JPH0235757B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel halogen-substituted β-lactam compound useful as a synthetic intermediate for pharmaceuticals and a method for producing the same. More specifically, the present invention provides the formula () (wherein, X and Y represent X=halogen, Y=hydrogen, or X=Y=halogen) and a method for producing the same. The halogen-substituted β-lactam compound represented by the formula () is a new compound that has not been described in any literature, and is important as a synthetic intermediate for pharmaceuticals. For example, the expression Azthreonam, represented by
SQ26776) is a β-lactam compound that has attracted attention as a new antibacterial substance that exhibits strong antibacterial activity against Gram-negative bacteria, and many analogs of this compound can be synthesized from the compound () of the present invention. For example, various derivatives in which the C ₃ and C ₄ configurations are cis or trans can be synthesized by the reactions shown below (see Japanese Patent Application No. 57-193239 filed by the present applicant). In the compound () of the present invention, the halogen represented by X and Y includes chlorine, bromine or iodine. Furthermore, the compound () of the present invention has X, Y
When X = halogen and Y = hydrogen, C ₆ and C ₇ positions are
Alternatively, when X=Y=halogen, the C ₆ position becomes an asymmetric carbon, and therefore, corresponding optical isomers exist in each case, and all of them are included in the present invention. That is, 6(R)-7(R)-halogeno-8-oxo-2,
2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane 6(R)-7(S)-halogeno-8-oxo-2,
2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane 6(S)-7(S)-halogeno-8-oxo-2,
2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane 6(S)-7(R)-halogeno-8-oxo-2,
2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane and mixtures of their optical isomers, namely ((6R, 7R) and (6R, 7S); (6S, 7S) and (6S,
7R); (6S, 7R) and (6R, 7S); (6S, 7S) and (6R, 7R); and (6R, 7R), (6R, 7S),
(6S, 7S), (6S, 7R) mixture, 6(R)-7-dihalogeno-8-oxo-2,2
-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane 6(S)-7-dihalogeno-8-oxo-2,2
-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane and mixtures thereof are included in the invention. Specific examples of typical compounds related to the present invention include the following compounds.

【formula】

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[Formula] In another aspect, the present invention provides a method for producing a compound represented by formula (), that is, a compound represented by formula () After reacting with a base, a halogenating reagent is applied to form the formula () (In the formula, X and Y are X=halogen, Y=hydrogen and/or X=Y=halogen.) Compound (a)

[Formula] (Hal = halogen) and compound (b) of formula () where X = Y = halogen Furthermore, the present invention provides a manufacturing method comprising separating and collecting a compound represented by the formula (), and then reacting the compound represented by the formula ( By acting with a halogenating reagent, the formula () (In the formula, X and Y are X=halogen, Y=hydrogen and/
or X=Y=halogen), and then form a compound (a) of formula () where X=halogen and Y=hydrogen.

[Formula] (Hal represents halogen) and compound (b) where X=Y=halogen in formula () The latter compound (b) is subjected to a reduction reactor in the presence of a catalyst to form the former compound (a).
The present invention provides a method for producing a compound represented by formula (), which comprises converting the compound into Hereinafter, the method for producing the compound () of the present invention will be explained in detail. The compound () of the present invention comprises a compound (a) in which X and Y are X=halogen and Y=hydrogen;
= halogen compound (b), and the ratio of both of them produced in one reaction varies depending on the halogenating reagent used, reaction conditions, etc. Therefore, depending on which compound is desired, the halogenating reagent, reaction conditions, etc. that produce the desired compound as the main product can be arbitrarily set. The reaction before the action of the halogenating reagent, that is,
formula() Known compound 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]
The step of reacting octane (manufacturing method will be described later) with a base to form an active anion is the step of reacting the two compounds (a,
b) It is a common essential reaction for production, and the bases used include butyllithium, lithium diisopropylamide, lithium dicyclohexylamide,
Organolithium compounds or lithium amide compounds such as lithium isopropylcyclohexylamide or lithium hexamethyldisilazide can be employed, and if necessary, hexamethylphosphamide, hexamethylenetetramine or 2,
Compounds produced in systems in which cation scavengers such as 2,6,6-tetramethylpiperidine coexist ()
A method of increasing the activity of the anion form is adopted. The anion form of the compound () generated in this way can be converted into the target compound () by acting on the anion form of the compound (), and as a halogenation reagent, a positive halogen reagent capable of releasing a positively charged halogen; For example, N-halogenosuccinimide, N-halogenoacetamide, benzenesulfonyl halide, p-toluenesulfonyl halide, N-halogenosaccharin, N-halogeno-N,N-dibenzenesulfonamide, t-butylhypohalide or molecular halogen, Specifically, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, N-
Bromoacetamide, benzenesulfonyl iodo, benzenesulfonyl bromide, p-toluenesulfonyl bromide, p-toluenesulfonyl chloride, N-bromosactucarin, N-bromo-
When N,N-dibenzenesulfonamide, t-butylhypobromide, bromine, iodine, etc. are used as a halogenating agent, the main product is compound (a) in formula () where X = halogen and Y = hydrogen. When a polyhaloalkane such as carbon tetrachloride, carbon tetrabromide or chlorotribromomethane is reacted with as a halogenating agent, a compound (b) in which X=Y=halogen in formula () is obtained.
