JPH0220637B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to isoxazoline derivatives represented by formula (). (In the formula, R ₁ , R ₂ and R ₃ are the same or different lower alkyl group, hydroxy lower alkyl group, amino lower alkyl group or carboxy lower alkyl group, and the hydroxy group, amino group or carboxy group is protected with a protecting group. It may be done.
R ₄ and R ₅ are the same lower alkoxy group or both together mean an ethylenedioxy group.
The lower alkyl group means a linear or branched group such as methyl, ethyl, propyl, butyl. ) This one is the expression () 3-(substituted thio)-6-(1-hydroxyalkyl)-7-oxo-1-azabicyclo[3,2,0]hept- ₂ -ene-carboxylic acid derivative represented by ' ₂ is the same or different lower alkyl group or a lower alkyl group substituted with a hydroxyl group, amino group or carboxyl group, R ₆ is a lower alkylthio group or a lower substituted with a hydroxy group, amino group, acylamino group, heterocycle, etc. means an alkylthio, alkylsulfinyl, alkenylthio, alkenylsulfinyl group, etc., or a heterocyclic thio group.) For example,
Carpetimycin (R ₁ = R ₂ = CH ₃ ,

It is an important intermediate in the synthesis of [Formula] R ₇ = R ₈ = H, 5R, 6R). Tokukai Akira (56−
8372) describes a compound () with R ₁ = H as a useful intermediate for the stereoselective synthesis of thienamycin, but there is no suggestion regarding the possibility of synthesizing compounds where R ₁ is alkyl. Nor. The present inventor has established a method for synthesizing carpetimycin A and its derivatives via 5,5-disubstituted isoxazoline () to azetidinone derivative (), which can be an important synthetic intermediate, and has completed the present invention. . The synthesis of the isoxazoline derivative will be described in detail below. 3-Nitropropanal dialkyl acetal () (R ₄ = R ₆ = alkoxy) or 3
- Nitropropanal ethylene acetal (R ₄
and R ₅ indicate -OCH ₂ CH ₂ O-. ) is dissolved in 3,3-dialkyl acrylate (), phenyl isocyanate and a catalytic amount of base, triethylamine, pyridine, N-methylpyrrolidine (preferably triethylamine) are added, and the temperature is gradually increased to 120-150 °C. °C (preferably 135-140
℃) for several hours (preferably 6 to 8 hours) and reflux. After the reaction is completed, the precipitated urea derivative is filtered, and the oil obtained by conventional treatment is distilled under reduced pressure.
By collecting a specific fraction and then purifying it by column chromatography, the desired asoxazoline derivative () can be obtained. This can then be converted into a key intermediate for the synthesis of carpetimycin and its derivatives () in the following manner. That is, the isoxazoline derivative () is dissolved in a polar solvent such as acetic acid, methanol, or ethanol (preferably acetic acid), and Adams platinum, Raney nickel, or palladium-carbon (preferably Adams platinum) is added as a catalyst, and the mixture is heated at room temperature under pressure for several days. , for example 5
Catalytic reduction was carried out under ~6 atmospheres for 3 days, and the catalyst and solvent were distilled off to obtain the amino ester compound (2). After protecting the hydroxyl group of the compound () with an appropriate protecting group, such as a tetrahydropyranyl group or a trimethylsilyl group (preferably a trimethylsilyl group), it is dissolved in an aprotection solvent such as tetrahydrofuran, and an ether solution of a Grignard reagent such as ethylmagnesium bromide is added. In addition, stir at room temperature for several hours (preferably 20 to 30 hours). After the reaction, the amount of the trans-form compound = () that is thought to be by-produced depends on the type of compound and reaction conditions (for example, the structure of R ₁ , R ₂ , R ₃ of compound (), and the structure of compound ()).
(Stereostructure of R ₃ and type of catalyst during catalytic reduction)
Separation of () and () is possible by silica gel column chromatography, although it depends on the One compound () is also important as an intermediate for the synthesis of epitinamycin C and D-related compounds. 2-Azetidinone derivative () obtained here
After removing the protecting group for the hydroxyl group of ( _R7 =-Si( _CH3 ) ₃ , _R9 =H), and selectively protecting the nitrogen atom with an appropriate protecting group, such as a tertiary butyldimethylsilyl group, The hydroxyl group is protected with a protecting group that can be removed by catalytic reduction, such as P-nitrobenzyloxycarbonyl group ()

