JPH06770B2 - Method for producing amide compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of general formula, which is a synthetic intermediate for β-lactam compounds having antibacterial activity. The present invention relates to a method for producing a compound having

R ¹ in the general formula (1) is a protecting group for an amino group (for example,
Allyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, etc.) and R ³ may have a substituent. Good aryl groups (eg phenyl or naphthyl groups, the substituents of which are lower alkyl groups (eg methyl, ethyl, propyl, isopropyl etc.), benzyl groups, lower alkoxy groups (eg methoxy, ethoxy or propoxy etc. ), A halogen atom (for example, a chlorine or bromine atom, etc.), a cyano group, or a nitro group, which may have 1 to 3 of the same or different substituents.] A compound having the general formula (1) Is the general formula The compound having the formula is reacted with formalin or acyloxymethyl halide to give a compound of the general formula It is obtained by leading to a compound having and reacting this with arylsulfinic acid. General formulas (2) and (3)
R ¹ has the same meaning as described above, R ² is a hydrogen atom, or an acyl group-COR ⁴ [wherein R ⁴ is a lower alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, or t- Butyl, etc.), a substituted lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, or t-butyl group, the substituent being chlorine, fluorine, methoxy, ethoxycarbonyl, etc. 1 for different substituents
You may have 3 pieces. ) Or an aryl group which may have a substituent (eg, a phenyl or naphthyl group, the substituent of which is a methyl, methoxy, cyano, chlorine, or nitro group, and these same or different It may have 1 to 3 substituents). ].

The compounds having the general formulas (1), (2) and (3) are considered to have various stereoisomers, but these formulas represent single substances or a mixture of isomers.

The compound having the general formula (1) is an important intermediate which can be converted into a carbapenem derivative having antibacterial activity by the methods described in JP-A-57-163362, JP-A-58-127143 and JP-A-59-51286. It is the body. The compound having the general formula (1) can also be synthesized by the method disclosed in JP-A-57-163362, but chloromethylphenyl sulfide and peracid used in the disclosed method are expensive and peracid. Depending on the type, there is an explosive risk. The present inventors have found that the object (1) can be obtained with a high yield by solving such drawbacks, and completed the present invention.

The compounds having the general formula (1) except the compounds having the general formula (3) and the compounds having the formula (1) in which R ¹ is an aryl group are novel compounds. The present invention is described in detail below.

The compound having the general formula (1) can be obtained by the method shown below.

In these formulas, R ¹ , R ³ and R ⁴ have the same meanings as described above, and X represents a chlorine, bromine or iodine atom.

Method for producing compound (4) A compound having the general formula (2) is dissolved in an aqueous formalin solution, and this is dissolved in a base (for example, triethylamine, diisopropylamine, dicyclohexylamine, pyridine,
An organic base such as picoline, dibutylamine, or dipropylamine, or an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or sodium hydrogen carbonate. )
Or in the presence of salts (for example, sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, sodium iodide, potassium iodide, magnesium chloride, calcium chloride, etc.), 0 ° to 100 ° C. 30 minutes ~
After reacting for 24 hours, after completion of the reaction, the target compound can be collected by a conventional method. For example, the reaction solution is extracted with an organic solvent such as ethyl acetate, washed with an acidic sodium sulfite aqueous solution, and dried, and then the organic solvent is removed. It can be obtained by distillation, and can be purified by column chromatography if necessary.

Method for producing compound (1) from compound (4) The compound (4) is treated with a solvent (for example, benzene, toluene, ethyl acetate, butyl acetate, dichloromethane, dichloroethane, chloroform, diethyl ether, hexane, cyclohexane, or diisopropyl ether, or a compound thereof). A mixed solvent, etc.), and 1 to 3 equivalents of an arylsulfinic acid which may have a substituent is added to this solution and reacted at 0 ° to 100 ° C. for 30 minutes to 24 hours. In this reaction, molecular sieves can be coexistent. To collect the desired product from the reaction solution, the crystals obtained by distilling off the solvent are recrystallized or the residue is subjected to column chromatography after distilling off the solvent.

Method for producing compound (5) from compound (4) Compound (4) is dissolved in a solvent (for example, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, benzene, or toluene), and a base (for example, triethylamine, trimethylamine, diisopropylethylamine, Pyridine, picoline, N,
In the presence of N-dimethylbenzylamine, N, N-diethylbenzylamine or the like, 1 to 3 equivalents of an acid halide R ⁴ COX or an acid anhydride (R ⁴ CO) ₂ O (wherein R ⁴ and X are , Has the same meaning as described above.)
Reaction at 0 ° C for 30 minutes to 24 hours, or compound (4)
Is dissolved in a solvent (which has the same meaning as described above), and 1
To 3 equivalents of a condensing agent (eg, dicyclohexylcarbodiimide etc.) in the presence of 1 to 3 equivalents of carboxylic acid R ⁴ CO
₂ H (wherein R ⁴ has the same meaning as described above) is 0
The reaction is allowed to proceed for 30 minutes to 48 hours at a temperature of 100 ° C. The compound (5) is obtained by treating the reaction solution according to a conventional method.