was found to be obtained as the main product. The proportion of compound (b) produced increases as the molar ratio of the halogenating reagent to the compound () increases, and usually each halogenating reagent is used in an amount of 1.0 to 3 times the molar equivalent of the compound (). This molar ratio can be increased or decreased depending on which of , a, and b is desired. A and b can be easily separated and collected by ordinary silica gel column chromatography. A series of reactions consists of tetrahydrofuran,
In an anhydrous organic solvent such as 1,2-dimethoxyethane, preferably under an inert gas atmosphere such as argon, nitrogen or helium, at a temperature usually in the range of -80°C to 25°C, preferably -80°C to It is carried out under cooling at 0°C. The 7-dihalogen-substituted compound (b) produced in the halogenation reaction can be converted into the 7-monohalogen-substituted compound (a) by subjecting it to a reduction reaction in the presence of a catalyst, if necessary. As the catalyst, a palladium catalyst, Raney nickel, etc. can be used, and the palladium catalyst is used in the form of 5% palladium-carbon, 10% palladium-carbon, 10% palladium- _BaSO4 , 30% palladium- _BaCO3 , etc. As the reaction solvent at this time, methanol, ethanol, dioxane, or a mixed solvent of this solvent and water is used. For example, when palladium is used as a catalyst, for compound (b),
Palladium metal is used in an amount of 1 to 10% by weight, preferably 1 to 2% by weight, and a base such as disodium hydrogen phosphate, sodium acetate, or sodium carbonate is used in an amount of 1 to 2.5% as a scavenger for hydrogen halide generated during the reaction process. Double molar equivalents were allowed to coexist, and the mixture was heated at 20°C to 100°C under a hydrogen gas atmosphere of normal pressure to several atmospheres.
Preferably, the reduction reaction can be carried out at 20°C to 40°C. In the case of the 7-monohalogen-substituted β-lactam compound (a) obtained by the method of the present invention, C ₆ ,
The stereochemistry at the _C7 position is obtained as a mixture of cis and trans configurations. For example, when a compound of formula () with the (6R) configuration is used as a starting material, the trans isomer of (6R, 7R) and the (6R, 7S)
In the case of a mixture of cis isomers, and in the case of a compound of formula () with a configuration of (6S), (6S, 7S)
It is obtained as a mixture of the trans isomer of (6S, 7R) and the cis isomer of (6S, 7R), and the mixing ratio is usually cis:trans=1:3 to 4, depending on the chemical equilibrium mainly controlled by thermodynamic stability. In many cases, the mixture can be used as an intermediate compound for the next reaction without any particular problem, but when it is necessary to isolate each isomer, high-performance liquid chromatography is used to
The cis and trans isomers can be separated. The compound () which is the starting material of the present invention is
For the optically active form of (6R) or (6S), the method of Ohno et al. [J.Am.Chem.Soc., 103]
Vol., p. 2405, (1981)] (4R) or (4S)-[(methoxycarbonyl)methyl]-2
- (4R) or (4S) -2 by subjecting azetidinone to a reduction reaction developed by the present applicant (Japanese Patent Application No. 57-49527)
-hydroxyethyl-2-azetidinone and pear,
This alcohol was prepared using the method of F. A. Bouffard et al. [F.
