether was added. The mixture was washed with water (3 times), saturated sodium bicarbonate and sodium chloride in that order, and dried over potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 7:
1) Purify the compound (8) as a colorless oil (152m)
g was obtained. (Yield 98%) Ogizaryl chloride 0.22m
was dissolved in 10 ml of methylene chloride at −78 ° C. with 0.29 ml of dimethyl sulfoxide in 2 ml of methylene chloride.
The solution dissolved in 1 was added. After stirring for 10 minutes, a solution of 439 mg of compound (8) dissolved in 5 ml of methylene chloride was added dropwise to the solution over 10 minutes. After stirring for another 30 minutes, the mixture was gradually heated to -45 ° C. After stirring the mixture at -45 ° C for 15 minutes, 0.81 ml of triethylamine was added to the mixture with vigorous stirring. The mixture was heated to 0 ° C., and a saturated aqueous ammonium chloride solution was added. The organic layer was separated, washed with brine, and dried over potassium carbonate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1) to obtain 357 mg of compound (9) as a colorless oil. (Yield 82%)

357 mg of compound (9), 5 ml of t-butyl alcohol, 1.5 ml of water, 106 mg of sodium dihydrogen phosphate dihydrate, 0.53 m of 2-methyl-2-butene
and 271 m of sodium chlorite are added to the mixture.
g was added slowly at room temperature. After stirring at room temperature for 1.5 hours, a 1N aqueous hydrochloric acid solution was added to form a hydrochloride. The mixture was extracted repeatedly with methylene chloride. The extracts were combined, dried over sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5: 1) to give compound (1) as a colorless oil.
0) 327 mg were obtained. Compound (10) ¹ H NMR (CDCl ₃ ) δ 0.12 (s, 3H), 0.21 (s, 3H), 0.94 (s, 9)
H), 0.97 (d, J = 6.2Hz, 3H), 1.47 (brs, 9H), 2.85 (m, 1H),
3.92 (m, 1H), 4.20 (d, J = 15.9Hz, 1H), 4.79 (m, 1H), 6.24 (d
d, J = 8.2,15.5Hz, 1H), 6.44 (m, 1H), 7.19-7.33 (m, 10H),
10.50 (br, 1H); IR (CCl ₄ ) 3370, 1690 cm ^-1 ; HRMS calcd for C ₃₁ H ₄₅ NSiO ₅ 539.3067, found 539.30
73.

Reference Example 3 (3S, 4S) -1-benzyl-3-[(1'S)-
1'-t-butyldimethylsilyloxyethyl] -4-
[(E) -styryl] -2-azetidinone:

Embedded image 0.5 ml of trifluoroacetic acid was added to a solution of 269 mg of the compound (10) in 5 ml of methylene chloride, and the mixture was allowed to stand at room temperature overnight. The solvent and excess trifluoroacetic acid were distilled off under reduced pressure, and the residue was dissolved in 30 ml of methylene chloride. 0.21 ml of triethylamine and 153 mg of 2-chloro-1-methylpyridium iodide were added to this solution at 0 ° C., and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 1) to give compound (1) as a colorless oil.
1) 100 mg (yield 47%) and compound (11 ') 27
mg (18% yield). Compound (11) ¹ H NMR (CDCl ₃ ) δ 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9
H), 1.28 (d, J = 6.1Hz, 3H), 3.31 (dd, J = 5.2,5.2Hz, 1H),
4.11 (d, J = 14.5Hz, 1H), 4.09-4.20 (m, 2H), 4.59 (d, J = 14.
5Hz, 1H), 6.23 (dd, J = 8.9,15.7Hz, 1H), 6.51 (d, J = 15.7H
z, 1H), 7.21-7.36 (m, 10H); IR (neat) 2940,1758,835 cm ^-1 ; HRMS calcd for C ₂₆ H ₃₅ O ₂ NSi 421.2437, found 421.240
1

[0012]

According to the production method of the present invention, the compound of the present invention represented by the general formula [I] can be produced in good yield by using a diamide copper lithium compound. It is important as an intermediate for β-lactam antibiotics.

Continuation of front page (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 275/06 C07C 229/34 C07C 229/30 CA (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (In the formula, R ₁ represents lower alkyl or phenyl, and X represents optically active bornansultam.) 2. A compound of the general formula (In the formula, R ₁ and X are. Of the same meaning as defined above) alpha is expressed by, beta, gamma, formula {C ₆ to δ- unsaturated carboxylic acid derivative H ₅ CH ₂ N [Si (CH _{3) 3} ] ₂ CuLi
Or {C ₆ H ₅ CH ₂ N [Si (CH ₃ ) ₃ ]} ₂ Cu
Reacting with a lithium diamide copper compound represented by (CN) Li ₂ , and then reacting with acetaldehyde. (Wherein, R ₁ and X have the same meanings as described above).