Method for producing compound (5) from compound (2) Method A: Compound (2) and 1 to 5 equivalents of acyloxymethyl halide are used without solvent, or with a solvent (for example, hydrocarbon such as hexane, benzene, or cyclohexane, dichloromethane, or Halogenated hydrocarbons such as dichloroethane, ethers such as diethyl ether, tetrahydrofuran or dioxane, esters such as ethyl acetate or butyl acetate, ketones such as acetone or methyl ethyl ketone, or N, N-dimethylformamide, or N, N- It is dissolved in an amide such as dimethylacetamide) and a base [eg, a lithium compound (eg, methyl lithium, butyl lithium, t-butyl lithium, or phenyl lithium)], an alkali metal amide (eg, Thium diisopropylamide, lithium hexamethyldisilazane, lithium amide, sodium amide, potassium amide, etc.), alkali metal hydride (eg sodium hydride or potassium hydride), alkali metal hydroxide (eg lithium hydroxide) , Sodium hydroxide, potassium hydroxide, etc.), amines (eg, triethylamine, 1,5 diazabicyclo [4.3.0])
Non-5-ene, or 1,8-diazabicyclo [5.4.
0] undec-7-ene etc.), or quaternary ammonium hydroxides (eg tetrabutylammonium hydroxide etc.)] in the presence of −50
Incubate for 30 minutes to 24 hours at ° -100 ° C. The target compound can be isolated according to a conventional method.

Method B: Compound (2) and 1 to 5 equivalents of acyloxymethyl hyrad are dissolved in a solvent (eg, dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane), and a phase transfer catalyst (eg, benzyltrimethylammonium) is dissolved. In the presence of iodide, benzyltrimethylammonium chloride, tetrabutylammonium bromide, etc.), the mixture is stirred with an aqueous solution of sodium hydroxide or potassium hydroxide at -50 ° C to 100 ° C for 30 minutes to 24 hours. Alternatively, the compound (2) and 1 to 3 equivalents of acyloxymethyl halide are dissolved in tetrahydrofuran, and sodium hydroxide or potassium hydroxide is suspended in the presence of a phase transfer catalyst (having the same meaning as described above) to give -5
Stir for 30 minutes to 24 hours at 0 ° C to 67 °. The desired product is isolated by treating the reaction solution according to a conventional method.

Method for producing compound (1) from compound (5) Compound (5) and 1 to 3 equivalents of arylsulfinic acid are used as a solvent (for example, hydrocarbon such as hexane, benzene, cyclohexane, or toluene, diethyl ether, diisopropyl ether, or dioxane). Dissolved in ether such as ether, ester such as ethyl acetate or butyl acetate, acetone, or ketone such as methyl ethyl ketone, and the like, without catalyst or with catalyst (for example, zinc chloride, stannic chloride, aluminum chloride, or titanium tetrachloride) Etc.) at −50 ° C. to 100 ° C. for 30 minutes
React for 24 hours. After completion of the reaction, the target compound can be collected according to a usual method. In many cases, the target compound of this reaction has good crystallinity, and the crystals precipitated after the reaction are collected, or the solvent is distilled off, and the target compound is added to a solvent in which the target compound is poorly soluble, and then crystallized and collected. Well, or if necessary, it can be purified by a recrystallization method or chromatography.

The starting compound (2) of the present invention can be synthesized using threonine (6) as a raw material according to the following formula.

In the formula, R ¹ and X have the same meanings as described above, and K represents sodium or potassium. Compound (8) is prepared from threonine (6) by the method of Shimazaki et al.
966)). The obtained salt (8) of β-methylglycidic acid was mixed with a hydrochloride of amine R ¹ NH ₂ (wherein R ¹ has the same meaning as described above) as a condensing agent (for example, dicyclohexylcarbodiimide or phosphorus oxychloride). -Pyridine etc.) or β-methylglycidyl chloride (9) obtained by reacting compound (8) with oxalyl chloride and amine R ¹ NH ₂ (wherein R ¹ is as described above). Compound (2) is obtained by reacting () with the same meaning as the above).

The present invention will be described below with reference to Examples and Reference Examples.

Example 1. (2R, 3R) -N-Hydroxymethyl-N- (P-methoxybenzyl) -2,3-epoxybutyramide To 5 ml of 37% formalin, 3 g of paraformaldehyde (water-soluble), 1 g of (2R, 3R) -N- (P-methoxybenzyl) -2,3-epoxybutyramide and 1 g of sodium bromide were added, and the mixture was heated at a bath temperature of 100 ° C. to 1 Heat and stir for hours.
Then it is cooled, filtered over insoluble crystals and washed with ethyl acetate, the ethyl acetate layer of the liquid is separated and the aqueous layer is extracted with further ethyl acetate. The ethyl acetate layers were combined, washed with a 5% aqueous solution of acidic sodium sulfite, dried over anhydrous sodium sulfate, the solvent was distilled off, and the remaining oil was subjected to silica gel chromatography (solvent; benzene: ethyl acetate (1: 1)). ) Purification gave the desired product as an oil. Yield 870 mg (Yield 77
%) NMR (CDCl ₃ ) δ _ppm : 1.25 (3H, d, J = 6Hz), 3.28 (1H, quintet, J = 5Hz), 3.6 to 3.85 (4H, br, s), 4.45 to 5.3 (4H, m) ), 6.65 to 7.40 (4H, m) Example 2. (2R, 3R) -N- (2,4-dimethoxybenzyl)-
N-hydroxymethyl-2,3-epoxybutyramide Instead of (2R, 3R) -N- (P-methoxybenzyl) -2,3-epoxybutyramide of Example 1, (2R, 3R) was used.
R) -N- (2,4-dimethoxybenzyl) -2,3-epoxybutyramide was similarly reacted and treated to give the desired product as an oil.

