JPH0325419B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 2-azetidinone derivative useful as a synthetic intermediate for pharmaceuticals and a method for producing the same. More specifically, the present invention relates to the general formula () (In the formula, R ¹ is hydrogen, azide or amino group, R ²
is a _C1 to _C4 alkyl group or phenyl, p-methylphenyl, p-methoxyphenyl, p-bromophenyl or benzyl group, ^R3 is hydrogen or _SO3
It is a group represented by M. M represents hydrogen or a cation. ) A novel 2-azetidinone derivative represented by: The 2-azetidinone derivative represented by the formula () is a novel compound that has not been described in any literature, and is an important compound 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 antibiotic that exhibits strong antibacterial activity against Gram-negative bacteria, and many insulators of this compound can be synthesized from the compound () of the present invention. In the compound () of the present invention, C ₃ and C ₄
There are asymmetric carbons at the positions (3S, 4S), (3R,
There are four types of optical isomers: (4R), (3S, 4R), and (3R, 4S), and all isomers are included in the scope of the present invention. The compound () of the present invention has the following formula () (In the formula, R ¹ is hydrogen, azide, or an amino group) and a compound represented by the general formula (In the formula, R ² is a C ₁ to C ₄ alkyl group, or phenyl, p-methylphenyl, p-methoxyphenyl, p-bromophenyl, or benzyl group, x
represents a chloro or N-imidazolyl group) in the presence of a base to form the general formula () (In the formula, R ¹ and R ² are the same as above.) A reaction product () is obtained. The compound () is further reacted with a sulfur trioxide complex as necessary to form the general formula () (In the formula, R ¹ and R ² are the same groups as above, and M
represents hydrogen or a cation). The compound () in which R ¹ is an azide group can be obtained by subjecting it to a reduction reaction to form the general formula () (wherein R ² and M are the same as above). Compound()
It is also possible to produce a compound () in which R ¹ is an amino group by subjecting it to a similar reduction reaction. For reactions carried out in the presence of a base, appropriate reaction conditions are selected depending on the type of base used. When using an organic base as the base, triethylamine, diisopropylethylamine, pyridine, 4-(N,N-dimethylamino)-pyridine,
Dimethylaniline, diethylaniline, imidazole, etc. are used, preferably triethylamine is coexisting in an organic solvent of 1 to 2 times the mole, preferably 1.2 to 1.5 times the mole of the compound (), preferably methylene chloride or benzene. A method is employed in which an organic sulfonyl compound (X is chlor) is reacted with 1 to 2 moles, preferably 1 to 1.5 moles, of the compound (). The reaction at this time is -
It is desirable to carry out under cooling at 20°C to 0°C.
When using an alkali metal hydride such as sodium hydride or potassium hydride as a base, 1 to 1% of the compound () is used in an organic solvent such as tetrahydrofuran, 1,2-dimethoxyethane, diglyme, N,N-dimethylformamide, A method of reacting 2 times the mole, preferably 1 to 1.5 times the mole of alkali metal hydride to form the compound () into an alcoholate, and then reacting with an organic sulfonyl compound (particularly preferably one in which X is an N-imidazolyl group). is selected. The reaction is carried out at temperatures ranging from room temperature to the boiling point of the solvent used. When anhydrous alkali metal or alkaline earth metal salts such as anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous barium carbonate, or anhydrous calcium carbonate are used as the base, anhydrous acetone is a preferable reaction solvent; The base is present in 1 to 10 times the mole of the compound (), preferably 3 to 5 times the mole, and the organic sulfonyl compound (X is chlorine) is 1 to 3 times the mole of the compound (), preferably 3 to 5 times the mole.