[Formula] R ₉ = -Si (CH ₃ ) ₂ tBu), then add a suitable acid, e.g. 80%
Hydrolyze the acetal with acetic acid or dilute mineral acid to form the aldehyde (). Thereafter, carbon addition and ring closure are performed to obtain the compound () according to the method of JP-A-55-27169, JCS Perkin 12287, 1981. Thereafter, according to the method of JCS Perkin12282 1981, () was treated with diphenylchlorophosphate to form phosphate ().

[Formula]), and then substituted with a lower alkylthio group or a lower alkylthio or alkenylthio group substituted with a hydroxyl group, an amino group, an acylamino group, a heterocycle, etc., or a heterocyclic thio group, the 3-position A derivative of carpetimycin A can be synthesized, and carpetimycin A itself can be synthesized by converting the phosphate into silver E-2-acetamide-1-
Ethenyl thiolate (

[Formula]) is reacted and R ₆ of formula () is

After making the compound of [formula], hydrogen peroxide (JACS 63 2941
1941, JACS 70 3848 1948) or metachloroperbenzoic acid (JACS 97 5020 1975), etc., to separate and purify the sulfoxide compound, and then remove the protecting groups for the hydroxyl and carboxyl groups to produce carpetimycin A()( In the formula, R ₁ = R ₂ = CH ₃ ,

[Formula] R ₇ =R ₈ =H) can be synthesized. The present invention will be explained below with reference to Examples. Example 1 3-(2,2-dimethoxyethyl)-4-methoxycarbonyl-5,5-dimethylisoxazoline (: R ₁ = R ₂ = R ₃ = methyl, R ₄ = R ₅ = methoxy) 3- Nitropropanal dimethyl acetal 10
Dissolve g in 16 ml of methyl 3,3-dimethylacrylate, add 15.9 g of phenyl isocyanate and 2 to 3 drops of triethylamine, and gradually raise the temperature.
Heat to reflux at 135-140°C for 6.5 hours. After the reaction is complete, the reaction solution is dissolved in ether, the by-product diphenyl urea crystals are filtered, the ether layer is washed with saturated brine, and after drying with sodium sulfate, the solvent is distilled off and the resulting oil is distilled under reduced pressure. Attach to. boiling point
The 112-120°C (0.1 mmHg) fraction was further subjected to silica gel column chromatography to obtain 5.74 g of the desired isoxazoline from the benzene-acetone (7:3 V/V) fraction. IR ν ^CHCl3 _nax cm ^- : 1720 (>C=O) NMR δ (CCl ₄ ): 1.20 (3H, s, 5-Me) 1.40 (3H, s, 5-Me) 3.30 (6H, s, 2×OMe ) 3.70 (3H, s, -CO ₂ Me) 4.36~4.73 (1H, m,