NMR (CDCl ₃ ) δ _ppm : 1.27 (3H, d, J = 6Hz), 3.28 (1H, quintet, J = 5Hz), 3.68 (1H, d, J = 5Hz), 3.77 (3H, s), 3.78 ( 3H, s), 4.40 to 5.23 (4H, m), 6.30 to 7.37 (3H, m), Example 3. (2R, 3R) -N-acetoxymethyl-N- (P-methoxybenzyl) -2,3-epoxybutyramide (2R, 3R) -N-Hydroxymethyl-N- (P-methoxybenzyl) -2,3-epoxybutyramide 530 mg
Was dissolved in 6 ml of dichloromethane, and 0.26 ml of triethylamine was added thereto while cooling to -20 DEG C. with stirring, and then a solution of 0.12 ml of acetyl chloride in 3 ml of dichloromethane was added dropwise over 10 minutes. After stirring for 10 minutes, 30 ml of ethyl acetate is added, washed with water, dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is purified by silica gel chromatography. The target product was obtained as an oil from the fraction eluted with benzene: ethyl acetate (1: 1). (Yield 500 mg, yield 85.
3%).

NMR (CDCl ₃ ) δ _ppm : 1.27 (3H, d, J = 6Hz), 2.42 (3H, s), 3.30 (1H, quintet, J = 5Hz), 3.65-3.85 (4H, br, s), 4.60 ( 2H, s), 5.18 to 5.62 (2H, m), 6.74 to 7.27 (4H, m) Example 4. (2R, 3R) -N-acetoxymethyl-N- (2,4-
Dimethoxybenzyl) -2,3-epoxybutyramide Instead of (2R, 3R) -N-hydroxymethyl-N- (P-methoxybenzyl) -2,3epoxybutyramide used in Example 3, (2R, 3R) -N-hydroxymethyl-N- (2 5,4-Dimethoxybenzyl) -2,3-epoxybutyramide (593 mg) was reacted in the same manner and treated to obtain the desired product as an oil. (Yield 490 mg,
Yield 72%) NMR (CDCl ₃ ) δ _ppm : 1.23 (3H, d, J = 6Hz), 2.0 (3H, s), 3.27 (1H, quintet, J = 5Hz), 3.72 (1H, d, J = 5Hz), 3.77 (6H, s), 4.60 (2H, s), 5.21 to 5.73 (2H, m), 6.28 to 7.37 (3H, m) Example 5. (2R, 3R) -N-chloroacetoxymethyl-N-
(P-Methoxybenzyl) -2,3-epoxybutyramide 5 g of (2R, 3R) -N-hydroxymethyl-N- (P-methoxybenzyl) -2,3-epoxybutyramide was dissolved in 50 ml of dichloromethane and cooled to -30 ° C., 3.6 ml of triethylamine and then monochloroacetyl chloride. A solution of 1.74 ml in 10 ml dichloromethane is added dropwise (10 minutes). Then, the mixture was stirred for 15 minutes, 200 ml of ethyl acetate was added, washed with water, the solvent was distilled off, and the residue was chromatographed on silica gel (solvent; benzene: ethyl acetate (5: 1)) to obtain 4.4 g of the desired product as an oil. (Yield 68%).

NMR (CDCl ₃ ) δ _ppm : 1.27 (3H, d, J = 6Hz), 3.30 (1H, quintet, J = 5Hz), ~ 3.8 (4H, br., OCH ₃ overlapping and unclear), 3.97 (2H, s), 4.60 (2H, s), 5.25-5.83 (2H, m), 6.67-7.37 (4H, m) Example 6. (2R, 3R) -N-acetoxymethyl-N- (P-methoxybenzyl) -2,3-epoxybutyramide About 30 ml of hexane was added to 0.89 g of sodium hydride (content: 55%), and the mixture was stirred and allowed to stand, the hexane layer was decanted off, 18 ml of dry dimethylformamide was added, and (2R, 3R) -N under ice cooling. -(P-methoxybenzyl)-
Add 3.0 g of 2,3-epoxybutyramide in small portions.
Stir for 20 minutes, cool to -30 ° C (until no bubbling) and add dropwise a solution of 1.76 g acetoxymethyl chloride in 18 ml dry tetrahydrofuran. Then 3
Stir for 0 minutes, add 150 ml of ethyl acetate and wash with 2% aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with 50 ml of ethyl acetate, combined with ethyl acetate solution, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of benzene: ethyl acetate (6: 1). 3.7 g of the product was obtained as an oil (yield 93%).

The physical constants of this substance were the same as those of the compound obtained in Example 3.

Example 7. (2R, 3R) -N-pivaloyloxymethyl-N-
(P-Methoxybenzyl) -2,3-epoxybutyramide (2R, 3R) -N- (P-methoxybenzyl) -2,3
-Epoxy butyramide 3g (13.6mM) was dissolved in 60ml of tetrahydrofuran and powdered caustic potash 2.23 under ice cooling.
g and interphase catalyst tetrabutylammonium bromide
0.45 g and 3.9 ml of pivaloyloxymethyl chloride are added, and the mixture is stirred at room temperature for 30 minutes. 200 ml of ethyl acetate was added, washed with 2% aqueous sodium hydrogen carbonate solution, the aqueous layer was extracted with ethyl acetate, the ethyl acetate solutions were combined, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, benzene: acetic acid. Elute with a mixed solvent of ethyl (6: 1) to obtain the desired product 4.
4 g was obtained as an oil. (Yield 96.5%) NMR (CDCl ₃ ) δ _ppm : 1.17 (9H, s), 1.28 (3H, d, J = 6Hz), 3.29 (1H, quintet, J = 5Hz), 3.7-3.8 (4H, br , OCH ₃ and unclear), 4.58 (2H, s), 5.16-5.57 (2H, m), 6.68-7.26 (4H, m) Example 8. (2R, 3R) -N-pivaloyloxymethyl-N-
(2,4-dimethoxybenzyl) -2,3-epoxybutyramide Hexane 3 to 1.3 g of sodium hydride (content 55%)
Add 0 ml, stir well, remove by decanting, add 25 ml of dimethylformamide, and cool with ice (2R, 3
R) -N- (2,4-dimethoxybenzyl) -2,3-epoxybutyramide (5.0 g) was added little by little, then stirred for 20 minutes, cooled to -30 ° C and 3.5 ml of pivaloyloxymethyl chloride was added. A solution dissolved in 50 ml of tetrahydrofuran was added dropwise, and then the mixture was stirred for 30 minutes and treated in the same manner as in Example 6 to obtain 6.72 g of the desired product as an oily substance (yield 92.3%) NMR (CDCl ₃ ) δ _ppm : 1.15 (9H, s), 1.23 (3H, d, J = 6Hz), 3.27 (1H, quintet, J = 5Hz), 3.70 (1H, d, J = 5Hz), 3.75 (3H, s), 4.57 (2H) , s), 5.13 to 5.63 (2H, m), 6.22 to 7.23 (3H, m) Example 9. (2R, 3R) -N-benzoyloxymethyl-N-
(2,4-dimethoxybenzyl) -2,3-epoxybutyramide When benzoyloxymethyl chloride was used instead of pivaloyloxymethyl chloride of Example 8, and the same reaction and treatment were carried out, the target compound was obtained as an oil.
(Yield 98%).