A method can be adopted in which 1.1 to 2 times the molar amount is applied. The reaction is carried out at temperatures ranging from 0°C to room temperature. The reaction product () of these reactions can be isolated by conventional organic solvent extraction and, if necessary, purified by column chromatography using silica gel. The organic sulfonyl compound is preferably mesyl chloride, mesylimidazole, tosyl chloride, tosylimidazole, or benzylsulfonyl chloride, but benzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride or their N-imidazolyl derivatives are also employed. can. When compound () is reacted with a sulfur trioxide complex, compound (), which is an important intermediate of azthreonam derivatives, can be produced. However, as a sulfur trioxide complex, pyridine-
Sulfur trioxide, lutidine-sulfur trioxide, N,N
-dimethylformamide-sulfur trioxide, or picoline-sulfur trioxide, etc. can be employed. The reaction is carried out in pyridine or N,N-dimethylformamide with, for example, chlorosulfonic acid trimethylsilyl ester [ClSO ₂ OSi(CH ₃ ) ₃ ], and the corresponding pyridine-sulfur trioxide or N,N- The desired compound () can also be produced by a reaction that forms dimethylformamide-sulfur trioxide. The compound in which R ¹ is an amino group in the formula () is an extremely important intermediate compound for producing many useful medicines by introducing various acyl groups into the amino group. R ¹ in ()
It can be easily obtained by subjecting a compound in which is an azide group to a reduction reaction. The reduction reaction is most preferably a catalytic reduction using platinum oxide, palladium, urushihara nickel or Raney nickel as a catalyst in an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran, or acetic acid ethyl ester, but zinc-acetic acid or methanol is most preferable. A reduction reaction using 1,3-propanedithiol can also be employed. Regarding the starting material compound () for producing the compound () of the present invention, compounds in which R ¹ is hydrogen can be prepared by the method proposed by the present applicant (Japanese Patent Application No. 1983-49527).
Using the following formula The compound shown can be obtained. In addition, a compound in which R ¹ is azide can be easily obtained by the method of the present applicant (Japanese Patent Application No. 1983-4515), and can be easily obtained by the following formula: The compound represented by can be prepared by removing the isopropylidene protecting group under acidic conditions. Hereinafter, the present invention will be explained in detail with reference to Examples. Example 1 Production of (4R)-(2-mesyloxyethyl)-2-azetidinone (4R)-(2-hydroxyethyl)-2-azetidinone [mp64-66.℃, [α] ²⁵ _D +13.4° (C2.0,
MeOH)] 346.5 mg (3.01 mmol) was dissolved in 10 ml of dry acetone, and 2.02 g (14.6
0.35 ml (4.52 mmol) of mesyl chloride was added while stirring vigorously at room temperature.
Further stirring was continued. Confirm the disappearance of the raw materials by thin layer chromatography (TLC) (2 hours), remove the inorganic salt from the reaction solution, wash the inorganic salt with fresh acetone, combine the washing solution and the solution, and concentrate. 0.92 g of oil was obtained. This was subjected to column chromatography using silica gel (Wakogel C200, 24 g) and developed with toluene-acetone (3:2, v/v) to obtain 463.6 mg (80%) of the target compound as white crystals. mp70~71℃,
[α] ²⁵ _D +8.7゜ (C2.0, MeOH) TLC Rf value: 0.13 (Toluene-acetone = 3:
2, HBr-ninhydrin coloration) IR ν ^KBr _nax : 3230, 1760 (sh), 1730, 1720, 1350
，
1180, 945cm ^{-1 1} HNMR (90MHz, CDCl ₃ ): δppm. Example 2 Production of (3R,4R)-3-azido-4-(2-mesyloxyethyl)-2-azetidinone (Method A) Compound (), [α] ²⁵ _D +141.3° (C1.16, MeOH)
，
0.71g (4.5mmol) and triethylamine 0.68g
(6.7 mmol) in 20 ml of dry methylene chloride (some of it is insoluble), cooled to below -10°C in an ice-salt bath, then 0.39 ml (5.0 mmol) of mesyl chloride was dissolved in 6 ml of dry methylene chloride. The solution was added dropwise over about 10 minutes. Heat the mixture at -10°C or below.