[Formula]) MS m/e: 245, 1273 [Calculated value C ₁₁ H ₁₉ NO ₅
(M ⁺ ) m/e 245, 1264] Reference Example 1 (1) 3-Amino-5-hydroxy-4-methoxycarbonyl-5-methylhexanal dimethyl acetal PtO obtained by activating 6 g of the isoxazoline compound obtained in Example 1 _2. Stir with 600 mg of acetic acid in 50 ml of acetic acid at room temperature for 3 days under a flow of hydrogen gas (5.5 to 6 atm) and shielded from light. After the reaction is completed, the catalyst is filtered off and washed with acetic acid, and the acetic acid is distilled off under reduced pressure at below 40°C. The residue was dissolved in chloroform, made alkaline with 10% aqueous ammonia under ice cooling, washed with saturated brine, dried with sodium sulfate, and the solvent was distilled off.
The amino ester was obtained as a pale yellow oil (5.92 g). IR ν ^CHCl3 _nax cm ^-1 : 1720 (C=O) NMR δ (CDCl ₃ ): 1.23, 1.36 (each 3H, each s, 2×5−
Me) 2.00 (6H, s, 2×OMe) 3.71 (3H, s, −Co ₂ Me) 4.50 (2H, bs, NH ₂ ) (2) Cis-4-(2,2-dimethoxyethyl)-3
-[(1-Trimethylsilyloxy-1-methyl)ethyl]2-azetidinone 2 g of the amino ester obtained from (1) was dissolved in anhydrous benzene, and 3.34 ml of triethylamine and 4
- Add 0.02 g of dimethylaminopyridine under a nitrogen stream and moisture-proof condition, and add dropwise 2.54 ml of trimethylchlorosilane dissolved in anhydrous benzene under ice cooling. After completion of the dropwise addition, stir at room temperature for 24 hours. After the silylation reaction is completed, the reaction product is filtered while passing nitrogen gas, washed with anhydrous benzene, and the solvent is distilled off. Dissolve the residue in 30 ml of anhydrous tetrahydrofuran.
8 ml of an ether solution (3 mol/) of ethylmagnesium bromide was added dropwise under ice-cooling.
Further stir for 24 hours at room temperature. After the reaction is complete, water 3
ml and evaporate the solvent. The residue was extracted with dichloromethane, the extract was dried with sodium sulfate, and the solvent was distilled off. The resulting orange oil was subjected to silica gel column chromatography, and the benzene-acetone (4:1 V/V) stream was used to obtain the desired product. 0.54 g of azethinone compound was obtained. IR ν ^CHCl3 _nax cm ^-1 : 3450 (NH), 1758 (C=O) NMR δ (CDCl ₃ ): 0.16 (9H, s, SiMe ₃ ) 1.40-1.50 (6H, m, 2×1'-Me) 1.90~2.00 (2H, m,

【formula】) 3.16 (1H, d, J=5.4Hz, 3-H) 3.37 (6H, s, 2×OMe) 4.50 (1H, t, J=4Hz,

[Formula]) 6.20 (1H, bs, -NH) (3) cis-4-(2,2-dimethoxyethyl)-3
-(1-hydroxy-1-methylethyl)2-
A solution of 1.25 g of hydrogen fluoride-pyridine compound in 12 ml of tetrahydrofuran was added to 500 mg of the silyl compound obtained from azetidinone (2), and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the target product was dissolved in 10 ml of dichloromethane, the unreacted hydrogen fluoride-pyridine compound crystals were filtered, and the pale yellow oil obtained after evaporation of the solvent was subjected to silica gel column chromatography and benzene-acetone. (7:3V/V) The desired alcohol was obtained as pale yellow crystals (300mg). This was recrystallized from dichloromethane-n-hexane to obtain white needle crystals with a melting point of 97-98°C. IR ν ^CHCl3 _nax cm ^-1 : 3450 (-NH), 1758 (C=O
) NMR δ (CDCl ₃ ): 1.33 (3H, s, 1′-Me) 1.50 (3H, s, 1′-Me) 2.90 (1H, s, 3-H) 3.33 (6H, s, 2×OMe) 4.47 (1H, t, J=6Hz,

[Formula]) 7.66 (1H, bs, -NH) Example 2 3-(2,2-ethylenedioxyethyl)-4-
Methoxycarbonyl-5,5-dimethylisoxazoline (: R ₁ = R ₂ = R ₃ = methyl, R ₄ + R ₅
= ethylenedioxy) 3-nitropropanal ethylene acetal
5.94g to 14ml of methyl 3,3-dimethylacrylate
9.62 g of phenyl isocyanate and 2 to 3 drops of triethylamine are added, the temperature is gradually raised, and the mixture is heated under reflux at 135 to 140°C for 6.5 hours. After the reaction is completed, the reaction solution is dissolved in ether, the by-product diphenyl urea crystals are separated by filtration, the ether layer is washed with saturated brine, dried over sodium sulfate, and the solvent is distilled off to obtain an oily product. Subject to vacuum distillation.
The fraction with a boiling point of 160-175°C (0.2-0.35 mmHg) was further subjected to silica gel column chromatography, and 2.44 g of the desired isoxazoline was obtained from the benzene-acetone (7:3 V/V) fraction. IR ν ^CHCl3 _nax cm ^-1 : 1720 (C=O) NMR δ (CCl ₄ ): 1.13 (3H, s, 5-Me) 1.36 (3H, s, 5-Me) 2.30-2.90 (2H, m,