NMR (CDCl ₃ ) δ _ppm : 1.25 (3H, d, J = 6Hz), 3.28 (1H, quintet, J = 5Hz), 3.6 to 3.9 (7H, br., OCH ₃ and unclear), 4.7 (2H , s), 5.45 to 6.03 (2H, m), 6.38 to 8.1 (8H, m) Example 10. (2R, 3R) -N- (P-nitrobenzoyloxy)
Methyl-N- (2,4-dimethoxybenzyl) -2,3-epoxybutyramide P-Nitrobenzoyloxymethyl chloride was used in place of benzoyloxymethyl chlorallide in Example 9, and the same reaction was carried out and treated to obtain the desired product as an oily substance (yield 91%) NMR (CDCl ₃ ) δ _ppm : 1.25 (3H, d, J = 6Hz), 3.30 (1H, quintet, J = 5Hz), 3.4 to 3.93 (7H, br, OCH ₃ overlapped and unclear), 4.7 (2H, br.s), 5.5 ~ 6.13 (2H, m), 6.23 ~ 7.43 (3H, m), 7.9 ~ 8.4 (4H, m) Example 11. (2R, 3R) -N-allyl-N-pivaloyloxymethyl-2,3-epoxybutyramide (2R, 3R) -N-allyl-2,3-epoxybutyramide 1.27g (9.01mmole), pivaloyloxymethyl chloride 2.70g (18mmole), tetrabutylammonium bromide 290mg (0.90mmole) was dissolved in tetrahydrofuran,
At 0 ° C., 1.26 g (22.5 mmole) of powdery caustic potash was added and stirred. After 10 minutes, the temperature is returned to room temperature and stirring is continued for 3 hours. Dilute with ethyl acetate and wash with water. After drying, the solvent is distilled off and the residue obtained, 4.0 g, is subjected to column chromatography using 40 g of silica gel. 2.76 g of crude product obtained by eluting with benzene: ethyl acetate (2: 1 to 1: 1)
Is purified using Lobar column B. Elute with a mixed solvent of benzene: ethyl acetate (2: 1 to 1: 1) to obtain the desired product 1.95.
g (85% yield) was obtained as an oil.

: 1729, 1681 NMR (CDCl ₃ ) δ _ppm 1.23 (9H, s), 1.29 (3H, d, J = 5Hz), 3.28 (1H, quintet, J = 5Hz), 3.75 (1H, d, J = 5Hz) , 4.03 (2H, br.d, J = 5.5Hz), 4.9 to 6.1 (3H, m), 5.41 (2H, s) Example 12. (2R, 3R) -N- (2,4-dimethoxybenzyl)-
N-phenylsulfonylmethyl-2,3-epoxybutyramide (2R, 3R) -N- (2,4-dimethoxybenzyl)-
N-hydroxymethyl-2,3-epoxybutyramide 61
To 1 mg (2.2 mM), 0.6 ml of isopropyl ether and 0.6 g of molecular sieve 4A, 615 mg of benzenesulfinic acid
(4.3 mM) was added, and the mixture was heated with stirring at 40 ° C. for 40 minutes. Then, the mixture was cooled, ethyl acetate was added to remove the insoluble matter, the solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with a mixed solvent of benzene: ethyl acetate (1: 4) to obtain the desired product.
352 mg was obtained. Crystallizes on standing.

Melting point: 112 to 113 ° C NMR (CDCl ₃ ) δ _ppm : 0.97 (3H, d, J = 6Hz), 2.93 to 3.40 (1H, br, quintet, J = 5Hz), 3.68 (1H, d, J = 5Hz) , 3.76 (3H, s), 3.78 (3H, s), 4.03 to 5.60 (4H, m), 6.20 to 7.28 (3H, m), 7.30 to 8.07 (5H, m) Example 13. (2R, 3R) -N- (P-methoxybenzyl) -N-
Phenylsulfonylmethyl-2,3-epoxybutyramide (2R, 3R) -N- (P-methoxybenzyl) -N-
Acetoxymethyl-2,3-epoxybutyramide 1.18 g
Ethyl acetate (12 ml) was added to (4.02 mM) and the mixture was melted. Benzenesulfinic acid (686 mg, 4.8 mM) and a small amount of zinc chloride were added in an ice-water bath, and the mixture was stirred at the same temperature for 6 hours. When 60 ml of isopropyl ether is added and left to stand, the desired product crystallizes. After collecting for about 1 hour, the solution was concentrated, and the residual oily substance was subjected to silica gel chromatography to obtain benzene: ethyl acetate (5:
A smaller amount of the desired product was obtained from the portion eluted with the mixed solvent of 1) (yield 1.18 g, yield 78%).