After stirring for 30 minutes, 100 ml of 0.5M potassium phosphate buffer (PH6.0) was added, and the methylene chloride layer was separated. The aqueous layer was saturated with sodium chloride, extracted with ethyl acetate (30 ml x 2, 60 ml x 2), dried together with the methylene chloride layer, and the solvent was removed under reduced pressure. The obtained oil was subjected to silica gel column chromatography (chloroform-acetone = 90:10,
85:15, 80:20) to obtain 0.84 g (80%) of the title compound () as a pale yellow syrup. n ²⁵ _D 1.575, [α] ²⁵ _D +93.2° (C2.0, MeOH). IR ν ^neat _nax : 3350, 2120, 1760, 1350, 1175cm ^{-1 1} HNMR (90MHz, CD ₃ OD): δppm. 2.2 (2H, m, CH ₂ CH ₂ OMs), 3.10 (3H, s,
OSO ₂ CH ₃ ), 3.37 (1H, d−t, H ₄ , J=
2, 3, 7.5Hz), 4.37 (2H, t, CH ₂ CH ₂
OMs, J=7.5Hz), 4.4(1H, d, H ₃ , J=
2.3Hz) <Method B> Dissolve 1.4 g (8.97 mmol) of compound () in 80 ml of anhydrous acetone, and add 12.4 g of anhydrous potassium carbonate.
(89.7 mmol) was added thereto, and while stirring vigorously at room temperature, 1.4 ml of mesyl chloride was added dropwise using a syringe over about 2 minutes. While vigorous stirring was continued, the reaction mixture became cloudy with fine powder of potassium chloride produced as a by-product. The raw materials disappeared in 2 hours, and the reaction mixture was freed of inorganic salts, washed with acetone, and the washings and liquid were combined and concentrated to obtain 3.53 g of a yellow oil. This was subjected to silica gel column chromatography (Wakogel C200 25g, L/D=80, developed with toluene-acetone=3:1) to obtain 1.87g (89%) of the target compound (2) as a pale yellow syrup. TLC Rf value: 0.18 (toluene-acetone = 3:
1) (Color development, ₂ adsorption or HBr-ninhydrin) <Method C> 346.5 mg (3.01 mmol) of compound () was reacted with 87 mg (3.6 mmol) of sodium hydride in 10 ml of dry N,N-dimethylformamide. alcoholate, then mesylimidazolide
A solution of 483 mg (3.3 mmol) dissolved in 5 ml of dry N,N-dimethylformamide was added all at once.
Stirred at 50°C for 2 hours. After cooling the reaction solution,
After diluting with 50 ml of 0.5M potassium phosphate buffer, extraction was performed with ethyl acetate (50 ml x 3), and the organic layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the yellow oil obtained was purified by the same column chromatography as described in Method B to obtain 1.78 g (85%) of a pale yellow syrup of the desired compound (). . Example 3 Production of (3R,4R)-3-azido-4-(2-mesyloxyethyl)-2-azetidinone () In method B of Example 2, anhydrous barium carbonate was used instead of anhydrous potassium carbonate. Compound () was obtained in the same manner except for that. Example 4 Production of tetra-orthobutylammonium (3R,4R)-3-azido-4-(2-mesyloxyethyl)-2-oxo-1-azetidinesulfonate () 1.65 g of compound () obtained by the method of Example 2
(7.04 mmol) was dissolved in 10 ml of dry N,N-dimethylformamide, to which 3.92 g (24.6 mmol) of pyridine-sulfur trioxide was added at once as a solid under a nitrogen atmosphere, and the reaction mixture was heated to a water bath temperature of 55-60°C.