[Formula]) 3.66 (3H, s, CO ₂ Me) 3.80~3.83 (4H, m,

[Formula]) 4.85 (1H, dd, J=5.5and5Hz,

[Formula]) MS m/e 243 (M ⁺ ): m/e 243, 1111 (calculated value
C ₁₁ H ₁₇ NO ₅ (M ⁺ ), m/e 243, 1107) Reference Example 2 (1) 3-Amino-5-hydroxy-4-methoxycarbonyl-5-methylhexanal ethylene acetal Isoxazoline obtained in Example 2 1 g of body was mixed with 100 mg of activated PtO ₂ in 15 ml of acetic acid at room temperature under a flow of hydrogen gas (5.5 to 6 atm), shielded from light.
Stir for days. After the reaction is completed, the catalyst is filtered off and washed with acetic acid, and the acetic acid is distilled off under reduced pressure. The residue was dissolved in chloroform, made alkaline with 10% ammonia water under ice cooling, and washed with saturated saline.
After drying with sodium sulfate, the solvent is distilled off to obtain the desired amino ester as a pale yellow oil (0.99 g).
obtained as. IR ν ^CHCl3 _nax cm ^-1 : 1720 (C=O) NMR δ (CCl ₄ ): 1.13 (3H, s, 5-Me) 1.36 (3H, s, 5-Me) 2.87 (2H, bs, -NH ₂ ) 3.70 (3H, s, -CO ₂ Me) 3.83~3.93 (4H, m,

[Formula]) 4.93 (1H, dd, J=5.5and5Hz,

[Formula]) (2) cis-4-(2,2-ethylenedioxyethyl)-3-[(1-trimethylsilyloxy-1
-Methyl)ethyl]-2-azetidinone 1.10 g of the amino ester obtained from (1) was dissolved in anhydrous benzene, and 1.88 ml of triethylamine and 4-
0.01g of dimethylaminopyridine under nitrogen stream,
Trimethylchlorosilane under ice-cooling in addition to moisture-proofing
Dissolve 1.43 ml in anhydrous benzene and add dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 8 hours. The resulting insoluble matter was filtered off under moisture-proof conditions, and the filtrate was concentrated to obtain an O-monosilyl compound. This was dissolved in 20 ml of anhydrous tetrahydrofuran, and 4.5 ml of an ether solution of ethylmagnesium bromide (3 mol/) was added dropwise under ice-cooling. do. After completion of the dropwise addition, stir at room temperature for 24 hours.
After the reaction is complete, 1 ml of water is added and the solvent is distilled off. The residue was extracted with dichloromethane, dried with sodium sulfate, and the solvent was distilled off. The resulting orange oil was subjected to silica gel column chromatography, and the desired azetidinone compound was extracted from the benzene-acetone (4:1 V/V) stream. 0.544g was obtained. IR ν ^CHCl3 _nax cm ^-1 : 3450 (-NH), 1758 (C=O
) NMR δ (CDCl ₃ ): 0.12 (9H, s, −OSiMe ₃ ) 1.23 (3H, s, 1′−Me) 1.40 (3H, s, 1′−Me) 3.16 (1H, d, J=5.6Hz , 3-H) 3.80-3.83 (4H, m,