Melting point: 110 to 112 ° C NMR (CDCl ₃ ) δ _ppm : 1.06 (3H, d, J = 6Hz), 2.98 to 3.37 (1H, br, quintet, J = 5Hz), 3.55 (1H, d, J = 5Hz) , 3.78 (3H, s), 4.1 to 5.45 (4H, m), 6.70 to 8.10 (9H, m) Example 14. (2R, 3R) -N- (2,4-dimethoxybenzyl)-
N-phenylsulfonylmethyl-2,3-epoxybutyramide (2R, 3R) -N- (2,4-dimethoxybenzyl)-
Ethyl acetate (15 ml) was added to N-pivaloyloxymethyl-2,3-epoxybutyramide (1.5 g) to melt, and the mixture was stirred in an ice-water bath while adding benzenesulfinic acid (0.7 g) and a small amount (60 mg) of zinc chloride. Stir at temperature for 6 hours.
Then, isopropyl ether is added and the mixture is allowed to stand and the target substance crystallizes and precipitates. This was collected, the liquid was concentrated, and the residue was separated and purified by silica gel chromatography to obtain a further small amount of crystals (amount 1.5 g, yield 90.3%).

The physical constants of this substance were the same as those of the compound obtained in Example 12.

Example 15. (2R, 3R) -N- (P-methoxybenzyl) -N-
Phenylsulfonylmethyl-2,3-epoxybutyramide 1.91 g of (2R, 3R) -N- (P-methoxybenzyl) -N-chloroacetoxymethyl-2,3-epoxybutyramide obtained in Example 6 was dissolved in 20 ml of ethyl acetate to obtain 1 g of benzenesulfinic acid. In addition, the reaction was carried out in the same manner as in Example 14 and the treatment was performed to obtain 1.94 g of the desired product as crystals (yield 88.7%).

The physical constant of this substance was the same as that of the compound obtained in Example 13.

Example 16. (2R, 3R) -N- (P-methoxybenzyl) -N-
Phenylsulfonylmethyl-2,3-epoxybutyramide (2R, 3R) -N- (P-methoxybenzyl) -N-
Pivaloyloxymethyl-2,3-epoxybutyramide
Dissolve 2.0 g in 20 ml of acetic acid and add benzenesulfinic acid 1.0
2 g and a small amount of zinc chloride were added, and the reaction was carried out in the same manner as in Example 14, and the reaction product was treated to obtain the desired product as crystals (yield 2.1 g, 94% yield).

The physical constant of this substance was the same as that of the compound obtained in Example 13.

Example 17. (2R, 3R) -N-allyl-N-phenylsulfonylmethyl-2,3-epoxybutyramide (2R, 3R) -N-allyl-N-pivaloyloxymethyl-2,3-epoxybutyramide 2.25 g (8.82 mmole)
Is dissolved in 25 ml of ethyl acetate, and benzenesulfinic acid 2.
00g (14.1mmole) and zinc chloride 20mg (0.88mmole) are added and stirred. Crystallization begins to occur after about 15 minutes. After 30 minutes, a large amount of chloroform is added to dissolve the crystals, and the crystals are washed with aqueous sodium hydrogen carbonate. The crystals obtained by distilling off the solvent were washed with a mixed solvent of ethyl acetate: hexane (2: 1) to obtain 1.71 g of crystals having an mp of 133 to 134 ° C. Recrystallize by concentrating the mother liquor Secondary crystal
0.61 g (mp 131-132 ° C) was obtained. The mother liquor was further subjected to column chromatography using 6 g of silica gel and eluted with a mixed solvent of benzene: ethyl acetate (2: 1 to 1: 1) to obtain 90 mg of the desired crystal. Total yield 2.41g (Yield
92.6%). Recrystallization from ethyl acetate gave pure needles with mp 138-138.5 ° C.

Specific rotation ▲ [α] ²⁵ _D ▼ + 52.4 ° (c = 0.46, CHCl ₃ ) : 1682, 1660 (sh.) NMR (CDCl ₃ ) δ _ppm : (3: 1 equilibrium mixture of two rotamers), absorption of main isomer: 1.02 (3H, d, J = 5Hz), 3.2 (1H , m), 3.46 (1H, d, J = 4Hz), 4.35 (2H, br.d, J = 5Hz), 4.62 (1H, d, J = 14Hz), 5.02 (1H, d, J = 14Hz), 5.0 to 6.1 (3H, m), 7.3 to 8.1 (5H, m); Main absorption of minor isomers: 1.19 (3H, d, J = 5Hz) Reference example 1. (2R, 3R) -N- (2,4-dimethoxybenzyl)-
2,3-epoxybutyramide (2R, 3R) -β-methylglycidic acid potassium salt 4.53
g (32.3 mM) was suspended in 45 ml of dry dichloromethane, -6
Cool to 0 ° C. To this, a solution of 2.82 ml of oxalyl chloride in 10 ml of dichloromethane is added dropwise with stirring. Then, a solution of 4.95 ml of triethylamine dissolved in 10 ml of dichloromethane was added, and then a solution of 5.37 g of 2,4-dimethoxybenzylamine dissolved in 20 ml of dichloromethane was added, followed by stirring at -60 ° C for 30 minutes. Dichloromethane is distilled off under reduced pressure, 100 ml of ethyl acetate is added to the residue, and the mixture is washed twice with water. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 5.5 g of the desired product. Crystallizes on standing. Melting point: 69 to 71 ° C NMR (CDCl ₃ ) δ _ppm : 1.18 (3H, d, J = 6.0Hz), 3.16 (1H, quintet, J = 5Hz), 3.40 (1H, d, J = 5Hz), 3.73 ( 3H, s), 3.77 (3H, s), 4.30 (2H, d, J = 6.0), 6.20 to 7.20 (4H, m) Reference example 2. (2R, 3R) -N- (2,4-dimethoxybenzyl)-
2,3-epoxybutyramide 400 ml of dichloromethane and 29 g of 2,4-dimethoxybenzylamine hydrochloride were added to 20.5 g of potassium (2R, 3R) -β-methylglycidate, and the mixture was stirred at room temperature for 1 hour. It is then cooled to 10-12 ° C and phosphorus oxychloride 14.6
A solution of 23 ml of pyridine and 23 ml of pyridine in 275 ml of dichloromethane under ice cooling is added over 30 minutes. After stirring for 30 minutes at the same room temperature, the solvent was distilled off under reduced pressure, and 600 ml of ethyl acetate was added to this.
Is added, the product is washed twice with water, dried over anhydrous Glauber's salt, and the solvent is distilled off to crystallize the desired product. A small amount of isopropyl ether was added to this to collect crystals, and the mother liquor was further concentrated. When isopropyl ether was added, a small amount of crystals were precipitated and collected (yield 33.2 g). The physical constants of this substance are shown in Reference Example 1.
It was the same as the physical constant of the target product obtained in.