A. Bouffard, DB Johnston, BG Christensen, Journal of Organ Chemistry (J.Org.Chem), vol. 45, p. 1130 (1980)) leads to (). The racemic form at the 6-position is described in the above-mentioned article by FA Bouffard et al. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 6(R)-7(R,S)-bromo-8-oxo-
Synthesis of 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () After suctioning the reactor with a vacuum pump, replace the reactor with nitrogen gas, and then add 0.4 g of diisopropylamine and nitrogen gas under a nitrogen stream. 4 ml of fresh tetrahydrofuran purified by atmospheric distillation is added, and the mixed solution is cooled with dry ice-acetone. Then a nitrogen stream,
While stirring, n-butyllithium (2.3 ml of 1.55M hexane solution) was added over 3 minutes, and the mixture was stirred for 35 minutes.
(6R)-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane (compound (), 6R form) was added to the thus prepared tetrahydrofuran solution of lithium diisopropylamide.
A solution of 0.5 g dissolved in 5 ml of tetrahydrofuran was added over 6 minutes and stirred for 40 minutes. Next, a solution of 0.6 g of N-bromosuccinimide dissolved in a mixture of 5 ml of tetrahydrofuran and 0.5 ml of hexamethylphosphoramide was added over 6 minutes.
The reaction was stirred for 5 hours under a dry ice-acetone and nitrogen atmosphere. After the reaction, 20 ml of saturated ammonium chloride water is added to stop the reaction, and the mixture is extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 1 g of oil.
This oil was purified using 13 g of silica gel (column prepared in toluene) and toluene-acetone as a developing solvent, and 0.3 g of white crystals of the title compound (40
%) was obtained. Based on the integral value of the NMR spectrum,
It was confirmed that the 6,7-trans:6,7-cis isomer ratio was 3:1. IR (KBr): 1760 cm ^-1 (β-lactam) ¹ HNMR (CDCl ₃ , 90MHz): δppm 1.45 (3H, S, 2-H ₃ ); 1.77 (3H, S, 2-
CH ₃ ); 1.5-2.2 (2H, m, H ₅ ); 3.63-4.0 (3H,
m, H ₄ and H ₆ ); 4.36(d), 4.93(d) (1H, H ₇ ) Silica gel thin layer chromatography (toluene-
Acetone = 4:1) R _f : 0.50 (detected 47% HBr-ninhydrin) Elemental analysis value C ₈ H ₁₂ BrNO ₂ Calculated value C; 41.04, H; 5.17, N; 5.98 Actual value C; 41.01, H; 5.12 , N; 5.92 6(R)-7-dibromo-8-oxo- from another fraction of the same silica gel column chromatography
2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained in a yield of 7.4%. Example 2 6(R)- was prepared using the same recipe as in Example 1 except that N-bromoacetamide was used as the brominating agent.
7(R,S)-bromo-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]
Obtained octane (). Yield 13%. (6,7-trans:6,7-cis isomer ratio = 3:1). Example 3 6 was prepared using exactly the same recipe as in Example 1 except that p-toluenesulfonyl bromide was used as the brominating agent.
(R)-7(R,S)-bromo-8-oxo-2,2
-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained. Yield 41%. (6,
7-trans:6,7-cis isomer ratio = 2.74:1).
Also 6(R)-7-dibromo-8-oxo-2,2
-Dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained in a yield of 16.3%. Example 4 6(R) was prepared using exactly the same recipe as in Example 1 except that benzenesulfonyl bromide was used as the brominating agent.
-7(R,S)-bromo-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]
Got Octane (). Yield 36%. (6,7-trans:6,7-cis isomer ratio = 2:1). Also 6
(R)-7-dibromo-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]
Octane () was obtained with a yield of 11%. Example 5 6(R)-7-dibromo-8-oxo-2,2-
Synthesis of dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () After suctioning the reactor with a vacuum pump, replace the reactor with nitrogen gas, and then distill with 6.6 ml of diisopropylamine under a nitrogen gas atmosphere. Add 40 ml of fresh purified tetrahydrofuran and cool the mixed solution with dry ice-acetone. Next, n-butyllithium (28.5 ml of a 1.55M hexane solution) was added over 8 minutes under a nitrogen stream and stirring, and the mixture was stirred for 100 minutes.
The compound () (6R
A solution obtained by dissolving 3.25 g of 3.25 g of chloride in 33 ml of tetrahydrofuran was added over 13 minutes, and the mixture was stirred for 60 minutes. Next, a solution of 13.89 g of carbon tetrabromide dissolved in 35 ml of tetrahydrofuran was added over 9 minutes, cooled with dry ice-acetone, stirred for 120 minutes under a nitrogen atmosphere, and then cooled with ice-water and reacted with stirring for an additional 20 minutes. PH after reaction
4.5 phosphate buffer (1M, 100ml) was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and pumped to obtain 13.63 g of a solid. This solid was purified using 146 g of silica gel (column prepared in toluene) and methylene chloride and toluene-acetone as a developing solvent to produce white crystals of the title compound.