【formula】) 4.92 (1H, t, J=4Hz,

[Formula]) 6.20 (1H, bs, NH) MS m/e: 287.1520 (calculated value C ₁₃ H ₂₅ NO ₄ Si
(M ⁺ ) m/e287.1554) (3) Cis-4-(2,2-ethylenedioxyethyl)-3-[(1-hydroxy-1-methyl)ethyl-2-azedinone (2) A solution of 250 mg of hydrogen fluoride-pyridine compound in 5 ml of tetrahydrofuran was added to 100 mg of the obtained silyl compound, and the mixture was stirred at room temperature for 7 hours. After the reaction was completed, the reactant was dissolved in 5 ml of dichloromethane, the unreacted hydrogen fluoride-pyridine compound crystals were filtered, and the pale yellow oil obtained after evaporation of the solvent was subjected to silica gel chromatography and benzene-acetone ( 7:3V/V) fraction, the desired alcohol was obtained as pale yellow crystals (32 mg). This was recrystallized from dichloromethane-n-hexane to obtain white needle crystals with a melting point of 155-157°C. Elemental analysis C ₁₀ H ₁₇ NO ₄ Calculated value C 55.80, H 7.96 N 6.51 Experimental value C 55.55, H 7.92 N 6.39 IR ν ^CHCl3 _nax cm ^-1 : 3450 (-NH), 1758 (C=O
) NMR δ (CDCl ₃ ): 1.38 (3H, s, 1′-Me) 1.50 (3H, s, 1′-Me) 3.14 (1H, d, J=5,6Hz, 3-8) 4.92 (1H, t, J=4Hz,

[Formula]) 6.20 (1H, bs, -NH) MS m/e: 215 (M ⁺ ) (4) cis-1-tertiary butyldimethylsilyl-4-
(2,2-ethylenedioxyethyl)-3-[(1
-Hydroxy-1-methyl)ethyl-2-azetidinone (3) 47 mg of the alcohol obtained from (3) was dissolved in 5 ml of anhydrous tetrahydrofuran, and 0.28 ml of n-butyllithium was added at -78°C, followed by stirring at the same temperature for 1 hour. Add 36mg of dimethylsilyl chloride -78
Stir at 1 hour at -30°C for 7 hours. After the reaction was completed, the reaction product was poured into ice and extracted with ether-dichloromethane (5:1 V/V). The extract was washed with saturated brine, dried with sodium sulfate, and the solvent was distilled off. The pale brown oil obtained was subjected to silica gel column chromatography, and the benzene-acetone (19:1 V/V) fraction was used for the purpose. 39 mg of N-silyl compound was obtained. IR ν ^CHCl3 _nax cm ^-1 : 1758 (C=O) NMR δ (CDCl ₃ ): 0.23 (6H, s, SiMe) 0.98 (9H, s, C( CH ₃ ) ₃ ) 3.10 (0.5H, d, J = 2.5Hz, 3-H (trans)) 3.40 (0.5H, d, J = 5.6Hz, 3-H (cis)) 3.90-3.98 (4H, m,

【formula】) 4.85~5.08 (1H, m,

[Formula]) (5) cis-1-tertiary butyldimethylsilyl-4-
(2,2-ethylenedioxyethyl)-3-[1
-(p-Nitrobenzyloxycarbonyloxy)-1-methyl]ethyl-2-azetidinone 26 mg of the N-silyl compound obtained from (4) was dissolved in 3 ml of anhydrous tetrahydrofuran, and 0.051 ml of n-butyllithium was added at -78°C. After stirring for 5 minutes, a solution of 51 mg of p-nitrobenzyl chloroformate in 3 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at -78°C for 6 hours. After the reaction is complete, the reaction mixture is poured into ice, saturated with sodium chloride, and extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent was distilled off, and the resulting pale brown oil was subjected to silica gel column chromatography, and chloroform-methanol (99.5:
0.5V/V) Target β-lactam from the flow
Obtained 31 mg. IR ν ^CHCl3 _nax cm ^-1 : 1760, 1750 (C=O), 1345 (-NO ₂ ) NMR δ (CDCl ₃ ): 0.28 (6H, s, SiMe ₂ ) 0.98 (9H, s, C ( CH _{3 )} ) 3.90~4.00 (4H, m,

[Formula]) 5.33 (2H, d, J=3Hz, CH ₂ −Ar) 7.66 (2H, d, J=9Hz, Ar−H) 8.34 (2H, d, J=9Hz, Ar−H)

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ , R ₂ and R ₃ are the same or different lower alkyl groups, and R ₄ and R ₅ are the same lower alkoxy group or both together mean an ethylenedioxy group.) derivative.