Reference example 3. (2R, 3R) -N- (P-methoxybenzyl) -2,3
-Epoxy butyramide 12.4 g of P-methoxybenzylamine hydrochloride, and (2
200 ml of dichloromethane was added to 10 g of potassium (R, 3R) -β-methylglycidate, and the mixture was stirred at room temperature for 1 hour. It is then cooled to 10-15 ° C. and phosphorus oxychloride 7
A solution of 23 ml of pyridine and 23 ml of pyridine in 100 ml of dichloromethane under ice cooling is added over 30 minutes. Then 1 at room temperature
After stirring for an hour, the solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate.
Add 200 ml and wash twice with water, and concentrate the ethyl acetate layer under reduced pressure to crystallize the desired product. Add a small amount of diisopropyl ether and collect. The mother liquor was further concentrated under reduced pressure, and a small amount of crystals were precipitated when diisopropyl ether was added. This was collected) 14.5 g, 92% yield).

Melting point: 74-76 ° C NMR (CDCl ₃ ) δ _ppm : 1.25 (3H, d, J = 6Hz), 3.21 (1H, quintet, J = 5Hz), 3.47 (1H, d, J = 5Hz), 3.86 (3H , s), 4,36 (2H, d, J = 7Hz), 6.2 to 6.7 (1H, br.), 6.75 to 7.3 (4H, m) Reference example 4. (2R, 3R) -N-allyl-2,3-epoxybutyramide 666 mg (11.7 mmole) of allylamine is dissolved in 8 ml of ethyl acetate, and 6.67 ml (11.7 mmole) of 6.4% (W / V) hydrogen chloride in diisopropyl ether is added under cooling. Then (2R, 3
R) -β-methylglycidic acid potassium salt 1.80 g (12.9 mmo
le) and stir at room temperature for 1 hour. To this suspension was added 1.79 g (11.7 mmole) of phosphorus oxychloride and 3.79 g (46.8 mm) of pyridine.
ole) was mixed with 36 ml of dichloromethane under ice cooling, and the solution was added with stirring at 20 ° C. and stirred for another 30 minutes. The extract is washed with saturated brine and dried, and the solvent is distilled off. The residue was subjected to column chromatography using 30 g of silica gel and eluted with benzene-ethyl acetate (1: 1) to obtain 1.54 g of the desired product (yield 93%) as an oil.