Gained 5.65g (86%). IR (KBr): 1765 cm ^-1 (β-lactam) ¹ HNMR (CDCl ₃ , 90MHz): δppm 1.45 (3H, S, 2-CH ₃ ); 1.77 (3H, S, 2-
CH ₃ ); 1.83-2.13 (2H, m, H ₅ ), 3.83-4.03
(2H, m, H ₄ ), 4.17 (1H, t, H ₆ ) [α] ²⁰ _D −0.36° (C1.12, EtOH), mp143−144°C Silica gel thin layer chromatography (Toluene:
Acetone = 4:1): R _f = 0.60 (detected 47% HBr-ninhydrin) Elemental analysis value C ₈ H ₁₁ Br ₂ NO ₂ Calculated value C: 30.70, H: 3.54, N: 4.48 Actual value C: 30.64, H; 3.51, N; 4.50 Example 6 6(R)-7(R,S)-bromo-8-oxo-
Synthesis of 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () 6(R)-7-dibromo-8-oxo-2,2-
Dimethyl-3-oxa-1-azabicyclo [4.2.
O] 6.74 g of octane (), 0.95 g of 10% palladium-carbon, and 7.73 g of disodium hydrogen phosphate decahydrate
Add 300 ml of ethanol and water (17 drops) to the mixture,
The reaction is stirred and reacted at room temperature under a hydrogen atmosphere of 1 atm until the raw materials disappear. After the reaction, the catalyst was removed by filtration, and the ethanol was distilled off from the liquid under reduced pressure. Water and methylene chloride were added to the resulting mixture, and the mixture was separated and extracted for three times.
Let's go around. After drying the organic layer with anhydrous magnesium sulfate, filtering, concentrating, and suctioning with a pump were performed.
4.5 g of 6(R)-7(R,S)-bromo-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained. Yield 89
%. (6,7-trans:6,7-cis isomer ratio=
2.3:1). Example 7 6(R)-7-dichloro-8-oxo-2,2-
Synthesis of dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () 6(R)-7-dichloro using exactly the same recipe as in Example 5 except that carbon tetrachloride was used instead of carbon tetrabromide. -8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained. Yield 58%. IR (KBr): 1780 cm ^-1 (β-lactam) ¹ HNMR (CDCl ₃ , 90MHz): δppm 1.47 (3H, S, 2-H ₃ ); 1.73 (3H, S, 2-
_CH3 ); 1.83-2.07 (2H, m, _H5 ), 3.86-4.03
(2H, m, H ₄ ), 4.13 (1H, t, H ₆ ) [α] ²⁰ _D -1.19° (C1.010, EtOH) Silica gel thin layer chromatography (toluene -
Acetone = 4:1): R _f = 0.55 (detected 47% HBr-ninhydrin) and 6(R)-7(R,S)-chloro-8-oxo-2,2-dimethyl-3-oxa-1- Azabicyclo[4.2.O]octane () was obtained with a yield of 16%. (6,7-trans:6,7-cis isomer ratio = 1:3) Example 8 6(R)-7(R,S)-chloro-8-oxo-
Synthesis of 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () Instead of using N-bromosuccinimide as the brominating agent in Example 1, p was used as the chlorinating agent.
-6(R)-7(R,S)-chloro-8-
Oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained. Yield 60%. (6,7-trans:6,7-cis isomer ratio = 3:1) IR (neat): 1760 cm ^-1 (β-lactam) ¹ HNMR (CDCl ₃ , 90MHz): δppm 1.43 (3H, S, 2- CH ₃ ); 1.76 (3H, S, 2-
_CH3 ); 1.53-2.20 (2H, m, _H5 ); 3.63-4.10
(3H, m, H ₄ and H ₆ ); 4.40(d), 4.90(d) (1H,
_H7 ) Silica gel thin layer chromatography (toluene-
Acetone = 4:1); R _f = 0.40 (detected 47% HBr-ninhydrin) Also, 6(R)-7-dichloro-8-oxo-
2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained in a yield of 6%. Example 9 6(S)-7(R,S)-bromo-8-oxo-
Synthesis of 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () In Example 1, (6R)-8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2 .O〕
Instead of octane (compound (), 6R form),
(6S)-8-Oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane (compound (), 6S form) was used, except that 6(S)-7 (R,S)-bromo-8-oxo-
2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained. Yield 41%.