After heating and stirring at ℃ for 3 hours, disappearance of the raw material was confirmed on TLC. After cooling, the reaction solution was diluted with KH ₂ PO ₄ 10.1
g (74.2 mmol) was dissolved in 100 ml of an aqueous solution, and the pH was adjusted to 5.8 with 2NKOH. Remove unnecessary neutral components with methylene chloride (50 ml x 3), concentrate the aqueous layer under reduced pressure to obtain approximately 50 ml of a homogeneous brown liquid,
Tetra-normal butylammonium hydrogen sulfate 2.91g
(8.57 mmole) of solid was added at once, and the resulting target compound () was extracted with methylene chloride (50 ml x 3). After washing the yellow extract with diluted saline, drying (anhydrous sodium sulfate) and concentrating under reduced pressure,
4.45 g of a brown oil containing N,N-dimethylformamide was obtained. ¹ HNMR spectrum showed that it was a mixture of compound () and N,N-dimethylformamide in a molar ratio of about 1:1.
Although this product can be used in subsequent reactions, the pure product () for obtaining analytical values was purified and isolated by silica gel column chromatography (linear gradient elution method of 0-20% EtOH in toluene). Shape: Pale yellow starch syrup-like substance. [α] ²⁵ _D +46.6° (C=2.08, MeOH). IR ν ^neat _nax : 2100, 1760, 1350, 1250, 1175,
1040cm ^{-1 1} HNMR (90MHz, CDCl ₃ ): δppm. 1.0 (12H, t, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.2 to 1.9
(16H, m, _CH2CH2CH2CH3 ), _{2.2 ~ 2.7}
(2H, m, CH ₂ CH ₂ OMs), 3.08 (3H, S,
CH ₂ OSO ₂ CH ₃ ), 3.27 (8H, t, CH ₂
CH ₂ CH ₂ CH ₃ ), 3.90 (1H, m, H ₄ ), 4.30
(1H, d, J = 2.4Hz, H ₃ ), 4.4~4.7 (2H,
(3R _{, 4R} )-3-azido-4-(2-mesyloxyethyl)-2-oxo-1-azetidinesulfonic acid tetra-orthobutylammonium Example 4 The same method was used, except that N,N-dimethylformamide-sulfur trioxide was used instead of pyridine-sulfur trioxide, and the reaction was carried out at room temperature.
The title compound was obtained. TLC Rf value: 0.10 (Toluene-EtOH=9:1)
0.43 (EtOAc- _EtOH -H2O=5:1:1) Example 6 (3R,4R)-3-amino-4-(2-mesyloxyethyl)-2-oxo-1-azetidinesulfonic acid tetra Production of normal butylammonium () (3R,4R)-3-azido-4-(2-mesyloxyethyl)-2-oxo-1-azetidinesulfonic acid tetrabutylammonium () 0.15g
(0.27 mmol) was dissolved in 0.6 ml of methanol, and 10
0.015 g of % palladium on carbon was added and the mixture was hydrogenated at atmospheric pressure for 2 hours. The catalyst was removed and the liquid was evaporated under reduced pressure to give 0.13 g (0.25 g) of the title compound ().
mmol, 91%) was obtained as a glass-like solid. Rf = 0.23 in thin layer chromatography (silica gel, ethyl acetate: ethator: water = 5:1:1). Example 7 Preparation of (3R,4R)-3-amino-4-(2-mesyloxyethyl)-2-oxo-1-azetidinesulfonic acid tetra-orthobutylammonium () Example 6 with 10% palladium/carbon Instead of,
Compound () was obtained in exactly the same manner except that 30% palladium/BaCO ₃ was used as palladium in an amount of 1.5% by weight of compound (). A pure product for analysis was purified and isolated using silica gel column chromatography. [α] ²⁵ _D +4.5゜(C=2.0, MeOH) IR ν ^KBr _nax :3400, 2960, 2880, 1760, 1470,
1350, 1245, 1175, 1045, 750, 635cm ^{-1 1} HNMR (90MHz, CDCl ₃ ): δppm. 1.0 (12H, t, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.2 to 1.8
(16H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 2.0 (2H,
NH ₂ ), 2.1 to 2.6 (2H, m, CH ₂
CH ₂ OSO ₂ CH ₃ ), 3.1 (3H, s, OSO ₂ CH ₃ ),
2.9~3.5 (8H, _t , _{CH2CH2CH2CH3 )} , _3.6 ~
3.9 (2H, m, H ₃ , H ₄ ), 4.6 (2H, m, CH ₂
CH ₂ OSO ₂ CH ₃ ) TLC Rf value: 0.59 (EtOAc−EtOH−H ₂ O=
2:1:1) (Detection: ₂ adsorption, ninhydrin...yellow) Example 8 (3R,4R)-3-amino-4-(2-mesyloxyethyl)-2-oxo-1-azetidinesulfonic acid tetra Production of normal butylammonium () Compound () was obtained in exactly the same manner as in Example 6 except that Urushibara Nickel A was used instead of 10% palladium/carbon. Example 9 (4R)-4-(2-tosyloxyethyl)-2-
Production of azetidinone () 90 mg of sodium hydride (mineral oil removed with n-hexane) was kept in 5 ml of dry N,N-dimethylformamide (DMF) and the compound () was added under ice cooling.