: 3430, 1670, 1529 NMR (CDCl ₃ ) δ _ppm 1.34 (3H, d, J = 5Hz), 3.26 (1H, quintet, J = 5Hz), 3.48 (1H, d, J = 5Hz), 3.90 (2H, br.t, J = 5Hz), 4.9 to 5.4 (2H, m), 5.83 (1H, ddt, J = 17.5,6,5Hz), 6.5 (1H, br.) Reference example 5. (3S, 4R) -1- (P-methoxybenzyl) -3-
((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone Hexamethyldisilazane 107 mg was dissolved in dry tetrahydrofuran 0.7 ml, and butyllithium hexane solution (1.65 mM
(/ ml) 0.4 ml was added for preparation. Under N-lithium hexamethyldisilazane solution under ice cooling (2R, 3R) -N- (P-
Methoxybenzyl) -N-phenylsulfonylmethyl-
A solution prepared by dissolving 124 mg of 2,3-epoxybutyramide in 2 ml of dry tetrahydrofuran is added, and then 0.4 ml of hexamethylphosphoramide is added, and the mixture is stirred at the same temperature for 30 minutes. Then, an ammonium chloride aqueous solution was added to this, diluted with ethyl acetate, washed with sodium hydrogen carbonate and brine, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, and cyclohexane: ethyl acetate (1: 1). 91 mg of the target compound was obtained from the portion eluted with. Crystallizes on standing. (Yield 85%) Melting point: 129 to 131 ° C NMR (CDCl ₃ ) δ _ppm : 1.02 (3H, d, J = 6Hz), 2.50 (1H, br.s), 3.20 to 3.40 (1H, m), 3.72 (3H, s), 3.80 to 4.40 (2H, m), 4.50,4.66 (2H, AB-q, J = 14Hz), 6.55 to 7.10 (4H, m), 7.40 to 7.90 (5H, m) Reference example 6 ． (3S, 4R) -1- (2,4-dimethoxybenzyl)-
3-((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone Instead of (2R, 3R) -N- (P-methoxybenzyl) -N-phenylsulfonylmethyl-2,3-epoxybutyramide of Reference Example 5, (2R, 3R) -N- (2,4-dimethoxybenzyl). ) -N-Phenylsulfonylmethyl-
The same reaction was performed using 2,3-epoxybutyramide,
Upon treatment, the target compound was obtained. Melting point: 60 to 62 ° C NMR (CDCl ₃ ) δ _ppm : 1.03 (3H, d, J = 6Hz), 2.72 (1H, br.s), 3.18 to 3.45 (1H, m), 3.68 (3H, s), 3.73 (3H, s), 3.80 to 4.20 (2H, m), 4.54,4.68 (2H, AB-q, J = 14Hz), 6.05 to 7.0 (3H, m), 7.30 to 8.05 (5H, m) Reference example 7. (3S, 4R) -3-[(R) -1-hydroxyethyl]
-4-Phenylsulfonyl-2-azetidinone To a mixture of 900 mg of potassium peroxodisulfate and 4 ml of water, (3S, 4R) -1- (P-methoxybenzyl) -3-
A solution of 100 mg of ((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone in 4 ml of acetone is added. The mixture is stirred under argon atmosphere at 50 ° C. for 6 hours. Then, the mixture was cooled, ethyl acetate was added, and the mixture was washed with an aqueous sodium hydrogen carbonate solution and brine, the solvent was distilled off, and the residue was developed with preparative thin-layer chromatography using cyclohexane: ethyl acetate (3: 7). The target substance was eluted with ethyl acetate and the solvent was distilled off to obtain 46 mg of the target compound. Melting point: 151-152 ° C Specific rotation ▲ [α] ²⁵ _D ▼ -5.6 ° (c = 0.39, CHCl ₃ ) : 3360, 1775 NMR (acetone-d ₆ ) δ _ppm : 1.13 (3H, d, J = 6Hz), 2.70 (1H, br.s), 3.45 (1H, dd, J = 4,2Hz), 3.9 to 4.4 (2H, m), 4.92 (1H, d, J = 2Hz), 7.6 to 8.2 (5H, m) Reference example 8. (3S, 4R) -3-((R) -1-hydroxyethyl)
-4-Phenylsulfonyl-2-azetidinone Instead of the P-methoxybenzyl derivative of Reference Example 7, 105 mg of a 2,4-dimethoxybenzyl derivative was used and reacted in the same manner and treated to obtain 55 mg of the target compound.

The physical constant of this substance was the same as that of the target compound of Reference Example 7.

Reference example 9. (3S, 4R) -1-Allyl-3-((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone A solution of lithium dicyclohexylamide in tetrahydrofuran [76 mg (0.42 mmole) of dicyclohexylamine and 1
(2R, 3R) -N-allyl-N-phenylsulfonylmethyl-2,3 obtained in Example 17 was prepared by mixing 0.29 ml (0.42 mmole) of 5% butyllithium in 0.8 ml of tetrahydrofuran at 0 ° C. -Epoxy butyramide 94mg
(0.32 mmole) was heated in a mixed solvent of 0.3 ml of hexamethylphosphoramide and 1.5 ml of tetrahydrofuran, and the dissolved solution was added at 0 ° C. After stirring for 5 minutes, it is placed in a water bath at 16 ° C. and stirred for another 5 minutes. Under ice cooling, 2 drops of acetic acid was added, the reaction solution was diluted with ethyl acetate, and washed with water, aqueous sodium hydrogen carbonate and saturated brine in this order. The solvent was distilled off, and the residue was ethyl acetate-
Recrystallization from hexane gave 42 mg of needles with a melting point of 133-134 ° C. The solvent was distilled off from the mother liquor and the residue was purified by silica gel preparative thin layer chromatography [developing solvent: benzene-ethyl acetate (3: 2)] to obtain 41 mg of the desired product. This was recrystallized to obtain another 35 mg of crystals. Total crystal 75 mg (yield 82%).

Elemental analysis value Calculated as C ₁₄ H ₁₇ NO ₂ S: C, 56.93; H, 5.80; N, 4.74; S, 10.85 Actual value: C, 56.94; H, 5.97; N, 4.75; S, 10.63 Specific optical rotation [Α] ▲ ²⁵ _D ▼ + 6.5 ° (c = 0.43, CHCl ₃ ) : 3400, 1768 NMR (CDCl ₃ ) δ _ppm : 1.08 (3H, d, J = 6.5Hz), 2.47 (1H, br.d, J = 4Hz), 3.30 (1H, dd, J = 3.5,2Hz), 3.3 to 3.7 (1H, m), 3.9 to 4.4 (2H, m), 4.78 (1H, d, J = 2Hz), 4.8 to 5.2 (2H, m), 5.3 to 6.0 (1H, m), 7.3 to 8.1 (5H, m) Reference example 10. (3S, 4R) -1- (1-propenyl) -3-((R)
-1-Hydroxyethyl) -4-phenylsulfonyl-
2-azetidinone (3S, 4R) -1-allyl-3-((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone 707 mg, rhodium (III) chloride 3.5 mg, ethanol 5.3 ml
And heat to reflux for 1 hour. The ethanol is distilled off under reduced pressure and the residue is subjected to column chromatography using 15 g of silica gel. 694 mg (yield 98%) of the desired product obtained by elution with benzene-ethyl acetate (1: 1) was crystallized from ethyl acetate-hexane to give 454 mg of crystals (E-isomer) having a melting point of 124.5-125.5 ° C. Obtained. Further, 75 mg of secondary crystal of E-isomer was obtained from the mother liquor. Remaining oil 16
From the NMR, 5 mg is a mixture of E: Z = 2: 1.