(6,7-trans:6,7-cis isomer ratio = 3:1) Also, 6(S)-7-dibromo-8-oxo-
2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () was obtained in a yield of 7%. Example 10 6(S)-7-dibromo-8-oxo-2,2-
Synthesis of dimethyl-3-oxa-1-azabicyclo[4.2.O]octane () Instead of compound () (6R form) in Example 5,
(6S)-8-Oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.O]octane (compound (), 6S form) was used, except that 6(S)-7 -dibromo-8-oxo-2,2-
Dimethyl-3-oxa-1-azabicyclo [4.2.
O]Octane () was obtained. Yield 85%.

Claims (1)

[Claims] 1 Formula () (In the formula, X and Y represent X=halogen, Y=hydrogen, or X=Y=halogen.) A halogen-substituted β-lactam compound represented by: 2. The compound according to claim 1, wherein in formula (), X=halogen and Y=hydrogen. 3. The compound according to claim 2, wherein the configuration at position 6 of formula () is (6R). 4. The compound according to claim 2, wherein the configuration at position 6 of formula () is (6S). 5. The compound according to claim 2, wherein the compound of formula () is a mixture of a compound having a (6R) configuration and a compound having a (6S) configuration. 6. The compound according to claim 3 or 4, wherein the configuration at position 7 of formula () is (7R). 7. The compound according to claim 3 or 4, wherein the configuration at position 7 of formula () is (7S). 8 The compounds of formula () are respectively (6R, 7R)
The compound according to claim 2, which consists of a mixture of two isomers having the configurations: and (6R, 7S). 9. The compound according to claim 1, wherein in formula (), X=Y=halogen. 10. The compound according to claim 9, wherein the configuration at position 6 of formula () is (6R). 11. The compound according to claim 9, wherein the configuration at position 6 of formula () is (6S). 12. The compound according to claim 9, wherein the compound of formula () consists of a mixture of two isomers having the configurations (6R) and (6S), respectively. 13 Formula () After reacting the compound represented by a base with a base, a halogenating reagent is applied to form the compound represented by the formula (). (In the formula, X and Y are X=halogen, Y=hydrogen and/or X=Y=halogen.) Compound (a) [Formula] (Hal = halogen) and compound (b) of formula () where X = Y = halogen The expression () is characterized by separating and collecting (In the formula, X and Y represent X=halogen, Y=hydrogen, or X=Y=halogen.) A method for producing a halogen-substituted β-lactam compound represented by the following formula. 14. The production method according to claim 13, wherein the base is lithium dialkylamide. 15. The manufacturing method according to claim 13, wherein the halogenating reagent is a positive halogen reagent capable of releasing positively charged halogen. 16. The production method according to claim 15, wherein the positive halogen reagent is N-bromosuccinimide, p-toluenesulfonyl bromide, or benzenesulfonyl bromide. 17. The production method according to claim 13, wherein the halogenating reagent is a polyhaloalkane. 18. The production method according to claim 17, wherein the polyhaloalkane is carbon tetrabromide. 19 formula () After reacting the compound represented by with a base, using a halogenating reagent, the formula () is obtained. (In the formula, X and Y are X=halogen, Y=hydrogen and/
or X=Y=halogen), and then a compound (a) where X=halogen and Y=hydrogen in formula () [Formula] (Hal=halogen) and X in formula () =Y=halogen compound (
b) In formula (), X
A method for producing a halogen-substituted β-lactam compound in which = halogen and Y = hydrogen. 20. The production method according to claim 19, wherein the base is lithium dialkylamide. 21. The production method according to claim 19, wherein the halogenating reagent is a positive halogen reagent capable of releasing positively charged halogen. 22. The production method according to claim 21, wherein the positive halogen reagent is N-bromosuccinimide, p-toluenesulfonyl bromide, or benzenesulfonyl bromide. 23. The production method according to claim 19, wherein the halogenating reagent is a polyhaloalkane. 24. The production method according to claim 23, wherein the polyhaloalkane is carbon tetrabromide. 25. The production method according to claim 19, wherein the catalyst for the reduction reaction is a palladium catalyst.