A solution of 392 mg (3.4 mmol) dissolved in 5 ml of DMF was added dropwise and stirred for 30 minutes. Then 5 ml of a DMF solution of 758 mg (3.4 mmol) of tosylimidazole was added,
The ice bath was removed and the mixture was stirred for 3 hours. Add 40ml of 0.25M phosphate buffer (PH6) and add ethyl acetate (50ml x 3)
The organic layer was washed with brine and dried. The organic solvent was removed under reduced pressure to obtain a crude solid of compound (). Crystallization was performed from methylene chloride-n-hexane to obtain 450 mg (49%) of white crystals. IR ν ^KBr _nax : 1725 (β-lactam) cm ^-1 TLC Rf value: 0.26 (Toluene-EtOH=9:1) Example 10 (3R,4R)-3-azido-4-(2-tosyloxyethyl )-2-azetidinone () production Sodium hydride (mineral oil free powder) 24mg
was kept in 6 ml of anhydrous tetrahydrofuran (THF), and 57.8 mg of the compound () was added at room temperature.
(0.37 mmol) in THF was added and stirred for 30 minutes. Next, 2 ml of a THF solution containing 76 mg of tosyl chloride was added and stirred for 2 hours, and disappearance of the raw material () was confirmed by TLC. 20 ml of 0.25M phosphate buffer (PH6) was added, extracted with ethyl acetate (30 ml x 2), washed with saline, dried, and the organic solvent was removed under reduced pressure to obtain 95 mg of yellow syrup. Purification by silica gel column chromatography (toluene-HtOH=95:5) gave 70 mg (61%) of the title compound () as a glass-like pale yellow solid. IR ν ^KBr _nax : 3360, 2120, 1740, 1340, 1160,
1090cm ^-1 TLC Rf value: 0.28 (Toluene-EtOH=9:1)

Claims (1)

[Claims] Linear formula (In the formula, R ¹ is hydrogen, azide or amino group, R ²
is a _C1 to _C4 alkyl group or phenyl, p-methylphenyl, p-methoxyphenyl, p-bromophenyl or benzyl group, ^R3 is hydrogen or _SO3
It is a group represented by M. M represents hydrogen or a cation) A 2-azetidinone derivative represented by: 2. The compound according to claim 1, wherein R ¹ is an azide group, R ² is a methyl group, and R ³ is hydrogen. 3 R ¹ is an azide group, R ² is a p-methylphenyl group,
A compound according to claim 1, wherein R ³ is hydrogen. 4 R ¹ is an azide group, R ² is a methyl group, R ³ is SO ₃
The compound according to claim 1, which is an M group (in the group, M represents hydrogen or a cation). 5 R ¹ is an amino group, R ² is a methyl group, R ³ is SO ₃
The compound according to claim 1, which is an M group (in the group, M represents hydrogen or a cation). 6. The compound according to claim 1, 4 or 5, wherein 6M is an alkali metal ion. 7. The compound according to claim 1, 4 or 5, wherein 7M is a tetra-normal butylammonium ion.