Calculated as elemental analysis (E-isomer) C ₁₄ H ₁₇ NO ₂ S: C, 56.93; H, 5.80; N, 4.74; S, 10.85 Found: C, 56.70; H, 5.83; N, 4.68; S , 10.92 Specific optical rotation (E-isomer) [α] ▲ ²⁵ _D ▼ -174 ° (c = 0.74, CHCl ₃ ) (E-isomer): 3400, 1765, 1668 NMR (CDCl ₃ ) δ _ppm : (E-isomer) 1.12 (3H, d, J = 6.5Hz), 1.59 (3H, dd, J = 6,1Hz) , 2.55 (1H, br.), 3.23 (1H, dd, J = 3.5,2Hz), 4.15 (1H, m), 4.92 (1H, d, J = 2Hz), 5.46 (1H, dq, J = 14, 6.5Hz), 6.02 (1H, dq, J = 14,1Hz), 7.3 ~ 8.0 (5H, m), (Z-isomer) 1.18 (3H, d, J = 6.5Hz), 1.64 (3H, dd, J = 6,1Hz), 3.35 (1H, dd, J = 4,2.5Hz), 4.87 (1H, d, J = 2.5Hz) Reference example 11. (3S, 4R) -1- (1-propenyl) -3-((R)
-1-Hydroxyethyl) -4-phenylsulfonyl-
2-azetidinone (3S, 4R) -1-allyl-3-((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone 100 mg, palladium (II) chloride 1.5 mg, and ethanol 1 ml.
And heat to reflux for 1 hour. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel preparative thin layer chromatography [developing solvent; benzene: ethyl acetate (3: 2)] to obtain 77 mg of the desired product (yield 77%). It was From the NMR spectrum, it is a mixture of E and Z isomers and the ratio is about 5: 1.
Is. The spectrum data is described in Reference Example 10.

Reference example 12. (3S, 4R) -1-Formyl-3-((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone (3S, 4R) -1- (1-propenyl) -3-((R)
-1-Hydroxyethyl) -4-phenylsulfonyl-
37 mg of 2-azetidinone are dissolved in 10 ml of dichloromethane, and ozone is bubbled in at -78 ° C for 3 minutes. After keeping the same temperature for 15 minutes, nitrogen gas is passed for 15 minutes to remove excess ozone. Add about 100 mg of dimethyl sulfide and bring the reaction solution to room temperature. After washing with water, the solvent was distilled off to obtain 36 mg of the target product ((yield ~ 100%) containing a small amount of dimethyl sulfoxide (NM
R)] was obtained as an oil.

: 3400, 1817, 1715 NMR (CDCl ₃ ) δ _ppm : 1.25 (3H, d, J = 6Hz), 2.8 (1H, br.), 3.82 (1H, t, J = 3Hz), 4.31 (1H, qd, J = 6,3Hz), 5.26 (1H, d, J = 3Hz), 7.3 ~ 8.0 (5H, m), 8.50 (1H, s) Reference example 13. (3S, 4R) -3-((R) -1-hydroxyethyl)
-4-Phenylsulfonyl-2-azetidinone (3S, 4R) -1-formyl-3-obtained in Reference Example 12
33 mg of ((R) -1-hydroxyethyl) -4-phenylsulfonyl-2-azetidinone was dissolved in 0.9 ml of methanol, 150 mg of silica gel was added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added 5 ml of ethyl acetate, the solvent was distilled off from the filtrate, and the resulting crystalline residue was recrystallized from ethyl acetate-hexane to give 17 mg of needle crystals having a melting point of 151-152 ° C.
Got Concentrate mother liquor, preparative thin-layer chromatography [developing solvent; chloroform-methanol (20: 1)]
The product was further purified by to obtain 8 mg of the desired product. Total yield 25mg
(Yield 84%).

The physical constant of this substance was the same as that of the target compound obtained in Reference Example 7.

Reference example 14. (3S, 4R) -3-[(R) -1-hydroxyethyl]
-4-Phenylsulfonyl-2-azetidinone (3S, 4R) -1- (1-propenyl) -3-[(R)
-1-Hydroxyethyl] -4-phenylsulfonyl-
2-Azetidinone 50 mg (0.17 mmole) is dissolved in tetrahydrofuran 1 ml, N-methylmorpholine N-oxide monohydrate 25 mg (0.185 mmole), osmium tetrachloride 1 mg
(0.004 mmole) was added and the mixture was stirred at room temperature for 3 hours and a half. 1 ml of methanol was added to the reaction solution, and the mixture was further stirred for 30 minutes. 10 ml of ethyl acetate was added, the mixture was washed with saturated saline and then dried, and the solvent was distilled off. The obtained residue was purified by silica gel preparative thin layer chromatography [developing solvent: ethyl acetate-benzene (3: 1)] to obtain 26 mg (yield 60%) of a solid. IR and NMR spectra were consistent with those of the compound described in Reference Example 7.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Noboru Ishida 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Sadao Ota 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company (72) Inventor Noriko Takeda 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo stock company

Claims (1)

[Claims] 1. A general formula A compound having the formula (R ¹ represents a protecting group for an amino group) is reacted with formalin or an acyloxymethyl halide to give a compound of the general formula (Wherein R ¹ represents an amino-protecting group and R ² represents a hydrogen atom or an acyl group), and the compound is reacted with arylsulfinic acid. (Wherein R ¹ represents a protecting group for an amino group and R ³ represents an aryl group which may have a substituent).